neuropeptide-y and Hyperinsulinism

To study the impact on glucose handling of the observed hyperinsulinaemia and hypercorticism of the genetically obese fa/fa rats, simplified animal models were used. In the first model, normal rats were exposed to hyperinsulinaemia for 4 days and compared to saline-infused controls. At the end of this experimental period, the acute effect of insulin was assessed during euglycaemic-hyperinsulinaemic clamps. White adipose tissue lipogenic activity was much more insulin responsive in the "insulinized" than in the control groups. Conversely muscles from "insulinized" rats became insulin resistant. Such divergent consequences of prior "insulinization" on white adipose tissue and muscle were corroborated by similar divergent changes in glucose transporter (GLUT 4) mRNA and protein levels in these respective tissues. In the second model, normal rats were exposed to stress levels of corticosterone for 2 days. This resulted in an insulin resistance of all muscle types that was due to an increased glucose-fatty acid cycle, without measurable alteration of the GLUT 4 system. In genetically obese (fa/fa) rats, local cerebral glucose utilization was decreased compared to lean controls. This could be the reason for adaptive changes leading to increased levels in their hypothalamic neuropeptide Y levels and median eminence corticotropin-releasing-factor. Thus, in a third model, neuropeptide Y was administered intracerebroventricularly to normal rats for 7 days. This produced hyperinsulinaemia, hypercorticosteronaemia, as well as most of the metabolic changes observed in the genetically obese fa/fa rats, including muscle insulin resistance. These data together suggest that the aetiology of obesity-insulin resistance of genetically obese rodents has to be searched within the brain, not peripherally.

Topics: Animals; Awards and Prizes; Brain; Central Nervous System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Europe; Glucose; Glucose Transporter Type 4; History, 20th Century; Humans; Hyperinsulinism; Hypothalamus; Monosaccharide Transport Proteins; Muscle Proteins; Neuropeptide Y; Obesity; Peripheral Nervous System Diseases; Rats; Rats, Mutant Strains; Societies, Medical; Switzerland

Insulin, ghrelin, neuropeptide Y (NPY) and leptin interact in the regulation of energy homeostasis. Most of these signals are altered in polycystic ovary syndrome (PCOS), which is characterized by a high prevalence of obesity. The present study was conducted to evaluate ghrelin-NPY and ghrelin-leptin interplays in relation to insulin secretion in obese PCOS subjects.. Pilot prospective study.. Seven obese PCOS women and seven age-weight matched controls.. Hormonal measurements, oral glucose tolerance test (OGTT) and a ghrelin test (1 microg/kg i.v. bolus). PCOS patients repeated the clinical work-up after 4 months of metformin treatment (1500 mg/day orally).. At baseline, PCOS women showed a significantly higher insulinaemic response to the OGTT compared to controls (P < 0.05). In basal conditions, PCOS women exhibited lower NPY levels than controls (P < 0.01). Ghrelin injection markedly increased NPY in controls (P < 0.01), whereas PCOS women showed a deeply blunted NPY response to the stimulus (area under the curve--AUC-NPY: P < 0.01 vs. controls.). Metformin treatment induced a significant decrease in insulin levels (P < 0.01) and the concomitant recovery of NPY secretory capacity in response to ghrelin (AUC-NPY: P < 0.05 vs. baseline) in PCOS women. Leptin levels, which were similar in the two groups, were not modified by ghrelin injection; metformin did not affect this pattern.. Hyperinsulinaemia seems to play a pivotal role in the alteration of NPY response to ghrelin in obese PCOS women. This derangement could be implicated in the physiopatology of obesity in these patients.

Topics: Adult; Female; Ghrelin; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Leptin; Metformin; Neuropeptide Y; Obesity; Pilot Projects; Polycystic Ovary Syndrome; Signal Transduction; Young Adult

An adverse intrauterine environment may induce adult disease in offspring, but the mechanisms are not well understood. It is reported that fresh embryo transfer (ET) in assisted reproductive technology leads to high maternal estradiol (E2), and prenatal high E2 exposure increases the risk of organ disorders in later life. We found that male newborns and children of fresh ET showed elevated fasting insulin and homeostasis model of assessment for insulin resistance index (HOMA-IR) scores. Male mice with high prenatal estradiol exposure (HE) grew heavier than control mice and developed insulin resistance; they also showed increased food intake, with increased orexigenic hypothalamic neuropeptide Y (NPY) expression. The hypothalamic insulin receptor (INSR) was decreased in male HE mice, associated with elevated promoter methylation. Chronic food restriction (FR) in HE mice reversed insulin resistance and rescued hypothalamic INSR expression by correcting the elevated Insr promoter methylation. Our findings suggest that prenatal exposure to high E2 may induce sex-specific metabolic disorders in later life through epigenetic programming of hypothalamic Insr promoter, and dietary intervention may reverse insulin resistance by remodeling its methylation pattern.

