leptin and Starvation

This narrative review aims to pinpoint mental and behavioral effects of starvation, which may be triggered by hypoleptinemia and as such may be amenable to treatment with leptin receptor agonists. The reduced leptin secretion results from the continuous loss of fat mass, thus initiating a graded triggering of diverse starvation related adaptive functions. In light of leptin receptors located in several peripheral tissues and many brain regions adaptations may extend beyond those of the hypothalamus-pituitary-end organ-axes. We focus on gastrointestinal tract and reward system as relevant examples of peripheral and central effects of leptin. Despite its association with extreme obesity, congenital leptin deficiency with its many parallels to a state of starvation allows the elucidation of mental symptoms amenable to treatment with exogenous leptin in both ob/ob mice and humans with this autosomal recessive disorder. For starvation induced behavioral changes with an intact leptin signaling we particularly focus on rodent models for which proof of concept has been provided for the causative role of hypoleptinemia. For humans, we highlight the major cognitive, emotional and behavioral findings of the Minnesota Starvation Experiment to contrast them with results obtained upon a lesser degree of caloric restriction. Evidence for hypoleptinemia induced mental changes also stems from findings obtained in lipodystrophies. In light of the recently reported beneficial cognitive, emotional and behavioral effects of metreleptin-administration in anorexia nervosa we discuss potential implications for the treatment of this eating disorder. We postulate that leptin has profound psychopharmacological effects in the state of starvation.

Topics: Animals; Anorexia Nervosa; Humans; Leptin; Mice; Obesity; Receptors, Leptin; Starvation

Leptin is an adipose tissue hormone that functions as an afferent signal in a negative feedback loop that maintains homeostatic control of adipose tissue mass. This endocrine system thus serves a critical evolutionary function by protecting individuals from the risks associated with being too thin (starvation) or too obese (predation and temperature dysregulation). Mutations in leptin or its receptor cause massive obesity in mice and humans, and leptin can effectively treat obesity in leptin-deficient patients. Leptin acts on neurons in the hypothalamus and elsewhere to elicit its effects, and mutations that affect the function of this neural circuit cause Mendelian forms of obesity. Leptin levels fall during starvation and elicit adaptive responses in many other physiologic systems, the net effect of which is to reduce energy expenditure. These effects include cessation of menstruation, insulin resistance, alterations of immune function, and neuroendocrine dysfunction, among others. Some or all of these effects are also seen in patients with constitutively low leptin levels, such as occur in lipodystrophy. Leptin is an approved treatment for generalized lipodystrophy, a condition associated with severe metabolic disease, and has also shown potential for the treatment of other types of diabetes. In addition, leptin restores reproductive capacity and increases bone mineral density in patients with hypothalamic amenorrhea, an infertility syndrome in females. Most obese patients have high endogenous levels of leptin, in some instances as a result of mutations in the neural circuit on which leptin acts, though in most cases, the pathogenesis of leptin resistance is not known. Obese patients with leptin resistance show a variable response to exogenous leptin but may respond to a combination of leptin plus amylin. Overall, the identification of leptin has provided a framework for studying the pathogenesis of obesity in the general population, clarified the nature of the biologic response to starvation, and helped to advance our understanding of the neural mechanisms that control feeding.

Topics: Adipose Tissue; Animals; Diabetes Mellitus; Humans; Hypothalamus; Leptin; Lipodystrophy; Mice; Neurons; Obesity; Receptors, Leptin; Starvation

Insulin resistance (IR) is a general phenomenon of many physiological states, disease states, and diseases. IR has been described in diabetes mellitus, obesity, infection, sepsis, trauma, painful states such as postoperative pain and migraine, schizophrenia, major depression, chronic mental stress, and others. In arthritis, abnormalities of glucose homeostasis were described in 1920; and in 1950 combined glucose and insulin tests unmistakably demonstrated IR. The phenomenon is now described in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, polymyalgia rheumatica, and others. In chronic inflammatory diseases, cytokine-neutralizing strategies normalize insulin sensitivity. This paper delineates that IR is either based on inflammatory factors (activation of the immune/ repair system) or on the brain (mental activation via stress axes). Due to the selfishness of the immune system and the selfishness of the brain, both can induce IR independent of each other. Consequently, the immune system can block the brain (for example, by sickness behavior) and the brain can block the immune system (for example, stress-induced immune system alterations). Based on considerations of evolutionary medicine, it is discussed that obesity per se is not a disease. Obesity-related IR depends on provoking factors from either the immune system or the brain. Chronic inflammation and/or stress axis activation are thus needed for obesity-related IR. Due to redundant pathways in stimulating IR, a simple one factor-neutralizing strategy might help in chronic inflammatory diseases (inflammation is the key), but not in obesity-related IR. The new considerations towards IR are interrelated to the published theories of IR (thrifty genotype, thrifty phenotype, and others).

Topics: Brain; Chronic Disease; Cytokines; Endocrinology; Energy Metabolism; Fasting; Humans; Inflammation; Insulin Resistance; Leptin; Models, Biological; Neuroimmunomodulation; Obesity; Selection, Genetic; Starvation; Stress, Psychological

Cloned in 1994, the ob gene encodes the protein hormone leptin, which is produced and secreted by white adipose tissue. Since its discovery, leptin has been found to have profound effects on behavior, metabolic rate, endocrine axes, and glucose fluxes. Leptin deficiency in mice and humans causes morbid obesity, diabetes, and various neuroendocrine anomalies, and replacement leads to decreased food intake, normalized glucose homeostasis, and increased energy expenditure. Here, we provide an update on the most current understanding of leptin-sensitive neural pathways in terms of both anatomical organization and physiological roles.

Topics: Adaptation, Physiological; Adipose Tissue, White; Animals; Body Weight; Brain; Disease Models, Animal; Energy Metabolism; Feeding Behavior; Glucose; Humans; Hypothalamus; Leptin; Mice; Mice, Obese; Models, Biological; Overnutrition; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Leptin; Starvation; Sympathetic Nervous System

The impact of bariatric surgery on insulin sensitivity and glucose tolerance has refocused interest in the role of gut-derived factors in the regulation of insulin secretion and action. The incretins, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are released from endocrine cells in the small intestinal mucosa primarily in response to oral nutrient ingestion. They have various effects, including augmentation of glucose-stimulated insulin secretion (GSIS), actions that promote the cellular assimilation and storage of dietary glucose and lipid as liver and skeletal muscle glycogen and adipocyte triacylglycerol (TAG) respectively. Similarly, increased delivery of fatty acids (FA) acutely augments GSIS, and the resultant enhancement of GSIS facilitates FA storage as adipocyte TAG. Leptin secretion from white adipocytes curbs appetite to limit dietary nutrient intake and adipocyte TAG storage and, potentially, GSIS, thereby curtailing insulin-dependent TAG storage. On fasting, GSIS is curbed, an effect the mechanism of which is even now incompletely understood, but which may reflect augmented β-cell FA oxidation. The orexigen ghrelin, systemic concentrations of which increase with fasting, exerts enigmatic effects on GSIS, in that acylated ghrelin and unacylated ghrelin exert opposing effects on GSIS, whereas acylated ghrelin and unacylated ghrelin share protective effects on islet survival. This review will build on these emerging studies to evaluate the roles of the incretins, leptin, lipids and acylated and unacylated ghrelin in modulating islet function and survival during feasting and fasting.

Topics: Fasting; Ghrelin; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Leptin; Satiation; Signal Transduction; Starvation

The roles of corticotrophin-releasing factor (CRF), opioid peptides, leptin and ghrelin in anorexia nervosa (AN) were discussed in this paper. CRF is the key mediator of the hypothalamo-pituitary-adrenal (HPA) axis and also acts at various other parts of the brain, such as the limbic system and the peripheral nervous system. CRF action is mediated through the CRF1 and CRF2 receptors, with both HPA axis-dependent and HPA axis-independent actions, where the latter shows nil involvement of the autonomic nervous system. CRF1 receptors mediate both the HPA axis-dependent and independent pathways through CRF, while the CRF2 receptors exclusively mediate the HPA axis-independent pathways through urocortin. Opioid peptides are involved in the adaptation and regulation of energy intake and utilization through reward-related behavior. Opioids play a role in the addictive component of AN, as described by the "auto-addiction opioids theory". Their interactions have demonstrated the psychological aspect of AN and have shown to prevent the functioning of the physiological homeostasis. Important opioids involved are β-lipotropin, β-endorphin and dynorphin, which interact with both µ and κ opioids receptors to regulate reward-mediated behavior and describe the higher incidence of AN seen in females. Moreover, ghrelin is known as the "hunger" hormone and helps stimulate growth hormone (GH) and hepatic insulin-like-growth-factor-1(IGF-1), maintaining anabolism and preserving a lean body mass. In AN, high levels of GH due to GH resistance along with low levels of IGF-1 are observed. Leptin plays a role in suppressing appetite through the inhibition of neuropeptide Y gene. Moreover, the CRF, opioid, leptin and ghrelin mechanisms operate collectively at the HPA axis and express the physiological and psychological components of AN. Fear conditioning is an intricate learning process occurring at the level of the hippocampus, amygdala, lateral septum and the dorsal raphe by involving three distinct pathways, the HPA axis-independent pathway, hypercortisolemia and ghrelin. Opioids mediate CRF through noradrenergic stimulation in association with the locus coeruleus. Furthermore, CRF's inhibitory effect on gonadotropin releasing hormone can be further explained by the direct relationship seen between CRF and opioids. Low levels of gonadotropin have been demonstrated in AN where only estrogen has shown to mediate energy intake. In addition, estrogen is involved in regulating µ rece

Topics: Adolescent; Adult; Anorexia Nervosa; Child; Female; Ghrelin; Humans; Leptin; Opioid Peptides; Starvation; Young Adult

Hypoleptinemia is a key endocrinological feature of anorexia nervosa (AN). Several symptoms in acute AN are related to the low circulating leptin levels including amenorrhea and semi-starvation-induced hyperactivity. The drop in leptin levels results from the loss of fat mass; once leptin levels fall below specific thresholds the hypothalamic-pituitary-gonadal and -thyroid axes are down-regulated; in contrast, the hypothalamic-pituitary-adrenal axis is up-regulated. Hypoleptinemia is the major signal underlying both somatic and behavioral adaptations to starvation. Because the mechanisms involved in this adaptation are similar in rodents and humans, rodent models can be used to investigate the relevant central pathways which underly the respective starvation-induced symptoms. During therapeutically induced weight gain, leptin levels can intermittently increase above normal concentrations. This hyperleptinemia could predispose to renewed weight loss.

Topics: Adolescent; Amenorrhea; Anorexia Nervosa; Body Weight; Female; Humans; Leptin; Motor Activity; Neurosecretory Systems; Osteoporosis; Starvation; Weight Loss

Leptin is a hormone with pleiotropic functions affecting several tissues. Because leptin has a crucial role in the adaptation of an organism to semi-starvation, anorexia nervosa (AN) serves as a model disorder to elucidate the functional implications of hypoleptinaemia; vice versa, several symptoms in patients with this eating disorder are related to the low leptin levels, which are characteristic of acute AN. Weight gain in AN patients can induce relative hyperleptinaemia in comparison to controls matched for body mass index; circulating leptin concentrations in AN patients thus transverse from subnormal to supranormal levels within a few weeks. We review findings on leptin secretion in AN and focus on implications, particularly for the hypothalamus-pituitary-gonadal axis, bone mineral density and physical hyperactivity. Undoubtedly, the elucidation of leptin's function as a trigger of diverse neuroendocrine adaptations to a restricted energy intake has substantially advanced our knowledge of the pathogenesis of distinct symptoms of AN, including amenorrhoea that represents one of the four diagnostic criteria. The fact that hypoleptinaemia can induce hyperactivity in a rat model for AN has led to a series of studies in AN patients, which support the notion that application of leptin to severely hyperactive patients might prove beneficial.

Topics: Animals; Anorexia Nervosa; Humans; Leptin; Starvation

Leptin was originally identified as an adipocyte-derived cytokine with a key role in the regulation of the energy balance. Subsequent research revealed that leptin's biological action is not restricted to its effects on appetite and food intake, but instead has a much more pleiotropic character. There is now ample evidence that leptin has important functions in reproduction, hematopoiesis, HPA-axis endocrinology and angiogenesis. In this review we have focused on the effects of leptin in the antigen-specific immunity and in the inflammatory effector system.

Topics: Adaptation, Physiological; alpha-MSH; Animals; Anorexia; Humans; Immunity; Inflammation; Leptin; Macrophages; Metallothionein; Monocytes; Receptors, Cell Surface; Receptors, Leptin; Starvation; Systemic Inflammatory Response Syndrome; T-Lymphocytes

The blood-brain barrier (BBB) prevents the unrestricted movement of peptides and proteins between the brain and blood. However, some peptides and regulatory proteins can cross the BBB by saturable and non-saturable mechanisms. Leptin and insulin each cross the BBB by their own transporters. Impaired transport of leptin occurs in obesity and accounts for peripheral resistance; that is, the condition wherein an obese animal loses weight when given leptin directly into the brain but not when given leptin peripherally. Leptin transport is also inhibited in starvation and by hypertriglyceridemia. Since hypertriglyceridemia occurs in both starvation and obesity, we have postulated that the peripheral resistance induced by hypertriglyceridemia may have evolved as an adaptive mechanism in response to starvation. Insulin transport is also regulated. For example, treatment of mice with lipopolysaccharide (LPS) increases insulin transport across the BBB by about threefold. Since many of the actions of CNS insulin oppose those of peripheral insulin and since LPS releases proinflammatory cytokines, enhanced transport of insulin across the BBB could be a mechanism which promotes insulin resistance in sepsis. The brain endothelial cells which comprise the BBB secrete many substances including cytokines. Such secretion can be stimulated from one side of the BBB with release into the other side. For example, it appears that adiponectin can inhibit release of interleukin-6 from brain endothelial cells. Overall, the BBB represents an important interface in mediating gut-brain axes.

