leptin and Atrophy

The thymus is essential for T cell development and maturation. It is extremely sensitive to atrophy, wherein loss in cellularity of the thymus and/or disruption of the thymic architecture occur. This may lead to lower naïve T cell output and limited TCR diversity. Thymic atrophy is often associated with ageing. What is less appreciated is that proper functioning of the thymus is critical for reduction in morbidity and mortality associated with various clinical conditions including infections and transplantation. Therefore, therapeutic interventions which possess thymopoietic potential and lower thymic atrophy are required. These treatments enhance thymic output, which is a vital factor in generating favourable outcomes in clinical conditions. In this review, experimental studies on thymic atrophy in rodents and clinical cases where the thymus atrophies are discussed. In addition, mechanisms leading to thymic atrophy during ageing as well as during various stress conditions are reviewed. Therapies such as zinc supplementation, IL7 administration, leptin treatment, keratinocyte growth factor administration and sex steroid ablation during thymic atrophy involving experiments in animals and various clinical scenarios are reviewed. Interventions that have been used across different scenarios to reduce the extent of thymic atrophy and enhance its output are discussed. This review aims to speculate on the roles of combination therapies, which by acting additively or synergistically may further alleviate thymic atrophy and boost its function, thereby strengthening cellular T cell responses.

Topics: Aging; Animals; Atrophy; Bone Marrow Transplantation; Cytokines; Dietary Supplements; Gene Rearrangement, T-Lymphocyte; Graft vs Host Disease; Humans; Interleukin-7; Leptin; T-Lymphocytes; Thymus Gland; Zinc

Leptin is a hormone secreted by adipose tissue in direct proportion to amount of body fat. The circulating leptin levels serve as a gauge of energy stores, thereby directing the regulation of energy homeostasis, neuroendocrine function, and metabolism. Persons with congenital deficiency are obese, and treatment with leptin results in dramatic weight loss through decreased food intake and possible increased energy expenditure. However, most obese persons are resistant to the weight-reducing effects of leptin. Recent studies suggest that leptin is physiologically more important as an indicator of energy deficiency, rather than energy excess, and may mediate adaptation by driving increased food intake and directing neuroendocrine function to converse energy, such as inducing hypothalamic hypogonadism to prevent fertilization. Current studies investigate the role of leptin in weight-loss management because persons who have recently lost weight have relative leptin deficiency that may drive them to regain weight. Leptin deficiency is also evident in patients with diet- or exercise-induced hypothalamic amenorrhea and lipoatrophy. Replacement of leptin in physiologic doses restores ovulatory menstruation in women with hypothalamic amenorrhea and improves metabolic dysfunction in patients with lipoatrophy, including lipoatrophy associated with HIV or highly active antiretroviral therapy. The applications of leptin continue to grow and will hopefully soon be used therapeutically.

Topics: Adipose Tissue; Amenorrhea; Animals; Atrophy; Energy Metabolism; Female; Humans; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Neurosecretory Systems; Obesity; Recombinant Proteins; Weight Loss

Thymopoiesis is essential for development and maintenance of a robust and healthy immune system. Acute thymic atrophy is a complication of many infections, environmental stressors, clinical preparative regimens, and cancer treatments used today. This undesirable sequela can decrease host ability to reconstitute the peripheral T cell repertoire and respond to new antigens. Currently, there are no treatments available to protect against acute thymic atrophy or accelerate recovery, thus leaving the immune system compromised during acute stress events. Several useful murine models are available for mechanistic studies of acute thymic atrophy, including a sepsis model of endotoxin-induced thymic involution. We have identified the IL-6 cytokine gene family members (i.e., leukemia inhibitory factor, IL-6, and oncostatin M) as thymosuppressive agents by the observation that they can acutely involute the thymus when injected into a young, healthy mouse. We have gone on to explore the role of thymosuppressive cytokines and specifically defined a corticosteroid-dependent mechanism of action for the leukemia inhibitory factor in acute thymic atrophy. We also have identified leptin as a novel, thymostimulatory agent that can protect against endotoxin-induced acute thymic atrophy. This review will highlight mechanisms of stress-induced thymic involution and focus on thymosuppressive agents involved in atrophy induction and thymostimulatory agents that may be exploited for therapeutic use.