Topics: Animals; Child; Child, Preschool; Embryo Transfer; Energy Intake; Estradiol; Female; Fertility Agents, Female; Gene Expression Regulation, Developmental; Humans; Hyperinsulinism; Hypothalamus; Infant, Newborn; Insulin Resistance; Male; Mice, Inbred C57BL; Neurons; Neuropeptide Y; Pregnancy; Prenatal Exposure Delayed Effects; Random Allocation; Receptor, Insulin; Weight Gain

The adipocyte-derived cytokine leptin acts as a metabolic switch, connecting the body's metabolism to high-energy consuming processes such as reproduction and immune responses. Accumulating evidence suggests that leptin plays a role in human pathologies, such as autoimmune diseases and cancer, thus providing a rationale for the development of leptin antagonists. In the present study, we generated and evaluated a panel of neutralizing nanobodies targeting the LR (leptin receptor). A nanobody comprises the variable domain of the naturally occurring single-chain antibodies found in members of the Camelidae family. We identified three classes of neutralizing nanobodies targeting different LR subdomains: i.e. the CRH2 (cytokine receptor homology 2), Ig-like and FNIII (fibronectin type III) domains. Only nanobodies directed against the CRH2 domain inhibited leptin binding. We could show that a nanobody that targets the Ig-like domain potently interfered with leptin-dependent regulation of hypothalamic NPY (neuropeptide Y) expression. As a consequence, daily intraperitoneal injection increased body weight, body fat content, food intake, liver size and serum insulin levels. All of these characteristics resemble the phenotype of leptin and LR-deficient animals. The results of the present study support proposed models of the activated LR complex, and demonstrate that it is possible to block LR signalling without affecting ligand binding. These nanobodies form new tools to study the mechanisms of BBB (blood-brain barrier) leptin transport and the effect of LR inhibition in disease models.

Topics: Adipose Tissue; Animals; Antibodies; Camelids, New World; Gene Expression Regulation; HEK293 Cells; Humans; Hyperinsulinism; Leptin; Liver; Mice; Mice, Inbred C57BL; Nanostructures; Neuropeptide Y; Organ Size; Protein Binding; Protein Structure, Tertiary; Receptors, Leptin; Signal Transduction; Weight Gain

Hormonal and metabolic factors signal the status of energy balance to hypothalamic nuclei. Obesity is characterized by neuronal, metabolic and hormonal alterations. We therefore hypothesized that hypothalamic responses to challenges of energy balance may differ between lean and obese animals. To test this, we compared c-Fos expression in the hypothalamic arcuate (ARC) and paraventricular nuclei (PVN) and the lateral hypothalamic area (LHA) of mice (1-year-old) with late-onset obesity (LOO) and of lean controls under different feeding conditions. Fourteen hours of fasting induced high c-Fos expression in neuropeptide-Y-positive ARC neurons, in the PVN and in the rostral LHA in lean but not in LOO mice. c-Fos expression in melanin-concentrating hormone (MCH) and orexin-containing neurons in the caudal LHA was not affected by fasting. LOO mice showed fasting hyperinsulinemia, hyperleptinemia, elevated fasting blood glucose and an attenuated hyperphagic response during refeeding. Moreover, the anorectic response to leptin and hypoglycemic response to insulin were reduced in LOO mice. We conclude that adiposity blunts the neuronal responses to metabolic challenges in hypothalamic centers which control feeding behavior and energy balance. Elevated blood glucose may be one factor that suppresses hypothalamic responsiveness in obese mice. A similar impact of hyperinsulinemia and hyperleptinemia in LOO mice is also likely although under the current experimental conditions responsiveness to some effects of these hormones appeared to be reduced.

Topics: Age of Onset; Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Fasting; Green Fluorescent Proteins; Hyperinsulinism; Hyperphagia; Hypothalamic Area, Lateral; Intracellular Signaling Peptides and Proteins; Leptin; Male; Melanins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Paraventricular Hypothalamic Nucleus; Proto-Oncogene Proteins c-fos