Topics: Adiponectin; Animals; Biological Transport; Blood-Brain Barrier; Digestive System Physiological Phenomena; Humans; Hypertriglyceridemia; Insulin; Insulin Resistance; Leptin; Starvation

It is suggested that the symptoms of anorexia nervosa are physiological responses to starvation. There is no evidence of a neural or non-neural dysfunction that predisposes women for anorexia nervosa and the endocrine and psychological consequences of starvation are reversed once patients have re-learnt how to eat and regained a normal body weight. Because variability in the supply of food may be a common evolutionary condition, it is more likely that body weight is variable than constant in normal circumstances. The role of the neuroendocrine system in times of feast and famine is to allow the individual to adopt behavioral strategies as needed rather than maintaining body weight homeostasis. Treatment of anorexic patients should aim at reducing their high level of physical activity in order to facilitate eating.

Topics: Anorexia Nervosa; Feeding and Eating Disorders; Female; Humans; Leptin; Mental Disorders; Neurosecretory Systems; Oligopeptides; Pyrrolidonecarboxylic Acid; Starvation

Cachexia is among the most debilitating and life-threatening aspects of cancer. Associated with anorexia, fat and muscle tissue wasting, psychological distress, and a lower quality of life, cachexia arises from a complex interaction between the cancer and the host. This process results from a failure of the adaptive feeding response seen in simple starvation and includes cytokine production, release of lipid-mobilizing and proteolysis-inducing factors, and alterations in intermediary metabolism. Cytokines play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin, a hormone secreted by adipose tissue, which is an integral component of the homeostatic loop of body weight regulation. The two major options for pharmacological therapy have been either progestational agents or corticosteroids. However, knowledge of the mechanisms of cancer anorexia-cachexia syndrome continues to lead to effective therapeutic interventions for several aspects of the syndrome. These include antiserotonergic drugs, gastroprokinetic agents, branched-chain amino acids, eicosapentanoic acid, cannabinoids, melatonin, and thalidomide, all of which act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release. The outcomes of drug studies in cancer cachexia should focus on the symptomatic and quality-of-life advantages rather than simply on nutritional end points, since the survival of cachexia cancer patients may be limited to weeks or months due to the incurable nature of the underlying malignancy. As weight loss shortens the survival time of cancer patients and decreases their performance status, effective therapy would extend patient survival and improve quality of life.

Topics: Adipose Tissue; Agouti Signaling Protein; Anorexia; Anti-Anxiety Agents; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Appetite Stimulants; Cachexia; Cytokines; Energy Metabolism; Gastrointestinal Agents; Glucocorticoids; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Neoplasms; Neuropeptide Y; Patient Care Team; Progesterone; Signal Transduction; Starvation; Syndrome

In this review, the mechanism of our "toxic environment's" effects on insulin and weight gain in the genesis of obesity is elaborated. The composition of our diet is highly insulinogenic. The insulin drives energy into fat, and interferes with leptin signaling in the VMH. This results in weight gain and the sense of starvation, which results in decreased SNS activity, reducing energy expenditure and physical activity; and increased vagal activity, which promotes yet further insulin release and energy storage. Thus, hyperinsulinemia turns the leptin negative feedback system into a "vicious cycle" of obesity (see Figure 3, page 905). Externally, this appears as "gluttony and sloth" but it is biochemically driven. How does this work? A thin, insulin-sensitive, 13-year-old boy might consume a daily allotment of 2,000 kcal, and burn 2,000 kcal daily (or 50 kcal/kg fat-free mass) in order to remain weight-stable, with a stable leptin level. However, if that same 13-year-old became hyperinsulinemic and/or insulin resistant, perhaps as many as 250 kcal of the daily allotment would be shunted to storage in adipose tissue, promoting a persistent obligate weight gain. Due to the obligate energy storage, he now only has 1,750 kcal per day to burn. The hyperinsulinemia also results in a lower level of leptin signal transduction, conveying a CNS signal of energy insufficiency. The remaining calories available are lower than his energy expenditure; the CNS would sense starvation. Through decreased SNS tone, he would reduce his physical activity, resulting in decreased quality of life; and through increased vagal tone, he would increase caloric intake and insulin secretion, but now at a much higher level. Thus, the vicious cycle of gluttony, sloth, and obesity is promulgated. Is this personal responsibility, when a kid's brain thinks it's starving? Is it personal responsibility when the American Academy of Pediatrics still recommends juice for toddlers? Is it personal responsibility when the Women, Infant and Children program subsidizes fruit juice but not fruit? Is it personal responsibility when the first ingredient in the barbecue sauce is high-fructose corn syrup? Is it personal responsibility when high-fiber fresh produce is unavailable in poor neighborhoods? Is it personal responsibility when the local fast food restaurant is the only neighborhood venue that is clean and air-conditioned? Is it personal responsibility when in order to meet the criteria for No Child

Topics: Algorithms; Animals; Diet; Fructose; Humans; Hypothalamus, Middle; Leptin; Obesity; Satiety Response; Starvation; Vagus Nerve

In this review, we propose that actions of the lipid-lowering, apoptosis-inhibiting effects of certain "longevity genes" oppose the life-shortening consequences of lipotoxicity and lipoapoptosis. We note that lipotoxicity occurs whenever leptin action is deficient, or whenever satiety is overridden, as in forced or voluntary overfeeding ("supersizing"). The role of hyperleptinemia, we suggest, is to extend survival during famine by permitting the storage of surplus calories in adipocytes without concomitant injury to nonadipose tissues from ectopic lipid deposits. It achieves this lipid partitioning by (1) restraining the level of overnutrition so as not to exceed the available adipocyte storage space and (2) enhancing oxidation of any ectopic lipid overflow: The mechanisms of lipoapoptosis are discussed, and the possibility that metabolic syndrome is the human equivalent of rodent lipotoxicity is suggested.

Topics: Adipocytes; Animals; Apoptosis; Humans; Hyperphagia; Leptin; Lipids; Lipodystrophy; Longevity; Metabolic Syndrome; Proto-Oncogene Proteins c-bcl-2; Starvation

Topics: Animals; Bone Remodeling; Humans; Leptin; Mice; Osteogenesis; Phenotype; Puberty; Reproduction; Starvation

Patients with anorexia nervosa (AN) often show normal to elevated physical activity levels despite severe weight loss and emaciation. This is seemingly in contrast to the loss of energy and fatigue characteristic of other starvation states associated with weight loss. Despite the fact that historical accounts and clinical case studies of AN have regularly commented on the elevated activity levels, the behavior has become only recently the subject of systematic study. Because rodents and other species increase their activity upon food restriction leading to weight loss when given access to an activity wheel--a phenomenon referred to as activity-based anorexia or semi-starvation-induced hyperactivity (SIH)-it has been proposed that the hyperactivity in AN patients may reflect the mobilization of phylogenetically old pathways in individuals predisposed to AN. Exogeneous application of leptin in this animal model of AN has recently been shown to suppress completely the development of SIH. Hypoleptinemia, as a result of the food restriction, may represent the initial trigger for the increased activity levels in AN patients and in food-restricted rats. In the first and second parts of our review, we will summarize the relevant findings pertaining to hyperactivity in AN patients and in the rat model, respectively. We conclude with a synopsis and implications for future research.

Topics: Animals; Anorexia Nervosa; Disease Models, Animal; Exercise; Female; Humans; Hyperkinesis; Leptin; Motor Activity; Rats; Starvation; Weight Loss

Leptin was originally identified as an adipocyte-derived cytokine with a key role in the regulation of the energy balance. Subsequent research has, however, revealed that leptin's biological action is not restricted to its effects on appetite and food intake, but rather has a much more pleiotropic character. Evidence is now accumulating that it has important functions in reproduction, hematopoiesis, HPA-axis endocrinology and angiogenesis. In this review, we have focused on the effects of leptin in the immune system, which can be found in both the antigen-specific immunity and in the inflammatory effector system.

Topics: Adaptation, Physiological; Animals; Humans; Immunity; Immunity, Cellular; Inflammation; Leptin; Metallothionein; Neuropeptide Y; Starvation; Systemic Inflammatory Response Syndrome; T-Lymphocytes

A major advance in the understanding of the control of appetite, food intake, and energy expenditure came with the discovery of leptin. Leptin concentrations correlate with adipose tissue mass, and leptin acts via the central nervous system (CNS) to reduce food intake and increase energy expenditure. A variety of different neurotransmitters have been implicated in mediating the CNS effects of leptin. In humans, leptin deficiency is unlikely to be a major cause of obesity. Most humans are not leptin deficient, but have a leptin concentration raised in proportion to their fat mass. A recent clinical trial looking at the use of recombinant leptin in treating human obesity has resulted in only variable amounts of weight loss. The role of leptin extends beyond the control of food intake and energy expenditure. Leptin reverses many of the physiological responses to starvation. It is suggested that the main role of leptin might be in response to food deprivation and not in obesity.

Topics: Animals; Carrier Proteins; Humans; Leptin; Mice; Obesity; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins; Starvation

Several observations suggest the presence of an interaction between immune and the endocrine systems. Leptin is an adipocyte-derived hormone, that belongs structurally to the long-chain helical cytokine family such as interleukin-2 (IL-2), interleukin-12 (IL-12), growth hormone (GH), and signals by a class I cytokine receptor (Ob-R). This cytokine represents an important link between fat mass on the one side and the regulation of energy balance and reproductive function on the other. Indeed, obese leptin-deficient ob/ob mice display low body temperature, hyperphagia, infertility and evidence of immune defects with lymphoid organ atrophy, mainly affecting thymic size and cellularity. Acute starvation, associated with decreased leptin levels, causes thymic atrophy and reduces the delayed type hypersensitivity (DTH) reaction to antigens in normal mice, resembling that observed in ob/ob mice. Leptin replacement reverses the immunosuppressive effects of acute starvation in mice. Leptin differentially affects the in vitro proliferation and cytokine production by naive and memory T cells, increasing IL-2 secretion and proliferation of naive T cells, while inducing IFN-g production in memory T cells with little effect on their proliferation. Presence of leptin seems to be necessary for the induction and maintenance of the pro-inflammatory Th1 immune response. These findings support the hypothesis that leptin plays a key role in linking nutritional state to the T cell function. According to this view, leptin might represent an important target for immune intervention in a variety of pathophysiological conditions.

Topics: Animals; Humans; Hypersensitivity, Delayed; Immune System; Leptin; Mice; Mice, Obese; Nutritional Status; Starvation; T-Lymphocytes

Leptin, the product of the ob gene, is a pleiotropic molecule that regulates food intake as well as metabolic and endocrine functions. Leptin also plays a regulatory role in immunity, inflammation, and hematopoiesis. Alterations in immune and inflammatory responses are present in leptin- or leptin-receptor-deficient animals, as well as during starvation and malnutrition, two conditions characterized by low levels of circulating leptin. Both leptin and its receptor share structural and functional similarities with the interleukin-6 family of cytokines. Leptin exerts proliferative and antiapoptotic activities in a variety of cell types, including T lymphocytes, leukemia cells, and hematopoietic progenitors. Leptin also affects cytokine production, the activation of monocytes/macrophages, wound healing, angiogenesis, and hematopoiesis. Moreover, leptin production is acutely increased during infection and inflammation. This review focuses on the role of leptin in the modulation of the innate immune response, inflammation, and hematopoiesis.

Topics: Adaptation, Physiological; Adipose Tissue; Animals; Anorexia; Apoptosis; Cachexia; Carrier Proteins; Cell Division; Cytokines; Eating; Endocrine System; Hematopoiesis; Humans; Immune System; Infections; Inflammation; Interleukin-6; Leptin; Lymphopenia; Mice; Mice, Mutant Strains; Multigene Family; Neovascularization, Physiologic; Obesity; Organ Specificity; Phagocytes; Rats; Receptors, Cell Surface; Receptors, Cytokine; Receptors, Leptin; Signal Transduction; Starvation; T-Lymphocyte Subsets

A neuroendocrine signal may play an important role in the antiaging action of dietary restriction (DR). Recent studies have suggested that falling leptin levels by starvation activate the hypothalamic-pituitary-adrenal axis, and suppress gonadal, somatotropic, and thyroid axes as a response for adaptation. Accumulated evidence indicates that similar hormonal changes also occur in DR rodents. In this article, we advance that a reduction in plasma leptin levels in DR rodents might be a critical neuroendocrine modulator in the antiaging action of dietary restriction.