Topics: Animals; Atrophy; Cytokines; Humans; Leptin; Life Expectancy; Lipopolysaccharides; Models, Animal; Satiety Response; Stress, Physiological; T-Lymphocytes; Thymus Gland

Animal studies provide strong evidence that the CNS directly regulates bone remodeling through the actions of the hypothalamus via two distinct pathways, the neural (mediated by leptin) arm and neurohumoral (mediated by neurohormones and growth factors) arm. The impact of AD on central regulatory mechanisms of bone mass is not known.. To test a model that assesses the relationship between hypothalamic atrophy and bone loss in Alzheimer's disease (AD) and potential mediation through neural (leptin) and neurohumoral (insulin-like growth factor -1, IGF-1) mechanisms.. AD-related hypothalamic structural change alters neural and neurohumoral regulatory systems of bone remodeling and contributes to bone loss in early AD.. A secondary data analysis of data obtained in a two-year longitudinal study with path analysis and longitudinal mediation modeling.. The data were collected as a part of the University of Kansas Brain Aging Project, a two-year observational study of 71 older adults with early stage AD and 69 non-demented controls.. Demographic characteristics and measures of bone density, body composition, and hypothalamic volume, serum levels of leptin, growth hormone, and IGF-1 were collected.. Hypothalamic atrophy and bone loss were observed in AD group and were associated. Data modeling suggests that bone loss may precede measurable changes in the brain. Leptin increased over two years in AD and the increase in leptin was associated with hypothalamic atrophy. However, changes in leptin or IGF-1 levels did not mediate the relationship between hypothalamic atrophy and bone loss.. This study extends previous findings by suggesting that bone loss in AD may be related to neurodegenerative changes (atrophy) in the hypothalamus. Further studies are needed to explore the role of brain atrophy and mediating mechanisms in bone loss. Further exploring temporal relationship between bone loss and AD may have an important diagnostic value.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Animals; Atrophy; Body Composition; Bone Density; Bone Diseases, Metabolic; Brain; Case-Control Studies; Central Nervous System; Female; Human Growth Hormone; Humans; Hypothalamus; Insulin-Like Growth Factor I; Leptin; Life Style; Longitudinal Studies; Male; Models, Statistical

Adiposity predictors, body mass index (BMI), waist circumference (WC), and blood leptin and total adiponectin levels were associated with components of cerebral small vessel disease (CSVD) and brain volumetry in 503 adults with CSVD who were ≥50 years of age and enrolled in the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort (RUN DMC).. RUN DMC participants were followed up for 9 years (2006-2015). BMI, WC, brain imaging, and dementia diagnoses were evaluated at baseline and follow-up. Adipokines were measured at baseline. Brain imaging outcomes included CSVD components, white matter hyperintensities, lacunes, microbleeds, gray and white matter, hippocampal, total brain, and intracranial volumes.. Cross-sectionally among men at baseline, higher BMI, WC, and leptin were associated with lower gray matter and total brain volumes, and higher BMI and WC were associated with lower hippocampal volume. At follow-up 9 years later, higher BMI was cross-sectionally associated with lower gray matter volume, and an obese WC (>102 cm) was protective for ≥1 lacune or ≥1 microbleed in men. In women, increasing BMI and overweight or obesity (BMI ≥25 kg/m. Anthropometric and metabolic adiposity predictors were differentially associated with CSVD components and brain volumetry outcomes by sex. Higher adiposity is associated with a vascular-neurodegenerative spectrum among adults at risk for vascular forms of cognitive impairment and dementias.

Topics: Adiponectin; Adiposity; Aged; Aged, 80 and over; Atrophy; Body Mass Index; Brain; Cerebral Small Vessel Diseases; Cross-Sectional Studies; Female; Follow-Up Studies; Gray Matter; Hippocampus; Humans; Leptin; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Obesity; Overweight; Risk Factors; Sex Factors; Waist Circumference; White Matter

Exchange protein directly activated by cAMP (Epac) 2a-knockout (KO) mice exhibit accelerated diet-induced obesity and are resistant to leptin-mediated adipostatic signaling from the hypothalamus to adipose tissue, with sustained food intake. However, the impact of Epac2a deficiency on hypothalamic regulation of sympathetic nervous activity (SNA) has not been elucidated. This study was performed to elucidate the response of Epac2a-KO mice to dexamethasone-induced muscle atrophy and acute cold stress. Compared to age-matched wild-type mice, Epac2a-KO mice showed higher energy expenditures and expression of myogenin and uncoupling protein-1 in skeletal muscle (SM) and brown adipose tissue (BAT), respectively. Epac2a-KO mice exhibited greater endurance to dexamethasone and cold stress. In wild-type mice, exogenous leptin mimicked the responses observed in Epac2a-KO mice. This suggests that leptin-mediated hypothalamic signaling toward SNA appears to be intact in these mice. Hence, the potentiated responses of SM and BAT may be due to their high plasma leptin levels. [BMB Reports 2018; 51(1): 39-44].