We recently showed that intracerebroventricular infusion of neuropeptide Y (NPY) hampers inhibition of endogenous glucose production (EGP) by insulin in mice. The downstream mechanisms responsible for these effects of NPY remain to be elucidated. Therefore, the aim of this study was to establish whether intracerebroventricular NPY administration modulates the suppressive action of insulin on EGP via hepatic sympathetic or parasympathetic innervation.. The effects of a continuous intracerebroventricular infusion of NPY on glucose turnover were determined in rats during a hyperinsulinemic-euglycemic clamp. Either rats were sham operated, or the liver was sympathetically (hepatic sympathectomy) or parasympathetically (hepatic parasympathectomy) denervated.. Sympathectomy or parasympathectomy did not affect the capacity of insulin to suppress EGP in intracerebroventricular vehicle-infused animals (50 +/- 8 vs. 49 +/- 6 vs. 55 +/- 6%, in hepatic sympathectomy vs. hepatic parasympathectomy vs. sham, respectively). Intracerebroventricular infusion of NPY significantly hampered the suppression of EGP by insulin in sham-denervated animals (29 +/- 9 vs. 55 +/- 6% for NPY/sham vs. vehicle/sham, respectively, P = 0.038). Selective sympathetic denervation of the liver completely blocked the effect of intracerebroventricular NPY administration on insulin action to suppress EGP (NPY/hepatic sympathectomy, 57 +/- 7%), whereas selective parasympathetic denervation had no effect (NPY/hepatic parasympathectomy, 29 +/- 7%).. Intracerebroventricular administration of NPY acutely induces insulin resistance of EGP via activation of sympathetic output to the liver.

Topics: Animals; Blood Glucose; Glucose Clamp Technique; Hyperinsulinism; Hypoglycemic Agents; Injections, Intraventricular; Insulin; Insulin Resistance; Liver; Male; Neuropeptide Y; Parasympathectomy; Rats; Rats, Wistar; Sympathectomy; Sympathetic Nervous System

Two known types of leptin-responsive neurons reside within the arcuate nucleus: the agouti gene-related peptide (AgRP)/neuropeptide Y (NPY) neuron and the proopiomelanocortin (POMC) neuron. By deleting the leptin receptor gene (Lepr) specifically in AgRP/NPY and/or POMC neurons of mice, we examined the several and combined contributions of these neurons to leptin action. Body weight and adiposity were increased by Lepr deletion from AgRP and POMC neurons individually, and simultaneous deletion in both neurons (A+P LEPR-KO mice) further increased these measures. Young (periweaning) A+P LEPR-KO mice exhibit hyperphagia and decreased energy expenditure, with increased weight gain, oxidative sparing of triglycerides, and increased fat accumulation. Interestingly, however, many of these abnormalities were attenuated in adult animals, and high doses of leptin partially suppress food intake in the A+P LEPR-KO mice. Although mildly hyperinsulinemic, the A+P LEPR-KO mice displayed normal glucose tolerance and fertility. Thus, AgRP/NPY and POMC neurons each play mandatory roles in aspects of leptin-regulated energy homeostasis, high leptin levels in adult mice mitigate the importance of leptin-responsiveness in these neurons for components of energy balance, suggesting the presence of other leptin-regulated pathways that partially compensate for the lack of leptin action on the POMC and AgRP/NPY neurons.

Topics: Agouti-Related Protein; Animals; Body Composition; Eating; Energy Metabolism; Fertility; Hyperinsulinism; Hyperphagia; Lactation; Male; Mice; Neuropeptide Y; Pro-Opiomelanocortin; Receptors, Leptin

The ATP-sensitive potassium (K(ATP)) channels are gated by intracellular adenine nucleotides coupling cell metabolism to membrane potential. Channels comprised of Kir6.2 and SUR1 subunits function in subpopulations of mediobasal hypothalamic (MBH) neurons as an essential component of a glucose-sensing mechanism in these cells, wherein uptake and metabolism of glucose leads to increase in intracellular ATP/ADP, closure of the channels, and increase in neuronal excitability. However, it is unknown whether glucose and/or insulin may also regulate the gene expression of the channel subunits in the brain. The present study investigated whether regulation of K(ATP) channel subunit gene expression might be a mechanism by which neuronal populations adapt to prolonged changes in glucose and/or insulin levels in the periphery. Ovariectomized, steroid-replaced rats were fitted with indwelling jugular catheters and infused for 48 h with saline, glucose (hyperglycemia-hyperinsulinemia), insulin and glucose (hyperinsulinemia), diazoxide (control), or glucose and diazoxide (hyperglycemia). At the end of infusions, the MBH, preoptic area, and pituitary were dissected for RNA isolation and RT-PCR. Hyperglycemia decreased Kir6.2 mRNA levels in the MBH in both the presence and absence of hyperinsulinemia. These same conditions also produced a trend toward decreased SUR1 mRNA levels in the MBH; however, it did not exceed statistical significance. Hyperglycemia increased whereas hyperinsulinemia reduced neuropeptide Y mRNA levels when these groups were compared with each other. However, neither was significantly different from values observed in saline-infused controls. In conclusion, hyperglycemia per se may alter expression of K(ATP) channels and thereby induce changes in the excitability of some MBH neurons.