Topics: Aging; Animals; Diet; Humans; Leptin; Models, Theoretical; Neurosecretory Systems; Starvation

Topics: Animals; Genotype; Humans; Leptin; Obesity; Proteins; Starvation

Here we summarize recent progress in the biology of leptin, concentrating on its central nervous system (CNS) actions. The product of the ob gene, leptin is a circulating hormone produced by white adipose tissue that has potent effects on feeding behavior, thermogenesis and neuroendocrine responses. Leptin regulates energy homeostasis, as its absence in rodents and humans causes severe obesity. We consider the physiological mechanisms underlying leptin action, along with several novel hypothalamic neuropeptides that affect food intake and body weight. The molecular causes of several other obesity syndromes are discussed to illuminate how the CNS regulates body weight. We describe neural circuits that are downstream of leptin receptors and propose a model linking populations of leptin-responsive neurons with effector neurons underlying leptin's endocrine, autonomic and behavioral effects.

Topics: Brain; Humans; Hypothalamic Area, Lateral; Leptin; Models, Neurological; Obesity; Proteins; Starvation

Leptin, the product of the ob gene, controls appetite through the hypothalamus and may affect many other tissues because of the widespread distribution of its receptors. Leptin is synthesized by white adipose tissue (WAT) under conditions of high energy availability and insulin stimulus. Glucocorticoids enhance this synthesis and catecholamines hamper leptin production. Leptin diminishes insulin secretion by the pancreatic beta cells and induces insulin resistance. In fact leptin hampers insulin action on WAT itself in a negative feedback loop. The evidence acquired in studies on diabetics, starvation, refeeding and insulin and glucose clamps supports this interpretation, which may also explain part of the difficulties encountered by the current postulate that links leptin to WAT mass size signalling to the brain. Leptin may be, essentially, a counter-regulatory hormone limiting the insulin drive to store energy in the form of fat, its effects reaching from a decrease in food intake to lower insulin secretion and increased resistance to insulin and lower glucose uptake and fat synthesis by WAT.

Topics: Adipose Tissue; Animals; Choroid Plexus; Energy Metabolism; Feedback; Glucose; Hormones; Humans; Insulin; Insulin Resistance; Leptin; Obesity; Proteins; Starvation

Topics: Adipose Tissue; Animals; Body Weight; Endocrine System Diseases; Homeostasis; Humans; Hypothalamo-Hypophyseal System; Leptin; Neuropeptide Y; Pituitary-Adrenal System; Proteins; Starvation; Wasting Syndrome; Weight Loss

Topics: Adult; Appetite Regulation; Energy Metabolism; Female; Humans; Leptin; Male; Middle Aged; Obesity; Proteins; Starvation; Treatment Failure; Weight Loss

Adaptive thermogenesis (AT) is the fat-free mass (FFM)-independent reduction of resting energy expenditure (REE) to caloric restriction (CR). AT attenuates weight loss and favors weight regain. Its variance, dynamics, and control remain obscure.. Our aims were to address the variance and kinetics of AT, its associations with body composition in the context of endocrine determinants, and its effect on weight regain.. Thirty-two nonobese men underwent sequential overfeeding (1 wk at +50% of energy needs), CR (3 wk at -50% of energy needs), and refeeding (2 wk at +50% of energy needs). AT and its determinants were measured together with body composition as assessed with the use of quantitative magnetic resonance, whole-body MRI, isotope dilution, and nitrogen and fluid balances.. Changes in body weight were +1.8 kg (overfeeding), -6.0 kg (CR), and +3.5 kg (refeeding). CR reduced fat mass and FFM by 114 and 159 g/d, respectively. Within FFM, skeletal muscle (-5%), liver (-13%), and kidneys (-8%) decreased. CR also led to reductions in REE (-266 kcal/d), respiratory quotient (-15%), heart rate (-14%), blood pressure (-7%), creatinine clearance (-12%), energy cost of walking (-22%), activity of the sympathetic nervous system (SNS) (-38%), and plasma leptin (-44%), insulin (-54%), adiponectin (-49%), 3,5,3'-tri-iodo-thyronine (T3) (-39%), and testosterone (-11%). AT was 108 kcal/d or 48% of the decrease in REE. Changes in FFM composition explained 36 kcal, which left 72 kcal/d for true AT. The decrease in AT became significant at ≤3 d of CR and was related to decreases in insulin secretion (r = 0.92, P < 0.001), heart rate (r = 0.60, P < 0.05), creatinine clearance (r = 0.79, P < 0.05), negative fluid balance (r = 0.51, P < 0.01), and the free water clearance rate (r = -0.90, P < 0.002). SNS activity and plasma leptin, ghrelin, and T3 and their changes with CR were not related to AT.. During early weight loss, AT is associated with a fall in insulin secretion and body fluid balance. This trial was registered at clinicaltrials.gov as NCT01737034.

Topics: Adaptation, Physiological; Adiponectin; Adult; Basal Metabolism; Body Composition; Body Mass Index; Body Weight; C-Peptide; Caloric Restriction; Creatinine; Energy Metabolism; Ghrelin; Heart Rate; Humans; Insulin; Insulin Secretion; Leptin; Male; Minnesota; Starvation; Testosterone; Thermogenesis; Triiodothyronine; Young Adult

Starvation induces a complex neuroendocrine response in humans thought to have evolved to defend against reduced energy intake. The drop in leptin levels observed during fasting has been implicated as a factor that triggers this adaptive response. To explore this hypothesis, we executed a randomized, double-blind, placebo-controlled study to investigate whether elevated leptin levels using long-acting pegylated human recombinant leptin (PEG-OB) influenced the neuroendocrine responses to semi-starvation in human subjects.. Twenty-four overweight male subjects (mean+/-s.e.m.; 34.8+/-1.3 yrs; 28.8+/-0.5 kg/m(2)) were prescribed a very low energy diet (2.1 MJ/day) to induce a state of semi-starvation for the next 46 days. In addition, all subjects received a weekly treatment of 80 mg PEG-OB or matching placebo. Hormone measurements were performed throughout the study period and included 5-h frequent hormone samplings and 24-h urine collections.. Weekly subcutaneous administration of PEG-OB led to significant additional weight loss (2.8 kg) but it did not reverse the fasting-induced changes in the thyroid, corticotropic, somatotropic axes and sympathetic nervous system activity. However, after adjustment for weight loss, the drop in mean luteinizing hormone levels was attenuated in the PEG-OB group compared with the placebo group.. These results suggest that a reduced level of leptin accompanying food restriction might be a component of the fasting-induced neuroendocrine inhibition of the human reproductive axis.

Topics: Adaptation, Physiological; Adolescent; Adult; Energy Intake; Energy Metabolism; Hormones; Humans; Leptin; Linear Models; Male; Middle Aged; Obesity; Polyethylene Glycols; Recombinant Proteins; Starvation; Weight Loss

The obese gene product--leptin (LEP)--is a hormone released from adipose tissue implicated in the regulation of nutritional state and energy balance. The aim of this study was to assess the relationship between plasma LEP levels and nutritional state, secretion of hormones of the hypothalamic-pituitary axis, and personality traits in patients with anorexia nervosa (AN). The study was performed in 22 women with AN aged 19.45 +/- 0.92 yrs, mean BMI of 15.48 +/- 0.29 kg/m2, 14 healthy women with normal body weight (NW), aged 29.71 +/- 2.4 yrs, mean BMI of 21.22 +/- 0.43 kg/m2, and 19 obese women without metabolic disorders (OTY), aged 34.5 +/- 2.65 yrs, mean BMI of 37.47 +/- 2.06 kg/m2. Hormone levels were measured with RIA test kits. Psychological examination was carried out by means of Gough-Helibrun's and Catell's personality tests. Body mass index (BMI) and body composition, i.e. body fat mass (BF) and body fat percentage (%BF) were determined with a DEXA instrument (Lunar Co., WI, USA). Absolute plasma LEP levels and the LEP/%BF index were lowest in patients with AN whereas LEP/BF index did not differ among AN, NW, and OTY groups (Table 1). In all groups, LEP levels were positively correlated with BMI, BF, and %BF (Table 2). Plasma neuropeptide Y (NPY), beta-endorphin (B-EP), and galanin (GAL) levels in AN were significantly higher than in NW and OTY groups (Table 3). Plasma GAL levels were positively correlated with LEP/BF and LEP/%BF in AN patients only. Moreover in the AN group, serum/plasma levels of insulin (I), insulin-like growth hormone-1 (IGF-1), luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2), and free triiodothyronine (fT3) were significantly lower, and levels of cortisol (F) significantly higher than in NW and OTY groups (Table 4). Plasma LEP levels in AN patients were positively correlated with IRI, IGF-1, free thyroxine (fT4), and FSH levels, and negatively correlated with thyrotrophin (TSH) levels. Personality traits in patients with AN were significantly correlated with hormone levels (Tables 5 and 6), BMI and body fat content (Table 6).. 1) Leptin secretion from adipose tissue is not related to the nutritional state. 2) High levels of NPY, beta-EP, and GAL in AN confirm that starvation is deliberate in these patients. Low LEP levels in AN may lead to secondary amenorrhea and thyroid function disorders, as well as enhanced cortisol and growth hormone secretion of hypothalamic origin. A positive correlation between levels of LEP and IGF-1 and IRI may reflect mechanisms preserving adipose tissue and protecting from hypoglycemia and insulin resistance. A positive correlation between LEP and fT4 levels suggests a tendency to energy-sparing under conditions of low energy intake. Lack of correlation between LEP and F levels apparently reflects peripheral cortisol resistance in AN. 3) Both undernutrition and abnormal hormone secretion (LEP, F, fT3, IGF-1, LH, E2) are related to social self-withdrawal, defensive attitudes, low self-esteem and high level of self-supervision in AN.

Topics: Adipose Tissue; Adult; Amenorrhea; Anorexia Nervosa; Female; Human Growth Hormone; Humans; Hydrocortisone; Hypothalamus; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Metabolic Diseases; Nutritional Status; Starvation; Thyroid Diseases

Molecular profiling of the hypothalamus in response to metabolic shifts is a critical cue to better understand the principle of the central control of whole-body energy metabolism. The transcriptional responses of the rodent hypothalamus to short-term calorie restriction have been documented. However, studies on the identification of hypothalamic secretory factors that potentially contribute to the control of appetite are lacking. In this study, we analyzed the differential expression of hypothalamic genes and compared the selected secretory factors from the fasted mice with those of fed control mice using bulk RNA-sequencing. We verified seven secretory genes that were significantly altered in the hypothalamus of fasted mice. In addition, we determined the response of secretory genes in cultured hypothalamic cells to treatment with ghrelin and leptin. The current study provides further insights into the neuronal response to food restriction at the molecular level and may be useful for understanding the hypothalamic control of appetite.

Topics: Animals; Appetite; Fasting; Gene Expression Profiling; Ghrelin; Hypothalamus; Leptin; Mice; Starvation

The hypothesis linking hyperactivity with weight loss associated hypoleptinemia in anorexia nervosa gained momentum after a study showing that leptin suppressed semi-starvation induced hyperactivity in rats. Alternatively, ambient temperature is a key modulating factor of activity in semi-starved rats. The aim of the study is to compare the efficacy of leptin with increased ambient temperature in the prevention of hyperactivity in semi-starved rats. 74 Sprague-Dawley male rats were employed in two experiments with the difference residing in the length of baseline. After an extended (28 days), or shorter (14 days) baseline with free access to food and the running wheel, housed at 21 °C, animals were either ad-lib feed or food restricted (60% of food ingested during previous week) and infused with same amount of leptin at 21 °C, 25 °C, or vehicle at 21 °C, 25 °C and 32 °C for a week. Animals housed at 32 °C significantly reduced wheel running and weight loss during food restriction while animals given leptin did not yield no differences in activity or weight loss. Moreover, unlike animals housed at 32 °C, body temperature of leptin infused animals housed at 21 °C was significantly reduced during food restriction. Furthermore, leptin treated rats without a preceding stable pattern of activity displayed a severe dysregulation of circadian rhythm in activity and a collapse of body temperature. Housing temperature plays a more critical role than leptin in the regulation of semi-starvation induced hyperactivity in rats, which may be of relevance for the management of hyperactivity in anorexia nervosa.

Topics: Animals; Anorexia Nervosa; Hyperkinesis; Leptin; Male; Motor Activity; Physical Conditioning, Animal; Psychomotor Agitation; Rats; Rats, Sprague-Dawley; Starvation; Temperature

The transition from the fed to the fasted state necessitates a shift from carbohydrate to fat metabolism that is thought to be mostly orchestrated by reductions in plasma insulin concentrations. Here, we show in awake rats that insulinopenia per se does not cause this transition but that both hypoleptinemia and insulinopenia are necessary. Furthermore, we show that hypoleptinemia mediates a glucose-fatty acid cycle through activation of the hypothalamic-pituitary-adrenal axis, resulting in increased white adipose tissue (WAT) lipolysis rates and increased hepatic acetyl-coenzyme A (CoA) content, which are essential to maintain gluconeogenesis during starvation. We also show that in prolonged starvation, substrate limitation due to reduced rates of glucose-alanine cycling lowers rates of hepatic mitochondrial anaplerosis, oxidation, and gluconeogenesis. Taken together, these data identify a leptin-mediated glucose-fatty acid cycle that integrates responses of the muscle, WAT, and liver to promote a shift from carbohydrate to fat oxidation and maintain glucose homeostasis during starvation.