Topics: Adipose Tissue, Brown; Animals; Atrophy; Cold-Shock Response; Dexamethasone; Guanine Nucleotide Exchange Factors; Hypothalamus; Leptin; Mice; Mice, Knockout; Muscle, Skeletal; Myogenin; Obesity; Signal Transduction; Sympathetic Nervous System; Uncoupling Protein 1

Protein malnutrition, the most deleterious cause of malnutrition in developing countries, has been considered a primary risk factor for the development of clinical visceral leishmaniasis (VL). Protein malnutrition and infection with Leishmania infantum leads to lymphoid tissue disorganization, including changes in cellularity and lymphocyte subpopulations in the thymus and spleen. Here we report that protein malnutrition modifies thymic chemotactic factors by diminishing the CCL5, CXCL12, IGF1, CXCL9 and CXCL10 protein levels in infected animals. Nevertheless, T cells preserve their migratory capability, as they were able to migrate ex vivo in response to chemotactic stimuli, indicating that malnutrition may compromise the thymic microenvironment and alter in vivo thymocyte migration. Decrease in chemotactic factors protein levels was accompanied by an early increase in the parasite load of the spleen. These results suggest that the precondition of malnutrition is affecting the cell-mediated immune response to L. infantum by altering T cell migration and interfering with the capacity of protein-deprived animals to control parasite spreading and proliferation. Our data provide evidence for a disturbance of T lymphocyte migration involving both central and peripheral T-cells, which likely contribute to the pathophysiology of VL that occurs in malnourished individuals.

Topics: Animals; Apoptosis; Atrophy; Body Weight; Cell Movement; Chemotaxis; Cytokines; Insulin-Like Growth Factor I; Leishmania infantum; Leishmaniasis, Visceral; Leptin; Ligands; Macrophages; Malnutrition; Mice, Inbred BALB C; Parasite Load; Parasites; Receptors, CXCR3; Spleen; T-Lymphocytes; Thymocytes; Thymus Gland

Type 1 diabetes is associated with subfertility in humans. The current treatment for type 1 diabetes, insulin monotherapy, is suboptimal to fully stabilize glycemia, potentially leading to this subfertility. Recent work has demonstrated that treatment with the energy-regulating hormone leptin, alone or in combination with insulin, can more effectively control glycemia in mouse models of type 1 diabetes. Here, we sought to determine whether the fertility defects in a type 1 diabetic mouse model, the Akita mouse, can be rescued with leptin monotherapy in the absence of any exogenous insulin. Akita homozygous mice treated with leptin alone had a larger total body size, testes, and seminal vesicles than their untreated siblings. Leptin treatment prevented testicular degeneration and rescued sperm motility to wild-type levels. Furthermore, sperm obtained from leptin-treated mice could successfully fertilize ooctyes in vitro. Despite completely rescuing spermatogenesis, the critical reproductive hormones LH and testosterone were only modestly higher than in untreated mice, indicating that a minimum threshold of these hormones must be met to maintain spermatogenesis. Cumulatively, these findings implicate the importance of leptin in maintaining fertility and support the use of leptin therapy in the treatment of type 1 diabetes.

Topics: Adiposity; Animals; Atrophy; Diabetes Mellitus, Type 1; Disease Models, Animal; Genetic Carrier Screening; Homozygote; Infertility, Male; Leptin; Luteinizing Hormone; Male; Mice; Spermatogenesis; Testosterone

Adiponectin (APN) is an adipose tissue-derived cytokine that regulates insulin sensitivity and inflammation. It is also involved in modulation of cell proliferation by binding to various growth factors. Based on its known effects in modulating cell proliferation and oxidative stress, APN may potentially be involved in regulating tissue damage and repair following irradiation. Adiponectin KO mice and their WT littermates were exposed to a single whole-body dose of 3 or 6Gy gamma radiation. Radiation-induced alterations were studied in jejunum, blood, bone marrow and thymus at days 1 and 5 post-irradiation and compared with sham-irradiated groups. In WT mice, irradiation did not significantly alter serum APN levels while inducing a significant decrease in serum leptin. Irradiation caused a significant reduction in thymocyte cellularity, with concomitant decrease in CD4(+), CD8(+) and CD4(+)CD8(+) T cell populations, with no significant differences between WT and APN KO mice. Irradiation resulted in a significantly higher increase in the frequency of micronucleated reticulocytes in the blood of APN KO compared with WT mice, whereas frequency of micronucleated normochromatic erythrocytes in the bone marrow at day 5 was significantly higher in WT compared with APN KO mice. Finally, irradiation induced similar alterations in villus height and crypt cell proliferation in the jejunum of WT and APN KO mice. Jejunum explants from sham-irradiated APN KO mice produced higher levels of IL-6 compared with tissue from WT animals, but the difference was no longer apparent following irradiation. Our data indicate that APN deficiency does not play a significant role in modulating radiation-induced gastrointestinal injury in mice, while it may participate in regulation of damage to the hematopoietic system.