Topics: Animals; ATP-Binding Cassette Transporters; Blood Glucose; Brain; Diazoxide; Drug Combinations; Estrogens; Female; Gene Expression Regulation; Glucose; Hyperglycemia; Hyperinsulinism; Hypothalamus; Infusions, Intravenous; Insulin; Multidrug Resistance-Associated Proteins; Neuropeptide Y; Osmolar Concentration; Ovariectomy; Potassium Channels, Inwardly Rectifying; Pro-Opiomelanocortin; Progesterone; Rats; Receptors, Drug; RNA, Messenger; Sulfonylurea Receptors

The link between obesity and diabetes is not fully understood but there is evidence to suggest that hypothalamic signalling pathways may be involved. The hypothalamic neuropeptides, pro-opiomelanocortin (POMC), neuropeptide Y (NPY) and agouti-related protein (AGRP) are central to the regulation of food intake and have been implicated in glucose homeostasis. Therefore, the expression of these genes was quantified in hypothalami from diabetic Zucker fatty (ZDF) rats and nondiabetic Zucker fatty (ZF) rats at 6, 8, 10 and 14 weeks of age. Although both strains are obese, only ZDF rats develop pancreatic degeneration and diabetes over this time period. In both ZF and ZDF rats, POMC gene expression was decreased in obese versus lean rats at all ages. By contrast, although there was the expected increase in both NPY and AGRP expression in obese 14-week-old ZF rats, the expression of NPY and AGRP was decreased in 6-week-old obese ZDF rats with hyperinsulinaemia and in 14-week-old rats with the additional hyperglycaemia. Therefore, candidate genes involved in glucose, and insulin signalling pathways were examined in obese ZDF rats over this age range. We found that expression of the ATP-sensitive potassium (K(ATP)) channel component, Kir6.2, was decreased in obese ZDF rats and was lower compared to ZF rats in each age group tested. Furthermore, immunofluorescence analysis showed that Kir6.2 protein expression was reduced in the dorsomedial and ventromedial hypothalamic nuclei of 6-week-old prediabetic ZDF rats compared to ZF rats. The Kir6.2 immunofluorescence colocalised with NPY throughout the hypothalamus. The differences in Kir6.2 expression in ZF and ZDF rats mimic those of NPY and AGRP, which could infer that the changes occur in the same neurones. Overall, these data suggest that chronic changes in hypothalamic Kir6.2 expression may be associated with the development of hyperinsulinaemia and hyperglycaemia in ZDF rats.

Topics: Agouti-Related Protein; Animals; Diabetes Mellitus; Gene Expression; Glucose; Hyperglycemia; Hyperinsulinism; Hypothalamus; Immunohistochemistry; Inflammation; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Pancreas; Potassium Channels, Inwardly Rectifying; Pro-Opiomelanocortin; Rats; Rats, Wistar; Rats, Zucker; Signal Transduction

Neuropeptide Y (NPY) is a key regulator of energy homeostasis and is implicated in the development of obesity and type 2 diabetes. Whereas it is known that hypothalamic administration of exogenous NPY peptides leads to increased body weight gain, hyperphagia, and many hormonal and metabolic changes characteristic of an obesity syndrome, the Y receptor(s) mediating these effects is disputed and unclear. To investigate the role of different Y receptors in the NPY-induced obesity syndrome, we used recombinant adeno-associated viral vector to overexpress NPY in mice deficient of selective single or multiple Y receptors (including Y1, Y2, and Y4). Results from this study demonstrated that long-term hypothalamic overexpression of NPY lead to marked hyperphagia, hypogonadism, body weight gain, enhanced adipose tissue accumulation, hyperinsulinemia, and other hormonal changes characteristic of an obesity syndrome. NPY-induced hyperphagia, hypogonadism, and obesity syndrome persisted in all genotypes studied (Y1(-/-), Y2(-/-), Y2Y4(-/-), and Y1Y2Y4(-/-) mice). However, triple deletion of Y1, Y2, and Y4 receptors prevented NPY-induced hyperinsulinemia. These findings suggest that Y1, Y2, and Y4 receptors under this condition are not crucially involved in NPY's hyperphagic, hypogonadal, and obesogenic effects, but they are responsible for the central regulation of circulating insulin levels by NPY.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Female; Humans; Hyperinsulinism; Hyperphagia; Hypothalamus; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y