Topics: Adipose Tissue, White; Alanine; Animals; Blood Glucose; Fatty Acids; Gluconeogenesis; Homeostasis; Insulin; Leptin; Lipolysis; Liver; Male; Mitochondria; Rats; Rats, Sprague-Dawley; Starvation

The human adaptive starvation response allows for survival during long-term caloric deprivation. Whether the physiology of starvation is adaptive or maladaptive is context dependent: activation of pathways by caloric restriction may promote longevity, yet in the context of caloric excess, the same pathways may contribute to obesity. Here, we performed plasma metabolite profiling of longitudinally collected samples during a 10-day, 0-calorie fast in humans. We identify classical milestones in adaptive starvation, including the early consumption of gluconeogenic amino acids and the subsequent surge in plasma nonesterified fatty acids that marks the shift from carbohydrate to lipid metabolism, and demonstrate findings, including (a) the preferential release of unsaturated fatty acids and an associated shift in plasma lipid species with high degrees of unsaturation and (b) evidence that acute, starvation-mediated hypoleptinemia may be a driver of the transition from glucose to lipid metabolism in humans.

Topics: Adaptation, Physiological; Adult; Blood Glucose; Caloric Restriction; Carbohydrate Metabolism; Fasting; Fatty Acids, Unsaturated; Female; Glucose; Healthy Volunteers; Humans; Leptin; Lipid Metabolism; Longitudinal Studies; Male; Metabolome; Metabolomics; Middle Aged; Starvation; Young Adult

Endocrine factors released from the central nervous system, gastrointestinal tract, adipose tissue and other peripheral organs mediate the regulation of food intake. Although many studies have evaluated the effect of fed-to-starved transition on the expression of appetite-related genes, little is known about how the expression of appetite-regulating peptides is regulated by the macronutrient composition of the diet. The aim of the present study was to examine the effect of diet composition and nutritional status on the expression of four peptides involved in food intake control in gilthead sea bream (Sparus aurata): neuropeptide Y (NPY), ghrelin, cholecystokinin (CCK) and leptin. Quantitative real-time RT-PCR showed that high protein/low carbohydrate diets stimulated the expression of CCK and ghrelin in the intestine and leptin in the adipose tissue, while downregulation of ghrelin and NPY mRNA levels was observed in the brain. Opposite effects were found for the expression of the four genes in fish fed low protein/high carbohydrate diets or after long-term starvation. Our findings indicate that the expression pattern of appetite-regulating peptides, particularly CCK and ghrelin, is modulated by the nutritional status and diet composition in S. aurata.

Topics: Animals; Body Composition; Body Weight; Cholecystokinin; Diet; Gene Expression Regulation; Ghrelin; Leptin; Linear Models; Neuropeptide Y; RNA, Messenger; Sea Bream; Starvation

Mammalian reproductive function depends upon a neuroendocrine circuit that evokes the pulsatile release of gonadotropin hormones (luteinizing hormone and follicle-stimulating hormone) from the pituitary. This reproductive circuit is sensitive to metabolic perturbations. When challenged with starvation, insufficient energy reserves attenuate gonadotropin release, leading to infertility. The reproductive neuroendocrine circuit is well established, composed of two populations of kisspeptin-expressing neurons (located in the anteroventral periventricular hypothalamus, Kiss1

Topics: Agouti-Related Protein; Animals; Circadian Clocks; Clozapine; Estrous Cycle; Female; Fertility; Gene Expression Regulation; Gonadotropin-Releasing Hormone; Hypothalamus; Kisspeptins; Leptin; Luteinizing Hormone; Male; Mice; Mice, Transgenic; Neurons; Optogenetics; Reproduction; Signal Transduction; Starvation; Stereotaxic Techniques

Body weight and the levels of stored body fat have fitness consequences. Greater levels of fat may provide protection against catastrophic failures in the food supply, but they may also increase the risk of predation. Animals may therefore regulate their fatness according to their perceived risks of predation and starvation: the starvation-predation trade-off model. We tested the predictions of this model in wood mice (Apodemus sylvaticus) by experimentally manipulating predation risk and starvation risk. We predicted that under increased predation risk individuals would lose weight and under increased starvation risk they would gain it. We simulated increased predation risk by playing the calls made by predatory birds (owls: Tyto alba and Bubo bubo) to the mice. Control groups included exposure to calls of a non-predatory bird (blackbird: Turdus merula) or silence. Mice exposed to owl calls at night lost weight relative to the silence group, mediated via reduced food intake, but exposure to owl calls in the day had no significant effect. Exposure to blackbird calls at night also resulted in weight loss, but blackbird calls in the day had no effect. Mice seemed to have a generalised response to bird calls at night irrespective of their actual source. This could be because in the wild any bird calling at night will be a predation risk, and any bird calling in the day would not be, because at that time the mice would normally be resting, and hence not exposed to avian predators. Consequently, mice have not evolved to distinguish different types of call but only to respond to the time of day that they occur. Mice exposed to stochastic 24h starvation events altered their behaviour (reduced activity) during the refeeding days that followed the deprivation periods to regain the lost mass. However, they only marginally elevated their food intake and consequently had reduced body weight/fat storage compared to that of the control unstarved group. This response may have been constrained by physiological factors (alimentary tract absorption capacity) or behavioural factors (perceived risk of predation). Overall the responses of the mice appeared to provide limited support for the starvation-predation trade-off model, and suggest that wood mice are much more sensitive to predation risk than they are to starvation risk.

Topics: Acoustic Stimulation; Analysis of Variance; Animals; Body Mass Index; Body Weight; Corticosterone; Eating; Fasting; Hyperphagia; Leptin; Models, Animal; Murinae; Oxygen Consumption; Predatory Behavior; Risk Factors; Starvation; Time Factors

Hypothalamic feeding circuits are essential for the maintenance of energy balance. There have been intensive efforts to discover new biological molecules involved in these pathways. Here we report that central administration of clusterin, also called apolipoprotein J, causes anorexia, weight loss and activation of hypothalamic signal transduction-activated transcript-3 in mice. In contrast, inhibition of hypothalamic clusterin action results in increased food intake and body weight, leading to adiposity. These effects are likely mediated through the mutual actions of the low-density lipoprotein receptor-related protein-2, a potential receptor for clusterin, and the long-form leptin receptor. In response to clusterin, the low-density lipoprotein receptor-related protein-2 binding to long-form leptin receptor is greatly enhanced in cultured neuronal cells. Furthermore, long-form leptin receptor deficiency or hypothalamic low-density lipoprotein receptor-related protein-2 suppression in mice leads to impaired hypothalamic clusterin signalling and actions. Our study identifies the hypothalamic clusterin-low-density lipoprotein receptor-related protein-2 axis as a novel anorexigenic signalling pathway that is tightly coupled with long-form leptin receptor-mediated signalling.

Topics: Animals; Anorexia; Body Weight; Cell Line; Clusterin; Epididymis; Feeding Behavior; Humans; Hypothalamus; Immunohistochemistry; Injections, Intraventricular; Leptin; Low Density Lipoprotein Receptor-Related Protein-2; Male; Mice; Obesity; Phosphorylation; Protein Binding; Rats; Receptors, Leptin; Signal Transduction; Starvation; STAT3 Transcription Factor

Science is marked by the death of dogmas; the discovery that adipocytes are more than just lipid-storing cells but rather produce potent hormones is one such example that caught physiologists by surprise and reshaped our views of metabolism. While we once considered the adipocyte as a passive storage organ for efficient storage of long-term energy reserves in the form of triglyceride, we now appreciate the general idea (once a radical one) that adipocytes are sophisticated enough to have potent endocrine functions. Over the past two decades, the discoveries of these adipose-derived factors ("adipokines") and their mechanistic actions have left us marveling at and struggling to understand the role these factors serve in physiology and the pathophysiology of obesity and diabetes. These hormones may serve an integral role in protecting nonadipose tissues from lipid-induced damage during nutrient-deprived or replete states. As such, adipocytes deliver not only potentially cytotoxic free fatty acids but, along with these lipids, antilipotoxic adipokines such as leptin, adiponectin, and fibroblast growth factor 21 that potently eliminate excessive local accumulation of these lipids or their conversion to unfavorable sphingolipid intermediates.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Energy Metabolism; Fibroblast Growth Factors; Homeostasis; Leptin; Lipid Metabolism; Starvation

Fasting is beneficial in the prevention and amelioration of the clinical manifestations of autoimmune diseases including systemic lupus erythematosus. The mechanisms responsible for these effects are not well understood. During fasting, there is a dramatic reduction of the levels of circulating leptin, an adipokine with proinflammatory effects. Leptin also inhibits CD4(+)CD25(+)Foxp3(+) regulatory T cells, which are known to contribute significantly to the mechanisms of peripheral immune tolerance. In this study, we show that fasting-induced hypoleptinemia in (NZB × NZW)F(1) lupus-prone mice induced an expansion of functional regulatory T cells that was reversed by leptin replacement. The specificity of the findings was indicated by the lack of these effects in leptin-deficient ob/ob mice and leptin receptor-deficient db/db mice. These observations help to explain the beneficial effects of fasting in autoimmunity and could be exploited for leptin-based immune intervention in systemic lupus erythematosus.

Topics: Animals; Cell Differentiation; Fasting; Female; Genetic Predisposition to Disease; Leptin; Lupus Erythematosus, Systemic; Mice; Mice, Inbred C57BL; Mice, Inbred NZB; Mice, Obese; Receptors, Leptin; Starvation; T-Lymphocytes, Regulatory

Being born small for gestational age (SGA), a proxy for intrauterine growth restriction (IUGR), and prenatal famine exposure are both associated with a greater risk of metabolic disease. Both associations have been hypothesized to involve epigenetic mechanisms. We investigated whether prenatal growth restriction early in pregnancy was associated with changes in DNA methylation at loci that were previously shown to be sensitive to early gestational famine exposure. We compared 38 individuals born preterm (< 32 weeks) and with a birth weight too low for their gestational age (-1SDS) and a normal postnatal growth (>-1SDS at 3 months post term; AGA). The SGA individuals were not only lighter at birth, but also had a smaller length (P=3.3x10 (-13) ) and head circumference at birth (P=4.1x10 (-13) ). The DNA methylation levels of IGF2, GNASAS, INSIGF and LEP were 48.5%, 47.5%, 79.4% and 25.7% respectively. This was not significantly different between SGA and AGA individuals. Risk factors for being born SGA, including preeclampsia and maternal smoking, were also not associated with DNA methylation at these loci. Growth restriction early in development is not associated with DNA methylation at loci shown to be affected by prenatal famine exposure. Our and previous results by others indicate that prenatal growth restriction and famine exposure may be associated with different epigenetic changes or non epigenetic mechanisms that may lead to similar later health outcomes.

Topics: DNA Methylation; Epigenesis, Genetic; Female; Fetal Growth Retardation; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Small for Gestational Age; Insulin-Like Growth Factor II; Leptin; Male; Pre-Eclampsia; Pregnancy; Smoking; Starvation

Nutritional deprivation or malnutrition suppresses immune function in humans and animals, thereby conferring higher susceptibility to infectious diseases. Indeed, nutritional deprivation induces atrophy of lymphoid tissues such as thymus and spleen and decreases the number of circulating lymphocytes. Leptin, a major adipocytokine, is exclusively produced in the adipose tissue in response to the nutritional status and acts on the hypothalamus, thereby regulating energy homeostasis. Although leptin plays a critical role in the starvation-induced T-cell-mediated immunosuppression, little is known about its role in B-cell homeostasis under starvation conditions. Here we show the alteration of B-cell development in the bone marrow of fasted mice, characterized by decrease in pro-B, pre-B, and immature B cells and increase in mature B cells. Interestingly, intracerebroventricular leptin injection was sufficient to prevent the alteration of B-cell development of fasted mice. The alteration of B lineage cells in the bone marrow of fasted mice was markedly prevented by oral administration of glucocorticoid receptor antagonist RU486 (11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one). It was also effectively prevented by intracerebroventricular injection of neuropeptide Y Y(1) receptor antagonist BIBP3226 [(2R)-5-(diaminomethylideneamino)-2-[(2,2-diphenylacetyl)amino]-N-[(4-hydroxyphenyl)methyl]pentanamide], along with suppression of the otherwise increased serum corticosterone concentrations. This study provides the first in vivo evidence for the role of central leptin signaling in the starvation-induced alteration of B-cell development. The data of this study suggest that the CNS, which is inherent to integrate information from throughout the organism, is able to control immune function.

Topics: Adipose Tissue; Adrenalectomy; Animals; B-Lymphocytes; Blood Glucose; Cell Differentiation; Flow Cytometry; Hypothalamus; Leptin; Male; Mice; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Starvation

Leptin is produced by white adipose tissue and other cell types and is involved in both short- and long-term appetite control. Here we studied effects of starvation on serum, pituitary and hypothalamic levels of leptin during 72 h period. Each of the starved groups was sacrificed simultaneously with the group of ad libitum fed animals. The progression of the discrete starvation response phases was monitored by testing the blood glucose, free fatty acid, urea and corticosterone levels. Starvation caused biphasic increase in corticosterone and free fatty acid levels, and significant but transient decrease in urea and glucose levels. Starvation also abolished diurnal rhythm of changes in leptin concentrations in serum and hypothalamic and pituitary tissues. Only 6 h starving period was sufficient to lock serum leptin at low levels, whereas 12 h were needed to silence leptin production/secretion in hypothalamus for the whole examined period. In contrast, leptin production by pituitary tissues of starved animals required 24 h to reach minimum, followed by full recovery by the end of starvation period. These results indicate the tissue specific pattern of leptin release and suggest that the locally produced leptin could activate its receptor in pituitary cells independently of serum levels of this hormone.

Topics: Animals; Biomarkers; Blood Glucose; Circadian Rhythm; Corticosterone; Disease Models, Animal; Energy Metabolism; Fatty Acids, Nonesterified; Food Deprivation; Hypothalamus; Leptin; Male; Pituitary Gland; Rats; Rats, Wistar; Starvation; Time Factors; Urea

We examined which factors suppress the rise of ghrelin secretion under hunger in 16-h-starved rats, and compared the responses of plasma ghrelin and leptin levels to various exogenous and endogenous stimuli in intact rats. Although an acute expansion of the stomach by infusion of 6 ml air or 3 ml water in rats starved for 16 h did not change the level of plasma acyl-ghrelin 3 ml corn starch solution, corn oil, or 20% ethanol significantly decreased it. Vagotomy inhibited suppression by nutrients but not by ethanol. Chronic infusion of ethanol into the stomach for 3 weeks in free-feeding rats caused widespread injury of the stomach mucosa, and increased both plasma ghrelin levels and the number of ghrelin cells. In intact rats, low temperature did not change ghrelin levels, but increased leptin levels. On the other hand, restriction stress decreased plasma ghrelin levels, but had the reverse effect on plasma leptin levels. Although insulin decreased and 20% glucose increased plasma glucose levels, they both decreased plasma ghrelin levels. Insulin elevated plasma leptin levels, but glucose had no effect. These results indicate that 1) acyl-ghrelin secretion from the stomach under fasting condition is suppressed by nutrients but not by mechanical expansion of the stomach; 2) high and low environmental temperature, stress, or administration of insulin reciprocally affect plasma levels of ghrelin and leptin; and 3) an increase of stomach ghrelin cell number and plasma ghrelin levels after chronic ethanol treatment may be involved in restoration of gastric mucosae.

Topics: Animal Nutritional Physiological Phenomena; Animals; Blood Glucose; Environment; Ethanol; Gastric Mucosa; Ghrelin; Insulin; Leptin; Male; Rats; Rats, Wistar; Starvation; Vagotomy; Vagus Nerve

Activity-based anorexia (ABA) is considered an animal model for anorexia nervosa (AN). By scheduled feeding and voluntary wheel running, it mimics severe body weight loss and increased physical activity in AN. Pharmacological, genetic and imaging studies implicate dopamine and serotonin in the regulation of feeding behavior, food-anticipatory activity, and food reward. Previous studies propose that the nucleus accumbens (NAc) plays an important role in these food-related processes. Here we determined dopamine and serotonin levels in the NAc upon exposure to the ABA model. Surprisingly, the release of dopamine and serotonin in the NAc were not increased during the initiation of food-anticipatory behavior in ABA rats. Dopamine release in the NAc was increased during feeding behavior in ABA rats. During ABA, levels of serotonin were low and circadian activity is blunted. We conclude that during the early stages of development of food-anticipatory activity, increased dopamine does not trigger hyperactivity.

Topics: 3,4-Dihydroxyphenylacetic Acid; Analysis of Variance; Animals; Body Temperature; Body Weight; Chromatography, High Pressure Liquid; Disease Models, Animal; Dopamine; Eating; Female; Homovanillic Acid; Hydroxyindoleacetic Acid; Hyperkinesis; Insulin; Leptin; Microdialysis; Nucleus Accumbens; Radioimmunoassay; Rats; Rats, Wistar; Serotonin; Starvation

Prenatal famine in humans has been associated with various later-life consequences, depending on the gestational timing of the insult and the sex of the exposed individual. Epigenetic mechanisms have been proposed to underlie these associations. Indeed, animal studies and our early human data on the imprinted IGF2 locus indicated a link between prenatal nutritional and DNA methylation. However, it remains unclear how common changes in DNA methylation are and whether they are sex- and timing-specific paralleling the later-life consequences of prenatal famine exposure. To this end, we investigated the methylation of 15 loci implicated in growth and metabolic disease in individuals who were prenatally exposed to a war-time famine in 1944-45. Methylation of INSIGF was lower among individuals who were periconceptionally exposed to the famine (n = 60) compared with their unexposed same-sex siblings (P = 2 x 10(-5)), whereas methylation of IL10, LEP, ABCA1, GNASAS and MEG3 was higher (all P < 10(-3)). A significant interaction with sex was observed for INSIGF, LEP and GNASAS. Next, methylation of eight representative loci was compared between 62 individuals exposed late in gestation and their unexposed siblings. Methylation was different for GNASAS (P = 1.1 x 10(-7)) and, in men, LEP (P = 0.017). Our data indicate that persistent changes in DNA methylation may be a common consequence of prenatal famine exposure and that these changes depend on the sex of the exposed individual and the gestational timing of the exposure.

Topics: Aged; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Chromogranins; CpG Islands; DNA Methylation; Female; GTP-Binding Protein alpha Subunits, Gs; Humans; Interleukin-10; Leptin; Male; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Proteins; RNA, Long Noncoding; Sex Factors; Siblings; Starvation; Time Factors

Patients with eating disorders often exhibit abnormal eating conditions like food restriction, adipocyte and body weight reduction, and pathologic anxiety-like behavior. The role of leptin, which is recognized as an adipocyte-derived hormone, on anxiety-like behavior in eating disorders is still unclear.. We investigated the role of leptin on anxiety-like behavior with or without semi-starvation using the elevated plus-maze test in adolescent female rats. In our first experiment, anxiety-like behavior was evaluated with the elevated plus-maze test 30 min after intracerebroventricular administration of 3 microg of leptin or vehicle. In our second experiment, the rats were allowed access to food for only 2 hr each day for 7 days. Then, leptin or vehicle was administered to the rats after the last 2 hr feeding period, and anxiety-like behaviors were evaluated in the same way as in the first experiment.. In the first experiment, there was no difference between the anxiety-like behaviors observed after leptin administration and those seen after vehicle administration. Under the conditions of semi-starvation, however, the percentage of time spent in the open arms in the rats given leptin was lower than that in rats given vehicle.. These results suggest that leptin administration causes anxiety-like behavior only after semistarvation. Leptin might play an important role in pathologic anxiety-like behavior in eating disorders.

Topics: Animals; Anorexia Nervosa; Anxiety; Corticotropin-Releasing Hormone; Estrus; Feeding and Eating Disorders; Female; Injections, Intraventricular; Leptin; Maze Learning; Rats; Rats, Wistar; Starvation

Topics: Adipocytes; Animals; Blood Glucose; Brain; Cannabinoid Receptor Modulators; Hypothalamus; Infusions, Intravenous; Insulin; Leptin; Lipid Metabolism; Lipogenesis; Lipolysis; Models, Biological; Neurons; Phosphatidylinositol 3-Kinases; Rats; Signal Transduction; Starvation; Sympathetic Nervous System

The AMP-activated protein kinase (AMPK) is involved in the control of food intake by the hypothalamus. The aim of this work was to investigate if modification of hypothalamic AMPK regulation could be related to the spontaneous food restriction of Lou/C rats, a strain resistant to obesity exhibiting a 40% reduction in caloric intake compared with their lean Wistar counterparts.. Three-month-old male Lou/C rats were compared with age-matched male Wistar rats in both fed ad libitum and 24-h food deprivation state.. We first confirmed that starvation activated both isoforms of AMPK catalytic alpha subunits and enhanced the phosphorylation state of its downstream targets acetyl-CoA carboxylase and elongation factor 2 in the hypothalamus of Wistar rats. These changes were not observed in the hypothalamus of Lou/C rats. Interestingly, the starvation-induced changes in hypothalamic mRNA levels of the main orexigenic and anorexigenic neuropeptides were also blunted in the Lou/C rats. Analysis of the concentrations of circulating substrates and hormones known to regulate hypothalamic AMPK indicated that the starvation-induced changes in ghrelin, adiponectin and leptin were not observed in Lou/C rats. Furthermore, an increased phosphorylation state of signal transducer and activator of transcription 3 (STAT3), which admittedly mediates leptin signaling, was evidenced in the hypothalamus of the starved Lou/C rats, as well as modifications of expression of the leptin-sensitive genes suppressor of cytokine signaling-3 and stearoyl-coenzyme A desaturase 1. In addition, despite reduced leptin level in fed Lou/C rats, the phosphorylation state of hypothalamic STAT3 remained similar to that found in fed Wistar rats, an adaptation that could be explained by the concomitant increase in ObRb leptin receptor mRNA expression.. Activation of hypothalamic AMPK by starvation, which stimulates food intake through changes in (an)orexigenic neuropeptides in the normal rats, was not observed in the spontaneously hypophagic Lou/C rats.

Topics: Adiponectin; AMP-Activated Protein Kinases; Animals; Blotting, Western; Disease Susceptibility; Eating; Enzyme Activation; Ghrelin; Hypothalamus; Leptin; Male; Multienzyme Complexes; Neuropeptides; Obesity; Phosphorylation; Protein Serine-Threonine Kinases; Rats; Rats, Inbred Strains; Rats, Wistar; RNA, Messenger; Species Specificity; Starvation

S100B protein is mainly synthesized in glial cells and modulates the balance between cell proliferation and differentiation in neurons and glial cells. However, S100B is not CNS-specific since its production was detected in numerous non-cerebral tissues e.g. adipocytes. In this study we investigated the influence of chronic fasting and subsequent weight gain on serum levels of S100B in patients with anorexia nervosa. We found that nutritional status was an important factor influencing serum levels of S100B.

Topics: Adolescent; Age Factors; Anorexia Nervosa; Biomarkers; Body Composition; Body Mass Index; Chronic Disease; Dietary Proteins; Down-Regulation; Female; Humans; Leptin; Nerve Growth Factors; Nutritional Status; Predictive Value of Tests; Recovery of Function; Reference Values; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Starvation; Weight Gain

Leptin is an adipocyte-derived hormone that declines dramatically during fasting and plays a pivotal role in the neuroendocrine response to starvation. Previously, we employed leptin-deficient (ob/ob) mice to identify an important role for leptin in the host defense against Klebsiella pneumonia.. To assess the effects of fasting on the innate immune response against pneumococcal pneumonia and to determine the effects of maintaining circulating leptin levels on host defense in fasted mice.. C57BL/6 mice were either fed ad libitum or fasted for 48 h and given an intraperitoneal injection of saline or recombinant leptin (1 microg/g of body weight) twice daily for 48 h before bacterial challenge. Mice were challenged with 10(5) cfu of Streptococcus pneumoniae via the intranasal route.. Lung homogenate S. pneumoniae burden was nearly 20-fold greater in the fasted as compared with fed mice. The impairment in bacterial clearance observed in fasted animals was associated with reduced bronchoalveolar lavage neutrophil counts and interleukin-6 and macrophage inflammatory protein-2 levels. Alveolar macrophages from fasted animals also exhibited defective phagocytosis and killing of S. pneumoniae and reduced calcium-ionophore-stimulated leukotriene B(4) synthesis in vitro. In contrast, the provision of exogenous leptin to fasted animals restored bacterial clearance, bronchoalveolar lavage levels of neutrophils and cytokines, alveolar macrophage bacterial killing, and leukotriene B(4) synthesis.. These results suggest that reduced leptin levels substantially contribute to the suppression of pulmonary antibacterial host defense during starvation and that administration of this adipokine may be of therapeutic benefit clinically.

Topics: Acute Disease; Animals; Blood Glucose; Body Weight; Bronchoalveolar Lavage; Corticosterone; Disease Models, Animal; Fasting; Interleukin-6; Leptin; Leukocytes; Leukotriene B4; Lung; Mice; Mice, Inbred C57BL; Neutrophils; Phagocytosis; Pneumonia, Pneumococcal; Sodium Chloride; Starvation; Streptococcus pneumoniae

The aim of this study was to compare the postprandial leptin response in rats with and without metabolic syndrome induced by a fructose-enriched diet. The effect of aging and the association between variations in metabolic substrates was also evaluated. Oral glucose tolerance test (OGTT) and fasting/re-feeding test were used to evaluate the responses of leptin and to explore the dynamic relationship between endogenous leptin and metabolic substrates, including glucose, insulin and triglycerides (TG). At the 7th week, plasma leptin was unchanged in control rats after oral glucose loading. However, plasma leptin levels increased in fructose-fed rats with insulin resistant OGTT curves. At the 11th month, plasma leptin level was reduced during starvation and returned to the level prior to starvation during re-feeding in control rats. In contrast, the starvation-induced reduction in leptin showed a potentially larger rebound effect during re-feeding in fructose-fed rats. Analysis of covariance demonstrated that there alone was no interactive effect of dietary manipulation between leptin and TG, suggesting that fructose diet-induced insulin resistance-related metabolic syndrome may concomitantly elevate leptin and TG. Furthermore, multiple regression analysis suggests TG was the primary correlative determinant of endogenous leptin concentration. Our data showed that there are different patterns of leptin response to OGTT and fasting/re-feeding tests in rats with and without metabolic syndrome. The results suggest that these effects may be related to a TG-mediated impairment of leptin function and a protective mechanism to reduce lipid-induced tissue damage in patients with metabolic syndrome.