The effects of diet and adiposity have been implicated in disturbances of female reproductive function. In an effort to better elucidate the relationship between obesity and female fertility, we analyzed the effect of increasing dietary fat content on body composition, insulin sensitivity, and pregnancy rates in two common inbred mouse strains, DBA/2J and C57BL/6J. After 16 wk, females of both strains on the high fat diet developed glucose intolerance and insulin resistance, but only the female DBA/2J mice developed dietary-induced obesity and hyperleptinemia. The high fat diet was associated with more than a 60% decrease in natural pregnancy rates of female DBA/2J mice, whereas the fertility of female C57BL/6J mice was unaffected. Despite developing a similar degree of obesity, insulin resistance, and hyperleptinemia, male DBA/2J mice did not manifest diminished fertility. Obese female DBA/2J mice achieved normal ovulatory responses and pregnancy rates after exogenous gonadotropin stimulation, suggesting their fertility defect to be central in origin. Real-time PCR quantification of hypothalamic cDNA revealed a 100% up-regulation of neuropeptide Y and a 50% suppression of GnRH expression accompanied by a 95% attenuation of leptin receptor type B expression in obese female DBA/2J mice. These findings suggest that obesity-associated hyperleptinemia, and not insulin resistance or increased dietary fat per se, gradually induces central leptin resistance, increases hypothalamic neuropeptide Y-ergic tone, and ultimately causes hypothalamic hypogonadism. The data establish high fat-fed female DBA/2J mice as a wild-type murine model of obesity-related infertility.

Topics: Animals; Body Composition; Dietary Fats; Female; Gene Expression; Hyperinsulinism; Hypothalamus; Infertility, Female; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neuropeptide Y; Obesity; Pregnancy; Receptors, Cell Surface; Receptors, Leptin; Repressor Proteins; Species Specificity; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factors

Central administration of neuropeptide Y (NPY) stimulates hyperphagia and hyperinsulinemia. Recent evidence has suggested that the Y1 and Y5 receptor subtypes may both mediate NPY-stimulated feeding. The present study attempts to further characterize the role of central NPY receptor subtypes involved in hyperinsulinemia. NPY and peptide analogs of NPY that selectively activated the NPY Y1 or Y5 receptor subtype induced feeding and hyperinsulinemia in satiated Long Evans rats, whereas NPY analogs that selectively activated the NPY Y2 or Y4 receptor subtype did not. To determine whether NPY-induced hyperinsulinemia is secondary to its hyperphagic effect, we compared the plasma insulin levels in the presence and absence of food after a 1-min central infusion of NPY and its analogs at 15, 60, and 120 min postinfusion. Our data suggest that selective activation of central NPY Y1 receptor subtype induced hyperinsulinemia independent of food ingestion, whereas the NPY Y5 receptor-induced hyperinsulinemia was dependent on food ingestion. Central administration of the selective Y1 receptor agonist D-Arg25 NPY eventually decreased plasma glucose levels 2 h postinfusion in Long Evans rats.

Topics: Animals; Biotransformation; Blood Glucose; Eating; Glucagon; Hyperinsulinism; Injections, Intraventricular; Insulin; Male; Neuropeptide Y; Rats; Rats, Long-Evans; Receptors, Neuropeptide Y

Recent evidence demonstrates that hypothalamic insulin signaling is required for inhibition of endogenous glucose production. The downstream mechanisms that are responsible for the effects of hypothalamic insulin receptor activation on hepatic fuel flux remain to be determined. To establish whether downregulation of neuropeptide Y (NPY) release by insulin is mandatory for its capacity to suppress glucose production, we examined the effects of a continuous intracerebroventricular (ICV) infusion of NPY (10 microg/h for 3-5 h) on glucose flux during a hyperinsulinemic-euglycemic clamp in mice. We also evaluated the effects of ICV NPY administration on free fatty acid and glycerol flux and VLDL production in this experimental context. In basal conditions, none of the metabolic parameters was affected by NPY infusion. In hyperinsulinemic conditions, peripheral glucose disposal was not different between vehicle- and NPY-infused animals. In contrast, hyperinsulinemia suppressed endogenous glucose production by approximately 8% vs. 30% in NPY- vs. vehicle-infused mice, respectively (P < 0.05). Also, VLDL production was significantly higher during hyperinsulinemia in NPY- compared with vehicle-infused mice (97.5 +/- 18.0 vs. 54.7 +/- 14.9 micromol. kg(-1). h(-1); P < 0.01). These data suggest that the neurophysiological action of insulin to downregulate hypothalamic NPY release is a prerequisite for its ability to suppress hepatic fuel production, whereas it is not mandatory for its capacity to modulate glucose disposal or lipolysis.