Topics: Aging; Animals; Blood Glucose; Blood Pressure; Eating; Fructose; Glucose Tolerance Test; Insulin; Leptin; Male; Postprandial Period; Rats; Rats, Sprague-Dawley; Starvation; Triglycerides

The purpose of the present study was to elucidate the possible role of leptin in food intake and body weight regulation in goldfish. We examined the effects of i.c.v. or i.p. acute leptin administration on food intake in food-deprived goldfish at different time intervals post-injection (0-2, 2-8 and 0-8 h). Food intake was reduced by i.p. administered leptin (1 microg) at 8 h post-injection, without statistically significant differences after i.c.v. treatment. The present study shows for the first time in a teleost that chronic (10 days) leptin treatment (i.p.) reduces food intake, body weight gain, specific growth rate and food efficiency ratio. Moreover, lipid and carbohydrate metabolism seems to be regulated by leptin in fish. Chronic leptin treatment increased lipid mobilization and carbohydrate storage as hepatic and muscle glycogen. Finally, leptin could mediate its actions on energy homeostasis in fish, at least in part, through interactions with hypothalamic catecholamines, since chronic leptin treatment reduced both hypothalamic noradrenergic and dopaminergic turnover without significant modifications in hypothalamic serotoninergic and neuropeptide Y (NPY) systems. In summary, our results suggest that leptin can regulate feeding behaviour and body weight homeostasis in fish.

Topics: Animals; Body Weight; Carbohydrate Metabolism; Catecholamines; Eating; Energy Metabolism; Glycogen; Goldfish; Hypothalamus; Injections, Intraperitoneal; Injections, Intravenous; Leptin; Lipid Metabolism; Liver; Muscles; Neuropeptide Y; Serotonin; Starvation; Time Factors

Topics: AMP-Activated Protein Kinases; Animals; Appetite; Body Weight; Diet; Eating; Energy Metabolism; Homeostasis; Hypothalamus; Leptin; Leucine; Multienzyme Complexes; Neural Pathways; Neurons; Obesity; Protein Kinases; Protein Serine-Threonine Kinases; Rats; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; Starvation; Thinness; TOR Serine-Threonine Kinases

The mechanisms of the increased serum leptin in response to feeding are poorly understood. Therefore, we used metabolic labeling to directly assess leptin biosynthesis, secretion, and turnover in adipose tissue from 14 h-starved compared with fed 12-14 week old rats. Starvation decreased serum leptin (-47 +/- 7%), adipose tissue leptin content (-32 +/- 5%), and leptin secretion during 3 h of incubation (-65 +/- 12%). Starvation did not affect leptin mRNA levels but decreased rates of leptin biosynthesis by tissue fragments, as determined by [(35)S]methionine/cysteine incorporation into immunoprecipitable leptin. Insulin in vitro did not acutely increase leptin biosynthesis or rates of (125)I-leptin degradation. Pulse-chase studies showed that in adipose tissue from fed but not starved rats, insulin accelerated the secretion of [(35)S]leptin by approximately 2-fold after 30 and 60 min of chase. Degradation of newly synthesized leptin was slower in adipose tissue of starved than fed rats (half-lives of 50 and 150 min, respectively). Inhibitor experiments showed that both lysosomes and proteosomes contributed to leptin degradation. In conclusion, feeding compared with starvation influences leptin production at multiple posttranscriptional levels: synthesis, tissue storage, turnover, and secretion. The insulin-stimulated release of leptin from a preformed intracellular leptin pool may contribute to increases in serum leptin levels after meals.

Topics: Adipocytes; Adipose Tissue; Animals; Blotting, Northern; Body Weight; Chloroquine; Cycloheximide; Insulin; Iodine Isotopes; Leptin; Leupeptins; Lysosomes; Male; Rats; Rats, Wistar; RNA, Messenger; Starvation; Sulfur Isotopes

The decrease in leptin after energy restriction is a starvation signal to the brain. Several studies have found an association between this decrease and subjective appetite; however, no solid data are available on the acute decrease in fasting leptin concentration and subsequent caloric compensation.. The objective was to assess the effect of acute decreases in fasting leptin concentrations, induced by energy restriction, on subsequent energy intake compensation. We hypothesized that men with a large decrease in fasting leptin concentrations would have larger ad libitum energy intakes than would men with a small decrease in leptin.. Thirty-four male unrestrained eaters [age: 23 +/- 3 y; body mass index (in kg/m(2)): 22.3 +/- 1.6] participated in a semicontrolled intervention study. Fasting serum leptin and insulin concentrations were measured before and 2 d after 62% energy restriction. Energy intake was measured on the 2 following days on which food was provided ad libitum.. During energy restriction, fasting leptin and insulin concentrations decreased by 27.2% (95% CI: -34.4%, -19.9%) and 30.7% (95% CI: -41.0%, -20.4%), respectively. Subjects consumed 143 +/- 27% of their estimated energy requirements (18.3 +/- 2.9 MJ) on the first day and 124 +/- 20% (16.0 +/- 2.6 MJ) on the second day of ad libitum intake. No significant correlations were observed between decreases in fasting leptin or insulin concentrations and subsequent ad libitum energy intake; however, decreases in insulin were correlated with an increase in carbohydrate intake (r=-0.49, P < 0.01).. Although fasting leptin concentrations decreased significantly during energy restriction and subjects showed compensatory behavior during subsequent ad libitum food intake, no association was observed between the decrease in fasting leptin concentrations and caloric compensation.

Topics: Adult; Appetite; Confidence Intervals; Dietary Carbohydrates; Eating; Energy Intake; Energy Metabolism; Fasting; Humans; Insulin; Leptin; Male; Nutritional Requirements; Odds Ratio; Starvation

This study investigated the effect of starvation on mRNA levels of hepatic acyl coenzyme A synthetase (ACS), carnitine palmitoyltransferase-I (CPT-I), and acetyl coenzyme A carboxylase (ACC) and on serum concentrations of leptin, insulin, and glucose in male Sprague-Dawley rats.. Rats were fed an AIN-76 diet for 5 wk and then assigned to a normal group (NG) and a starvation group (SG). The SG was starved for 48 h and the NG was fasted for 12 h before being killed. Serum and hepatic lipids and serum levels of leptin, insulin, and glucose were determined. Expressions of ACS, CPT-1, and ACC mRNA were assessed in liver.. Serum concentrations of triacylglycerol and high-density lipoprotein cholesterol in the SG were lower than those in the NG. Serum concentrations of low-density lipoprotein cholesterol in the SG were significantly higher than in the NG. Hepatic concentrations of total lipid in the SG were significantly higher than those in the NG, and triacylglycerol concentrations in the SG were significantly lower than those in the NG. Serum concentrations of leptin and glucose in the SG were significantly lower than those in the NG. The ratio of abdominal fat to total body weight in the SG was lower than that in the NG. Hepatic ACS and CPT-I mRNA levels in the SG were significantly higher than those in the NG, but hepatic ACC mRNA levels were lower in the SG than in the NG.. We demonstrated that starvation increases hepatic levels of ACS and CPT-I and decreases transcription levels of ACC, implicating increases in fatty acid oxidation. This research demonstrates a coordinated regulation of ACS, CPT-I, and ACC mRNA levels and serves to enhance our understanding of the molecular mechanisms underlying fatty acid metabolism during starvation.

Topics: Abdomen; Acetyl-CoA Carboxylase; Adipose Tissue; Animals; Blood Glucose; Blotting, Northern; Body Weight; Carnitine O-Palmitoyltransferase; Cholesterol; Coenzyme A Ligases; Insulin; Leptin; Lipid Metabolism; Liver; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger; Starvation; Triglycerides

The objective of this work was to determine the effects of starvation versus refeeding following a high-sucrose diet (HS) or high-fat diet (HF) on fatty acid metabolism in mice.. The mice were fed an AIN-76 control diet (CD), a modified HS, or an HF. The three dietary groups were subdivided into three groups each: those fed experimental diets for 12 wk, mice starved for 48 h after 12 wk on an experimental diet, and those with the same starvation treatment but with 72 h of refeeding after starvation, respectively.. Serum total cholesterol levels of CD and HF groups decreased and then increased under starvation and refeeding states, respectively. Refeeding HS and HF increased serum levels of low-density lipoprotein (LDL) cholesterol compared with refeeding of the CD group. Starvation significantly increased hepatic levels of total cholesterol in the HS and HF groups compared with the CD group. Hepatic acyl coenzyme A (CoA) synthetase (ACS) levels in the CD and HS groups but not the HF group increased and then decreased under starved and refed states, respectively; an opposite regulation was observed in the HF group. Levels of hepatic acetyl-CoA carboxylase (ACC) in the HS and HF groups were significantly increased by refeeding. Hepatic levels of carnitine palmitoyltransferase-I mRNA were significantly enhanced by starvation and refeeding in the HS group but decreased in CD and then increased in the HF group.. Changes in dietary energy nutrients, fasting, and refeeding affect hepatic ACS, CPT-I, and ACC mRNA expression, and these results will serve to enhance our understanding of the molecular mechanisms underlying regulation of fatty acid metabolism.

Topics: Acetyl-CoA Carboxylase; Animals; Blood Glucose; Blotting, Northern; Body Weight; Carnitine O-Palmitoyltransferase; Cholesterol; Coenzyme A Ligases; Diet; Dietary Fats; Eating; Energy Intake; Fatty Acids; Gene Expression; Insulin; Leptin; Liver; Male; Mice; Mice, Inbred ICR; RNA, Messenger; Starvation; Sucrose; Sweetening Agents

Leptin can regulate several immune functions. However, the role of leptin on lymphocyte function has not been recognized in vivo. Accordingly, we have investigated the effect of leptin on starvation-induced immune dysfunction using diet-induced obese mice. To induce obesity, C57BL/6J mice were fed a high-fat diet for 14 weeks and control mice were fed a standard diet for the same period. The obese and control groups of mice were then starved for 48 h, and received intraperitoneal injections of recombinant leptin or phosphate-buffered saline four times during starvation. Other control mice in both diet groups were free fed without being starved. Although starvation of the control mice dramatically reduced the weights of the immune organs, cytokine production and increased proliferation of cultured splenocytes, these levels returned to those of the free-feeding groups with exogenous leptin administration. However, these effects of leptin were not observed in obese mice. These findings provide some evidence that leptin can regulate the immune function in vivo. It is also suggested that the action of leptin might not appear in obesity.

Topics: Animals; Cell Division; Cytokines; Female; Leptin; Liver; Lymphocyte Count; Lymphocytes; Mice; Mice, Inbred C57BL; Models, Animal; Obesity; Organ Size; Spleen; Starvation; Thymus Gland

Plasma osteocalcin, a marker of osteoblastic activity, is reduced in starvation, malnutrition, and anorexia nervosa, resulting in low bone turnover osteoporosis. Contradictory findings about the role of leptin as a link between nutritional status and bone physiology have been reported. We demonstrate that leptin-deficient ob/ob and leptin-resistant db/db male mice have increased plasma osteocalcin, and that in male ob/ob mice osteocalcin is not decreased by starvation, unlike control mice. Intraperitoneal leptin administration increased plasma osteocalcin in male ob/ob mice, and prevented its fall during 24h fasting and 5 days of food restriction in normal male mice. This effect may be mediated via actions on the hypothalamic-pituitary-testicular or -growth hormone axes, or a direct action on osteoblasts. These studies support the hypothesis that the fall in leptin during starvation and weight loss is responsible for the associated reduction in osteoblast activity, and suggest a role for leptin in regulating bone turnover.

Topics: Animals; Leptin; Male; Mice; Mice, Inbred BALB C; Obesity; Osteocalcin; Pituitary Hormones; Starvation

Genetically obese (fa/fa) Zucker rats display markedly elevated circulating leptin levels compared with their lean counterparts; this is expected because of the lack of a LepR-mediated feedback inhibition. The aim of this study was to determine the effect of the leptin receptor mutation in the Zucker rat on gastric leptin production and on the response to 14 hours of starvation. The response to a short-term period of food intake (20 minutes) on gastric leptin release was also analyzed.. Leptin mRNA expression in the gastric mucosa and in adipose tissue depots (epididymal, retroperitoneal, mesenteric, and inguinal) was assessed by reverse transcriptase-polymerase chain reaction and serum and stomach leptin content by enzyme-linked immunosorbent assay.. Obese Zucker rats overexpressed leptin in the stomach. They overexpress leptin in the inguinal adipose tissue but not in visceral adipose tissue depots, indicating tissue-specific obesity-dependent differences. Gastric leptin expression is regulated by feeding conditions in lean but not in obese (fa/fa) rats. In lean animals, leptin mRNA levels decrease in fasting conditions and increase rapidly with a short period of food intake. Obese Zucker rats also overdisplay stomach leptin levels. Feeding acutely stimulates leptin secretion by the stomach in lean, and to a lesser extent, in obese rats.. These results indicate impaired regulation of leptin expression in the stomach of obese (fa/fa) Zucker rats. However, there is still an effect of the nutritional status on gastric leptin levels despite the lack of a functional leptin receptor.