Topics: Animals; Blood Glucose; Cerebral Ventricles; Fatty Acids, Nonesterified; Glucose; Glucose Clamp Technique; Glycerol; Hyperinsulinism; Infusions, Parenteral; Insulin; Kinetics; Lipoproteins, VLDL; Mice; Neuropeptide Y

Proopiomelanocortin (POMC) neurons in the hypothalamus are direct targets of the adipostatic hormone leptin and contribute to energy homeostasis by integrating peripheral and central information. The melanocortin and beta-endorphin neuropeptides are processed from POMC and putatively coreleased at axon terminals. Melanocortins have been shown by a combination of pharmacological and genetic methods to have inhibitory effects on appetite and body weight. In contrast, pharmacological studies have generally indicated that opioids stimulate food intake. Here we report that male mice engineered to selectively lack beta-endorphin, but that retained normal melanocortin signaling, were hyperphagic and obese. Furthermore, beta-endorphin mutant and wild-type mice had identical orexigenic responses to exogenous opioids and identical anorectic responses to the nonselective opioid antagonist naloxone, implicating an alternative endogenous opioid tone to beta-endorphin that physiologically stimulates feeding. These genetic data indicate that beta-endorphin is required for normal regulation of feeding, but, in contrast to earlier reports suggesting opposing actions of beta-endorphin and melanocortins on appetite, our results suggest a more complementary interaction between the endogenously released POMC-derived peptides in the regulation of energy homeostasis.

Topics: Animals; beta-Endorphin; Eating; Energy Metabolism; Glucose; Homeostasis; Hyperinsulinism; Hyperphagia; Leptin; Male; Mice; Mice, Knockout; Naloxone; Narcotic Antagonists; Neuropeptide Y; Obesity; Reference Values

Brain-derived neurotrophic factor has been associated previously with the regulation of food intake. To help elucidate the role of this neurotrophin in weight regulation, we have generated conditional mutants in which brain-derived neurotrophic factor has been eliminated from the brain after birth through the use of the cre-loxP recombination system. Brain-derived neurotrophic factor conditional mutants were hyperactive after exposure to stressors and had higher levels of anxiety when evaluated in the light/dark exploration test. They also had mature onset obesity characterized by a dramatic 80-150% increase in body weight, increased linear growth, and elevated serum levels of leptin, insulin, glucose, and cholesterol. In addition, the mutants had an abnormal starvation response and elevated basal levels of POMC, an anorexigenic factor and the precursor for alpha-MSH. Our results demonstrate that brain derived neurotrophic factor has an essential maintenance function in the regulation of anxiety-related behavior and in food intake through central mediators in both the basal and fasted state.

Topics: Animals; Anxiety; Body Weight; Brain; Brain-Derived Neurotrophic Factor; Fasting; Fluoxetine; Gene Deletion; Gene Expression; Hyperglycemia; Hyperinsulinism; Hyperkinesis; Hypothalamus; Integrases; Leptin; Mice; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; RNA, Messenger; Selective Serotonin Reuptake Inhibitors; Serotonin; Transfection; Viral Proteins

Hypothalamic neuropeptide Y is implicated in the aetiology of obesity and insulin resistance because of its hyperinsulinaemic, hyperphagic effects. We investigated the interaction of adrenal glucocorticoids and the parasympathetic nervous system in the hyperinsulinaemia caused by neuropeptide Y infusion in rats.. Neuropeptide Y was intracerebroventricularly given to normal or adrenalectomised rats for 3-6 days with pair-feeding, with or without subcutaneous dexamethasone infusion. We measured basal and intravenous glucose-induced insulinaemia and the effect of prior atropine injection.. Neuropeptide Y increased basal plasma insulin and C-peptide concentrations (380 +/- 90 and 1000 +/- 60 pmol/1, vs 190 +/- 20 and 590 +/- 50 pmol/1 in controls, p < 0.05). Neuropeptide Y also increased the plasma concentrations of these hormones as early as 60 s after glucose injection (1630 +/- 170 and 3200 +/- 170 pmol/1 for insulin and C peptide, respectively, vs 1080 +/- 80 and 1860 +/- 130 pmol/1 in controls, p < 0.05). Atropine reversed the effect of neuropeptide Y on basal plasma insulin and C-peptide concentrations but had no effect on post-glucose plasma concentrations. The hyperinsulinaemic effects of neuropeptide Y were prevented by adrenalectomy, but were restored by dexamethasone infusion. Dexamethasone in itself did not statistically significantly increase insulinaemia in adrenalectomised rats. As in intact rats, atropine attenuated the basal hyperinsulinaemia of adrenalectomised rats that had been infused with neuropeptide Y and dexamethasone but had no effect on post-glucose hyperinsulinaemia.. These data suggest firstly that neuropeptide Y infused centrally induces basal hyperinsulinaemia in rats through glucocorticoid-dependent parasympathetic activation to the pancreas. Secondly, neuropeptide Y potentiates glucose-induced insulinaemia through a pathway dependent on adrenal glucocorticoids that cannot be reversed by short-term blockade of the increased parasympathetic tonus.

Topics: Adrenalectomy; Animals; Atropine; Blood Glucose; C-Peptide; Cerebral Ventricles; Dexamethasone; Hyperinsulinism; Infusions, Parenteral; Insulin; Insulin Secretion; Kinetics; Male; Muscarinic Antagonists; Neuropeptide Y; Rats; Rats, Wistar; Reference Values

It has been claimed that factors favoring the development or maintenance of animal or human obesity may include increases in glucocorticoid production or hyperresponsiveness of the hypothalamic-pituitary-adrenal axis. In normal rats, glucocorticoids have been shown to be necessary for chronic intracerebroventricular infusion of neuropeptide Y to produce obesity and related abnormalities. Conversely, glucocorticoids inhibited the body weight-lowering effect of leptin. Such dual action of glucocorticoids may occur within the central nervous system, since both neuropeptide Y and leptin act within the hypothalamus. The aim of this study was to determine the effects of glucocorticoids (dexamethasone) given intracerebroventricularly to normal rats on body weight homeostasis and hypothalamic levels of neuropeptide Y and corticotropin-releasing hormone. Continuous central glucocorticoid infusion for 3 days resulted in marked sustained increases in food intake and body weight relative to saline-infused controls. The infusion abolished endogenous corticosterone output and produced hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia, three salient abnormalities of obesity syndromes. Central glucocorticoid infusion also produced a marked decrease in the expression of uncoupling protein (UCP)-1 and UCP-3 in brown adipose tissue and UCP-3 in muscle. Finally, chronic central glucocorticoid administration increased the hypothalamic levels of neuropeptide Y and decreased those of corticotropin-releasing hormone. When the same dose of glucocorticoids was administered peripherally, it resulted in decreases in food intake and body weight, in keeping with the decrease in hypothalamic neuropeptide Y levels. These results suggest that glucocorticoids induce an obesity syndrome in rodents by acting centrally and not peripherally.

Topics: Animals; Body Weight; Brain; Carrier Proteins; Corticosterone; Corticotropin-Releasing Hormone; Dexamethasone; Eating; Glucocorticoids; Homeostasis; Hyperinsulinism; Hypertriglyceridemia; Hypothalamus; Injections, Intraperitoneal; Ion Channels; Leptin; Membrane Proteins; Mitochondrial Proteins; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Zucker; Uncoupling Protein 1

This study aimed to elucidate possible age-related changes in islet blood perfusion in lean and obese C57BL/6 mice. Obese mice aged 1 mo were hyperglycemic and hyperinsulinemic and had an increased islet blood flow compared with age-matched lean mice. This augmented blood flow could be abolished by pretreatment with leptin. The islet blood perfusion was, in contrast to this, markedly decreased in obese 6- to 7-mo-old animals compared with age-matched lean mice. Reversal of hyperglycemia, but not hyperinsulinemia, in these obese mice with phlorizin normalized the islet blood flow. Spontaneous reversal of hyperglycemia, but not hyperinsulinemia, was seen in the 12-mo-old obese mice. Islet blood perfusion in obese mice at this age did not differ compared with lean mice. It is suggested that the initial increase in islet blood flow in obese mice is due to the leptin deficiency. The subsequent decrease in islet blood perfusion is probably caused by the chronic hyperglycemia. The described islet blood flow changes may be of importance for impairment of islet function in obese-hyperglycemic mice.

Topics: Aging; Animals; Arginine; Blood Glucose; Body Weight; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Organ Size; Pancreas; Perfusion; Phlorhizin; Proteins; Receptors, Leptin; Receptors, Neuropeptide Y; Regional Blood Flow

We examined the effect of streptozotocin-induced maternal diabetes of 6-day duration and 4- to 24-h intracerebroventricular and systemic hyperinsulinism on fetal brain neuropeptide Y (NPY) synthesis and concentrations. Maternal diabetes (n = 6) leading to fetal hyperglycemia (5-fold increase; P < 0.05) and normoinsulinemia caused a 40% decline (P < 0.05) in fetal brain NPY messenger RNA (mRNA) and a 50% decline (P < 0.05) in NPY radioimmunoassayable levels compared to levels in streptozotocin-treated nondiabetic (n = 7) and vehicle-treated control (n = 8) animals. In contrast, systemic hyperinsulinemia (n = 7) of 5- to 100-fold increase (P < 0.05) over the respective control (n = 7) with normoglycemia caused an insignificant (20-30%) decrease in fetal brain NPY mRNA and protein concentrations. However, fetal intracerebroventricular hyperinsulinism (n = 7) with no change in fetal glucose concentrations caused a 50-60% decline (P < 0.05) in only the NPY peptide levels, with no change in the corresponding mRNA amounts. We conclude that fetal hyperglycemia of 6-day duration and intracerebroventricular hyperinsulinism of 4-24 h suppress fetal brain NPY concentrations, the former by a pretranslational and the latter by either a translational/posttranslational mechanism or depletion of intracellular secretory stores. We speculate that fetal hyperglycemia and intracerebroventricular hyperinsulinism additively can inhibit various intrauterine and immediate postnatal NPY-mediated biological functions.