Topics: Adipose Tissue; Animals; Body Weight; Enzyme-Linked Immunosorbent Assay; Epididymis; Food; Gastric Mucosa; Gene Expression Regulation; Groin; Leptin; Male; Mesentery; Obesity; Rats; Rats, Zucker; Retroperitoneal Space; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Starvation

We compared the estradiol/progesterone-induced luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release between normally fed and leptin-supplemented starved ovariectomized female rats and studied also the effect of hyper-leptinaemia on the steroid-induced hormonal release in normally fed ovariectomized rats. Three days' starvation completely abolished steroid-induced LH and FSH release. Significant recovery of the hormonal release was shown in the leptin-supplemented starved group. The magnitudes of LH and FSH release in the normally fed animals with a higher dose of leptin were statistically the same as those in the normally fed group without leptin. These observations indicate that physiological concentrations of circulating leptin exert a stimulatory effect on steroid-induced LH and FSH release.

Topics: Analysis of Variance; Animals; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Follicle Stimulating Hormone; Hypothalamo-Hypophyseal System; Leptin; Luteinizing Hormone; Neuropeptide Y; Nitric Oxide; Ovariectomy; Rats; Reproductive Medicine; Starvation; Time Factors

HAP-1 is a huntingtin-associated protein that is enriched in the brain. To gain insight into the normal physiological role of HAP-1, mice were generated with homozygous disruption at the Hap1 locus. Loss of HAP-1 expression did not alter the gross brain expression levels of its interacting partners, huntingtin and p150glued. Newborn Hap1(-/-) animals are observed at the expected Mendelian frequency suggesting a non-essential role of HAP-1 during embryogenesis. Postnatally, Hap1(-/-) pups show decreased feeding behavior that ultimately leads to malnutrition, dehydration and premature death. Seventy percent of Hap1(-/-) pups fail to survive past the second postnatal day (P2) and 100% of Hap1(-/-) pups fail to survive past P9. From P2 until death, Hap1(-/-) pups show markedly decreased amounts of ingested milk. Hap1(-/-) pups that survive to P8 show signs of starvation including greatly decreased serum leptin levels, decreased brain weight and atrophy of the brain cortical mantel. HAP-1 is particularly enriched in the hypothalamus, which is well documented to regulate feeding behavior. Our results demonstrate that HAP-1 plays an essential role in regulating postnatal feeding.

Topics: Animal Nutritional Physiological Phenomena; Animals; Animals, Suckling; Body Constitution; Dynactin Complex; Eating; Homozygote; Huntingtin Protein; Hypothalamus; Leptin; Mice; Microtubule-Associated Proteins; Mutagenesis, Site-Directed; Nerve Tissue Proteins; Neurons; Nuclear Proteins; Starvation

Topics: Animals; Bees; Energy Metabolism; Immunity, Innate; Leptin; Starvation

Leptin, the protein product of the ob gene, is a potential placental growth factor and is integral to the body's system of energy regulation as shown in animal models. Premature infants are especially vulnerable to changes in energy regulation, and several studies have demonstrated a rapid fall in leptin values at birth. The purpose of the present investigation was to measure leptin levels in premature infants throughout hospitalization.. Eligible infants were less than 32 weeks' gestation, appropriate for gestational age, and hospitalized at Christiana Hospital Special Care Nursery. Serum samples for leptin analysis were drawn within 24 h of birth and twice a week thereafter until discharge. Concurrent growth measurements were obtained with each leptin sample. Body mass index, ponderal index, and midarm circumference/head circumference ratios were calculated to assess growth.. Leptin levels were low and remained low for the duration of the premature infants' hospitalization (mean +/- SD = 1.35 +/- 0.63 ng/ml/ml, range 0-3.06). After controlling for weight, there was a small (r(2) = 0.1, p < 0.00001) but significant correlation between leptin and postnatal age after 4 days of age. Despite an increase in caloric intake during the study period, there was no relationship between leptin and caloric intake. There were significant negative correlations between measurements of growth and both leptin and the leptin/weight ratio. Maternal diabetes and the use of steroids had small but significant effects on the leptin/weight ratio.. In this population of predominantly female premature infants, leptin levels were very low as compared to term infants, children and adults, and did not change appreciably over the study period. The low leptin levels seen in these premature infants are similar to those levels seen in malnourished adults, anorexics, and in animal models of starvation. We speculate that a critical adipose store needs to be reached before increased amounts of leptin can be adequately produced. Persistently low leptin levels may also reflect an immaturity in the hypothalamic-pituitary-adrenal axis.

Topics: Aging; Anthropometry; Body Mass Index; Energy Intake; Female; Gestational Age; Hospitalization; Humans; Infant, Newborn; Infant, Premature; Length of Stay; Leptin; Longitudinal Studies; Male; Regression Analysis; Starvation

Some hormonal disturbances were demonstrated in starvation. Leptin, NPY and galanin play an important role in the control of appetite and in the mechanism of hormone release.. In order to evaluate the effect of starvation on the relationship between leptin, neuropeptide Y (NPY) galanin and pituitary and gonadal hormones release, plasma leptin, NPY and galanin as well as serum LH, FSH, prolactin (PRL), estradiol, progesterone levels in non-starved female rats (in diestrus) and after 72 hrs of starvation were measured with RIA methods. Effects of leptin, NPY and galanin administration on pituitary and gonadal hormones were investigated in vivo and in vitro experiments.. Plasma leptin, NPY and galanin as well as serum estradiol and progesterone concentrations were significantly lower in starved rats as compared with non-starved rats. However serum prolactin level was significantly higher in starved rats. Opposite effects after leptin and NPY administration on hormone release in vivo and in vitro experiments were observed in non-starved rats. However, in starved rats we did not find changes in pituitary and gonadal hormones release after leptin, NPY and galanin injection or the hormonal response was blunted.. 1) The disturbances in neuropeptides activity and in hormones release were observed in starvation. 2) Leptin, NPY and galanin have direct and indirect effects on pituitary and gonadal hormones release. 3) In starvation the hormonal response to leptin, NPY and galanin is impaired.

Topics: Animals; Appetite Regulation; Energy Metabolism; Estradiol; Female; Follicle Stimulating Hormone; Galanin; Hormones; Leptin; Luteinizing Hormone; Neuropeptide Y; Neuropeptides; Progesterone; Prolactin; Rats; Starvation

During starvation, counterregulatory responses to loss of food (i.e. responses that lead to an increase in appetite) occur in the central nervous system (CNS). This study was designed to examine whether middle-aged rats show greater or smaller behavioural, peripheral and central hormonal responses during starvation compared to young rats. In experiment 1, refeeding following 4 days of starvation was measured in both middle-aged (72-week-old) and young (9-week-old) rats. The level of refeeding was similar to each prestarved level until 3 days after the end of starvation in both groups. From the 4th day, the level of refeeding in young rats increased and reached beyond the prestarved level, whereas refeeding in middle-aged rats remained similar to the prestarved level. Thus, overall refeeding throughout 7 days was greater in young rats than in middle-aged rats. In experiment 2, middle-aged and young rats were starved for 4 days and were killed in the morning. Middle-aged rats showed a smaller plasma corticosterone response than that of young rats. The magnitude of decreases in plasma glucose, insulin and leptin was similar in both groups. In the arcuate nucleus, the starvation-induced increase in neuropeptide Y (NPY) mRNA and the decrease in proopiomelanocortin (POMC) mRNA were smaller in middle-aged rats than in young rats. In contrast, the starvation-induced decrease in corticotrophin-releasing hormone (CRH) mRNA in the hypothalamic paraventricular nucleus was greater in middle-aged rats than young rats. The magnitude of decrease in type-2 CRH receptor mRNA in the ventromedial hypothalamus was similar in both groups. The results indicate that (a) ageing impaired refeeding response (b), middle-aged rats showed the same directional neuropeptide mRNA responses as seen in young rats during starvation and (c) the magnitude of these counterregulatory responses in the CNS in middle-aged versus young rats was not uniform, but rather was site-specific or neuropeptide-specific. This study suggests the importance of NPY and POMC responsiveness in the arcuate nucleus in the age-related differences resulting from starvation-induced refeeding.

Topics: Adrenocorticotropic Hormone; Aging; Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Corticosterone; Food; Hormones; Insulin; Leptin; Male; Neuropeptides; Protein Isoforms; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone; RNA, Messenger; Starvation

Topics: Adolescent; Age Factors; Analysis of Variance; Animals; Atrophy; Autopsy; Breast Feeding; Child; Cytokines; Data Interpretation, Statistical; Humans; Hypertrophy; Infant; Infant Food; Infant, Newborn; Leptin; Mice; Starvation; Sudden Infant Death; Thymus Gland; Ultrasonography

Topics: Agouti-Related Protein; alpha-MSH; Animals; Brain; Intercellular Signaling Peptides and Proteins; Leptin; Proteins; Receptors, Corticotropin; Receptors, Melanocortin; Starvation; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyrotropin-Releasing Hormone

To study the longitudinal changes in plasma levels of leptin, insulin and cortisol during the transition from the state of starvation to the state of refeeding focussing on diurnal secretion characteristics and their temporal relationships.. Leptin, insulin and cortisol were measured every 2h for 24h during acute starvation (T1). Sampling was repeated after reaching half the target-body mass index (BMI) (T2) and again at target-BMI (17. 5kg/m(2); T3). The temporal relationships between the diurnal secretion patterns were assessed by cross-correlation analysis.. Although BMIs at T1 were uniformly low, leptin levels varied widely within a range clearly below normal levels (0.03-1. 7microg/l). With increasing body fat during the course of refeeding, mean leptin levels increased from 0.64microg/l (range: 0.27-1. 73microg/l) (T1) to 1.61microg/l (range: 0.36-4.2microg/l) (T2) and to 3.67microg/l (range: 0.7-9.8microg/l) (T3). Circadian leptin secretion patterns showed maximal values uniformly around 0200h and minimal values around 0800h at all stages of the study. At all three weight levels, plasma leptin levels were highest between midnight and the early morning hours and lowest around the late morning hours. Refeeding neither profoundly changed secretion patterns of leptin nor did it change the positive, time-delayed relationship between leptin and insulin with increments in insulin secretion preceding those of leptin by 6h. A temporal relationship between leptin and cortisol could not be demonstrated in the state of semistarvation but emerged after a substantial weight gain; at that time, leptin increases preceded cortisol increases by 8h.. Absolute leptin, insulin and cortisol levels are profoundly changed during starvation in anorectic patients, while refeeding, paralleled by a BMI gain, reverses these changes. During refeeding the relationship between leptin and cortisol changed profoundly, showing no significant correlation in the state of starvation, whereas at T3 after refeeding a strong inverse relationship could be observed. Leptin and insulin did not correlate significantly at any of the three stages studied.

Topics: Adult; Anorexia Nervosa; Body Mass Index; Body Weight; Circadian Rhythm; Cohort Studies; Female; Food; Humans; Hydrocortisone; Insulin; Leptin; Longitudinal Studies; Male; Reference Values; Starvation

Malnutrition compromises immune function, reducing resistance to infection. We examine whether the decrease in leptin induced by starvation increases susceptibility to lipopolysaccharide (LPS)- and tumor necrosis factor (TNF)-induced lethality. In mice, fasting for 48 hours enhances sensitivity to LPS. Decreasing the fasting-induced fall in leptin by leptin administration markedly reduced sensitivity to LPS. Although fasting decreases basal leptin levels, LPS treatment increased leptin to the same extent as in fed animals. Fasting increased basal serum corticosterone; leptin treatment blunted this increase. Fasting decreased the ability of LPS to increase corticosterone; leptin restored the corticosterone response to LPS. Serum glucose levels were decreased in fasted mice and LPS induced a further decrease. Leptin treatment affected neither basal glucose nor that after LPS. LPS induced a fivefold greater increase in serum TNF in fasted mice, which was blunted by leptin replacement. In contrast, LPS induced lower levels of interferon-gamma and no differences in interleukin-1beta in fasted compared to fed animals; leptin had no effect on those cytokines. Furthermore, fasting increased sensitivity to the lethal effect of TNF itself, which was also reversed by leptin treatment. Thus, leptin seems to be protective by both inhibiting TNF induction by LPS and by reducing TNF toxicity.

Topics: Animals; Blood Glucose; Corticosterone; Cytokines; Disease Susceptibility; Fasting; Female; Leptin; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Shock, Septic; Starvation; Survival Analysis; Tumor Necrosis Factor-alpha

Leptin, the ob/ob gene product, is a recently discovered peptide hormone, secreted by adipocytes, which can act as a satiety factor to regulate food intake. Its levels thus will be related to the presence of food in the lumen of the gut, and food intake is one of the most potent stimuli for intestinal epithelial cell proliferation. Leptin has a variety of other actions and the aim of this study was to see if one of these was to stimulate mucosal growth.. Three groups of mice were fed ad libitum, starved for 48 h or starved for 48 h and given twice-daily intraperitoneal injections of recombinant leptin (1 microg/g).. Starvation led to a 20% decrease in body weight and a similar decrease in the weights of the intestines. Starvation also markedly inhibited intestinal epithelial cell proliferation. Leptin had little effect on the small intestine and did not stimulate proliferation. However, in the hind gut it was associated with small but significant decreases in caecal weight, distal colon mitotic counts (p = 0.036) and in colonic crypt area (approximately 20%, p<0.001).. Leptin did not stimulate intestinal cell proliferation, however it did have a paradoxical inhibitory action on the caecum and colon.