Topics: Acute Disease; Animals; Brain; Brain Diseases; Female; Fetal Diseases; Fetus; Hyperglycemia; Hyperinsulinism; Neuropeptide Y; Osmolar Concentration; Pregnancy; Pregnancy in Diabetics; Rats; Rats, Sprague-Dawley

The aim of this work was to determine the possible inter-relationship between neuropeptide Y (NPY, a hypothalamic stimulator of feeding) and adipose tissue expression of the ob protein (a novel potent inhibitor of feeding). Such a relationship could be of importance in the maintenance of normal body weight. To this end, normal rats were intracerebroventricularly (i.c.v.) infused for 6 days with NPY. NPY infusion resulted in hyperphagia and a marked increase in adipose tissue ob mRNA levels. The effect of NPY on ob expression persisted when hyperphagia was prevented by pair-feeding, and was reversed following cessation of NPY infusion. Basal and glucose-stimulated insulinaemia were increased by i.c.v. NPY infusion compared to control values, regardless of whether animals were ad libitum-fed or pair-fed. Cessation of NPY infusion was accompanied by normalisation of insulinaemia. These changes in insulinaemia produced by i.c.v. NPY infusion paralleled the observed changes in ob expression. When normal rats were made hyperinsulinaemic-euglycaemic for 24 h, such hyperinsulinaemia also resulted in increased ob mRNA levels in white adipose tissue. This suggested that NPY-induced hyperinsulinaemia could be responsible for the upregulation of ob mRNA levels of NPY-infused rats. It is concluded that central (i.c.v.) NPY infusion increases adipose tissue ob expression, a functional relationship that is linked, at least in part, via NPY-induced hyperinsulinaemia.

Topics: Adipose Tissue; Animals; Blood Glucose; Cerebral Ventricles; Female; Gene Expression; Glucose Clamp Technique; Hyperinsulinism; Hyperphagia; Infusions, Parenteral; Insulin; Leptin; Neuropeptide Y; Protein Biosynthesis; Rats; Rats, Zucker; Reference Values

Elevated hypothalamic neuropeptide Y (NPY) expression is found in several rodent genetic models of obesity, but any association in nongenetic models of obesity is unclear. Consequently, we have measured NPY mRNA levels in the ventromedial hypothalamus of a well-characterized model of obesity, the gold thioglucose (GTG)-injected mouse. Fourteen days after injection (early stage), animals were hyperphagic but not obese, hyperglycemic, or overtly hyperinsulinemic. Ten weeks after treatment (late stage), animals were obese, markedly hyperinsulinemic, and hyperglycemic. In both the early and late stages, NPY mRNA levels were reduced in the arcuate nucleus of GTG-injected animals. Although overnight fasting doubled NPY mRNA levels in control animals, there was no change at either stage in GTG-injected animals. NPY mRNA levels in the deep layers of the cerebral cortex and in the dentate gyrus were not affected by GTG treatment or overnight fasting. We conclude that GTG treatment reduces the expression of NPY mRNA in the arcuate nucleus and that, therefore, increased hypothalamic NPY expression is unlikely to be an important factor causing the obesity and other metabolic changes found in this model.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Aurothioglucose; Hyperglycemia; Hyperinsulinism; Hyperphagia; In Situ Hybridization; Male; Mice; Mice, Inbred CBA; Neuropeptide Y; Obesity; RNA, Messenger; Ventromedial Hypothalamic Nucleus

Acute administration of neuropeptide Y into the hypothalamus or cerebral ventricles produces hyperphagia and hyperinsulinemia. However, it is not known to what extent the hyperinsulinemia depends on the food intake. Consequently, serum insulin and glucose, as well as food and water consumption, were measured over 3 h, following injection of 1-20 micrograms neuropeptide Y into the third ventricle of adult female rats. In the presence of food, 1-10 micrograms neuropeptide Y produced a dose-dependent increase in food and water intake and serum insulin. Insulin levels were closely correlated with the quantity of food ingested. In the absence of food, 1-20 micrograms neuropeptide Y produced a dose-dependent increase in water intake, whereas 1-5 micrograms produced a does-dependent increase in serum insulin. We concluded that ICV neuropeptide Y can stimulate insulin secretion even at low doses and this response does not completely depend on food intake.

Topics: Animals; Dose-Response Relationship, Drug; Eating; Female; Hyperinsulinism; Hyperphagia; Injections, Spinal; Neuropeptide Y; Rats; Rats, Wistar

Topics: Adipose Tissue; Animals; Autonomic Nervous System; Brain; Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucocorticoids; Glucose; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Lipids; Liver; Muscles; Neuropeptide Y; Obesity; Rats; Weight Gain