Topics: Animals; Body Weight; Cell Division; Colon; Epithelial Cells; Injections, Intraperitoneal; Intestinal Mucosa; Intestine, Small; Leptin; Male; Mice; Mice, Inbred C57BL; Organ Size; Recombinant Proteins; Starvation

Semi-starvation induced hyperactivity (SIH) occurs in rodents upon caloric restriction. We hypothesized that SIH is triggered by the decline in leptin secretion associated with food restriction. To test this hypothesis, rats, which had established a stable level of activity, were treated with leptin or vehicle via implanted minipumps concomitantly to initiation of food restriction for 7 days. In a second experiment treatment was initiated after SIH had already set in. In contrast to the vehicle-treated rats, which increased their baseline activity level by 300%, the development of SIH was suppressed by leptin. Furthermore, leptin was able to stop SIH, after it had set in. These results underscore the assumed major role of leptin in the adaptation to semi-starvation. Because SIH has been viewed as a model for anorexia nervosa, we also assessed subjective ratings of motor restlessness in 30 patients with this eating disorder in the emaciated state associated with hypoleptinemia and after increments in leptin secretion brought upon by therapeutically induced weight gain. Hypoleptinemic patients ranked their motor restlessness higher than upon attainment of their maximal leptin level during inpatient treatment. Thus, hypoleptinemia might also contribute to the hyperactivity frequently associated with anorexia nervosa.

Topics: Animals; Anorexia Nervosa; Appetite; Energy Intake; Energy Metabolism; Hyperkinesis; Infusion Pumps, Implantable; Leptin; Male; Neurosecretory Systems; Physical Conditioning, Animal; Rats; Rats, Wistar; Starvation; Weight Gain

To identify the sequences of changes in putative signals, reception of these and responses to starvation, we sampled fed and starved rats at 2- to 6-h intervals after removal of food 2 h before dark. Metabolites, hormones, hypothalamic neuropeptide expression, fat depots, and leptin expression were measured. At 2 h, insulin decreased, and FFA and corticosterone (B) increased; by 4 h, leptin and glucose levels decreased. Neuropeptide Y messenger RNA (mRNA) increased 6 h after food removal and thereafter. Adrenal and plasma B did not follow ACTH and were elevated throughout, with a nadir at the dark-light transition. Leptin correlated inversely with adrenal B. Fat stores decreased during the last 12 h. Leptin mRNA in perirenal and sc fat peaked during the dark period, resembling plasma leptin in fed rats. We conclude that 1) within the first 4 h, hormonal and metabolic signals relay starvation-induced information to the hypothalamus; 2) hypothalamic neuropeptide synthesis responds rapidly to the altered metabolic signals; 3) catabolic activity quickly predominates, reinforced by elevated B, not driven by ACTH, but possibly to a minor extent by leptin, and more by adrenal neural activity; and 4) leptin secretion decreases before leptin mRNA or fat depot weight, showing synthesis-independent regulation.

Topics: Adipose Tissue; Animals; Body Weight; Eating; Hormones; Hypothalamo-Hypophyseal System; Hypothalamus; Leptin; Male; Neuropeptides; Organ Size; Pituitary-Adrenal System; Proteins; Rats; Starvation

Thymic atrophy is a prominent feature of malnutrition. Forty-eight hours' starvation of normal mice reduced the total thymocyte count to 13% of that observed in freely fed controls, predominantly because of a diminution in the cortical CD4(+)CD8(+) thymocyte subpopulation. Prevention of the fasting-induced fall in the level of the adipocyte-derived hormone leptin by administering exogenous recombinant leptin protected mice from these starvation-induced thymic changes. The ob/ob mouse, which is unable to produce functional leptin because of a mutation in the obese gene, has impaired cellular immunity together with a marked reduction in the size and cellularity of the thymus. We found that ob/ob mice had a high level of thymocyte apoptosis resulting in a ratio of CD4(+)CD8(+) (cortical) to CD4(-)CD8(-) (precursor) thymocytes that was 4-fold lower than that observed in wild-type mice. Peripheral administration of recombinant leptin to ob/ob mice reduced thymocyte apoptosis and substantially increased both thymic cellularity and the CD4(+)CD8(+)/CD4(-)CD8(-) ratio. In contrast, a comparable weight loss in pair-fed PBS-treated ob/ob mice had no impact on thymocyte number. In vitro, leptin protected thymocytes from dexamethasone-induced apoptosis. These data indicate that reduced circulating leptin concentrations are pivotal in the pathogenesis of starvation-induced lymphoid atrophy.

Topics: Animals; Annexin A5; Apoptosis; Atrophy; Dexamethasone; Insulin; Leptin; Lymphoid Tissue; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Starvation; Thymus Gland

Nutritional deprivation suppresses immune function. The cloning of the obese gene and identification of its protein product leptin has provided fundamental insight into the hypothalamic regulation of body weight. Circulating levels of this adipocyte-derived hormone are proportional to fat mass but maybe lowered rapidly by fasting or increased by inflammatory mediators. The impaired T-cell immunity of mice now known to be defective in leptin (ob/ob) or its receptor (db/db), has never been explained. Impaired cell-mediated immunity and reduced levels of leptin are both features of low body weight in humans. Indeed, malnutrition predisposes to death from infectious diseases. We report here that leptin has a specific effect on T-lymphocyte responses, differentially regulating the proliferation of naive and memory T cells. Leptin increased Th1 and suppressed Th2 cytokine production. Administration of leptin to mice reversed the immunosuppressive effects of acute starvation. Our findings suggest a new role for leptin in linking nutritional status to cognate cellular immune function, and provide a molecular mechanism to account for the immune dysfunction observed in starvation.

Topics: Adult; Animals; Carrier Proteins; CD4-Positive T-Lymphocytes; Humans; Immune Tolerance; Immunologic Memory; In Vitro Techniques; Interferon-gamma; Interleukin-2; Interleukin-4; Leptin; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Proteins; Receptors, Cell Surface; Receptors, Cytokine; Receptors, Leptin; Recombinant Proteins; Starvation; T-Lymphocytes

In the rat, high-dose corticosterone (Cort) administration, the hypercortisolism of starvation, and adrenalectomy are all associated with decreased food intake and weight loss. We report here a study of the effects of high-dose Cort administration, starvation, and adrenalectomy on two peripheral hormones known to influence food intake and energy use, insulin and leptin. We also studied the impact of these interventions on the levels of type 2 corticotropin-releasing hormone receptor (CRHR-2) mRNA in the hypothalamic paraventricular nucleus (PVN) and ventromedial hypothalamus (VMH). The VMH is classically referred to as the satiety center because electrical stimulation of the VMH leads to inhibition of food intake, whereas CRHR-2 are thought to transduce the profound anorexogenic effects of CRH or its related peptide urocortin. Starvation and adrenalectomy each lowered plasma insulin and leptin levels and were associated with decrements in CRHR-2 mRNA levels in the VMH. Cort administration increased plasma leptin levels profoundly, as well as plasma insulin levels and the levels of VMH CRHR-2 mRNA. Under all experimental conditions, a positive correlation was seen between plasma leptin levels and VMH CRHR-2 mRNA. These data suggest that decreased food intake and weight loss after high-dose Cort administration at least partially depend on the profound impact of Cort on plasma leptin secretion in the rat; they suggest, moreover, an additional mechanism for the satiety-inducing effects of leptin, namely increasing CRHR-2 in the VMH. The concordance of a fall in plasma insulin and leptin levels with the fall in VMH CRHR-2 mRNA levels further supports the idea that compensatory responses during starvation and adrenalectomy include not only the disinhibiting effects of reduced insulin and leptin levels on appetite through already-described mechanisms but also via an effect of leptin on VMH CRHR-2. Neither Cort administration, starvation, nor adrenalectomy influenced the levels of CRHR-2 mRNA in the PVN, suggesting that these receptors are differentially regulated in different hypothalamic regions.

Topics: Adrenalectomy; Animals; Blood Glucose; Corticosterone; Energy Intake; Feeding Behavior; Gene Expression Regulation; Insulin; Leptin; Male; Proteins; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone; RNA, Messenger; Starvation; Transcription, Genetic; Ventromedial Hypothalamic Nucleus

Topics: Humans; Immune Tolerance; Leptin; Models, Immunological; Nutrition Disorders; Obesity; Proteins; Starvation

Topics: Agouti Signaling Protein; alpha-MSH; Animals; Body Weight; Carrier Proteins; Hormones; Humans; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Obese; Neuropeptide Y; Obesity; Proteins; Receptors, Cell Surface; Receptors, Corticotropin; Receptors, Leptin; Receptors, Melanocortin; Starvation

The ob gene product leptin is secreted from adipose tissue. Leptin has dramatic effects on food intake and energy expenditure in rodents. Brown adipose tissue is the first form of adipose tissue to appear during development, and is present at birth in most species. The development of a leptin feedback system in early life and the relative role of the brown and white adipose tissues have not yet been revealed. We have investigated the expression of ob/leptin mRNA in brown adipose tissue around birth and with respect to feeding. Northern blotting analysis and in situ hybridization experiments demonstrated the presence of leptin mRNA in brown adipose tissue at 0, 18, and 24 h after birth. The leptin mRNA level was decreased at 8 h postpartum in fed animals and at 18 or 24 h in the absence of feeding. In addition, circulating leptin was detected in the plasma of newborn rats at 0, 10, or 24 h after birth, whereas it was not detectable in 10 h-old animals that did not suckle at their mother. The presence at birth of ob mRNA and circulating leptin, as well as the early effect of suckling on ob mRNA levels, suggests the precocious involvement of leptin in the control of food intake.

Topics: Adipose Tissue, Brown; Animals; Animals, Newborn; Animals, Suckling; Gene Expression; In Situ Hybridization; Leptin; Protein Biosynthesis; Rats; Rats, Wistar; RNA, Messenger; Starvation; Time Factors

Mitochondrial uncoupling proteins (UCPs) are transporters that are important for thermogenesis. The net result of their activity is the exothermic movement of protons through the inner mitochondrial membrane, uncoupled from ATP synthesis. We have cloned a third member of the UCP family, UCP3. UCP3 is expressed at high levels in muscle and rodent brown adipose tissue. Overexpression in yeast reduced the mitochondrial membrane potential, showing that UCP3 is a functional uncoupling protein. UCP3 RNA levels are regulated by hormonal and dietary manipulations. In contrast, levels of UCP2, a widely expressed UCP family member, showed little hormonal regulation. In particular, muscle UCP3 levels were decreased 3-fold in hypothyroid rats and increased 6-fold in hyperthyroid rats. Thus UCP3 is a strong candidate to explain the effects of thyroid hormone on thermogenesis. White adipose UCP3 levels were greatly increased by treatment with the beta3-adrenergic agonist, CL214613, suggesting another pathway for increasing thermogenesis. UCP3 mRNA levels were also regulated by dexamethasone, leptin, and starvation, albeit differently in muscle and brown adipose tissue. Starvation caused increased muscle and decreased BAT UCP3, suggesting that muscle assumes a larger role in thermoregulation during starvation. The UCP3 gene is located close to that encoding UCP2, in a chromosomal region implicated in previous linkage studies as contributing to obesity.

Topics: Adrenergic alpha-Agonists; Animals; Body Temperature Regulation; Carrier Proteins; Glucocorticoids; Ion Channels; Leptin; Male; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Molecular Sequence Data; Proteins; Rats; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; Receptors, Leptin; RNA, Messenger; Starvation; Thyroid Hormones; Uncoupling Protein 3

The ob gene mRNA expression in rat brown adipose tissue (BAT) and epididymal white adipose tissue (WAT) was measured on Northern blots hybridized with a rat ob gene probe. The level of ob gene mRNA in BAT was about 40% of that in WAT. Fasting (36 h) or semi-starvation (10 days) decreased the ob gene mRNA level in both tissues by 62-68%, and cold exposure at 6 degrees C (24 h) decreased it in BAT (-84%) but not in WAT. Acute administration of the beta 3-adrenergic agonist Ro 16-8714 decreased the ob gene mRNA level in BAT (-51%) and WAT (-28%) of lean Zucker rats and only in BAT (-74%) of obese falfa rats. This study demonstrates that, in the rat, the ob gene is not only expressed in WAT but also in BAT, and suggests that in these two tissues, the modulation of the ob gene expression might be more closely associated with known alterations in cell lipid content than with changes in sympathetic activity.

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Base Sequence; DNA Primers; Epididymis; Fasting; Gene Expression; Leptin; Male; Molecular Sequence Data; Obesity; Organ Specificity; Polymerase Chain Reaction; Protein Biosynthesis; Rats; Rats, Mutant Strains; Rats, Sprague-Dawley; RNA, Messenger; Starvation