Topics: Adiponectin; Animals; Atrophy; Cell Proliferation; Gamma Rays; Hematopoietic System; Jejunum; Leptin; Mice; Mice, Knockout; Micronuclei, Chromosome-Defective; Thymus Gland; Whole-Body Irradiation

Cushing's syndrome is characterized by marked central obesity and insulin insensitivity, effects opposite those seen with chronic AMP-activated protein kinase (AMPK) activation. This study was designed to determine whether chronic exposure to excess glucocorticoids influences LKB1/AMPK signaling in skeletal muscle. Corticosterone pellets were implanted subcutaneously in rats (hypercorticosteronemia, Hypercort) for 2 wk. Controls were sham operated and fed ad libitum or were sham operated and food restricted (pair-weighted group, Pair) to produce body weights similar to Hypercort rats. At the end of the 2-wk treatment period, rats were anesthetized, and the right gastrocnemius-plantaris (gastroc) and soleus muscles were removed. Left muscles were removed after electrical stimulation for 5 min. No significant differences were noted between treatment groups in ATP, creatine phosphate, or LKB1 activity. The alpha- and beta-subunit isoforms were not significantly influenced in gastroc by corticosterone treatment. Expression of the gamma3-subunit decreased, and gamma1- and gamma2-subunit expression increased. Both alpha2-AMPK and alpha1-AMPK activities were increased in the gastroc in response to electrical stimulation, but the magnitude of the increase was less for alpha2 in the Hypercort rats. Despite elevated plasma insulin and elevated plasma leptin in the Hypercort rats, phosphorylation of TBC1D1 was lower in both resting and stimulated muscle compared with controls. Malonyl-CoA content was elevated in gastroc muscles of resting Hypercort rats. These changes in response to excess glucocorticoids could be responsible, in part, for the decrease in insulin sensitivity and adiposity seen in Cushing's syndrome.

Topics: Adrenal Glands; AMP-Activated Protein Kinase Kinases; Animals; Atrophy; Blotting, Western; Body Weight; Corticosterone; Cyclic AMP-Dependent Protein Kinases; Electric Stimulation; Immunoprecipitation; Insulin; Insulin Resistance; Isoenzymes; Leptin; Lipid Metabolism; Male; Muscle Contraction; Muscle, Skeletal; Protein Serine-Threonine Kinases; Proteins; Rats; Rats, Sprague-Dawley; Signal Transduction

Numerous clinical and experimental studies have linked stress to changes in risk factors associated with the development of physiological syndromes, including metabolic disorders. How different mediators of the stress response, such as corticosterone (CORT), influence these changes in risk remains unclear. Although CORT has beneficial short-term effects, long-term CORT exposure can result in damage to the physiological systems it protects acutely. Disruption of this important physiologic signal is observed in numerous disparate disorders, ranging from depression to Cushing's syndrome. Thus, understanding the effects of chronic high CORT on metabolism and physiology is of key importance. We explored the effects of 4-wk exposure to CORT dissolved in the drinking water on the physiology and behavior of male mice. We used this approach as a noninvasive way of altering plasma CORT levels while retaining some integrity in the diurnal rhythm present in normal animals. This approach has advantages over methods involving constant CORT pellets, CORT injections, or adrenalectomy. We found that high doses of CORT (100 microg/ml) result in rapid and dramatic increases in weight gain, increased adiposity, elevated plasma leptin, insulin and triglyceride levels, hyperphagia, and decreased home-cage locomotion. A lower dose of CORT (25 microg/ml) resulted in an intermediate phenotype in some of these measures but had no effect on others. We propose that the physiological changes observed in the high-CORT animals approximate changes observed in individuals suffering from the metabolic syndrome, and that they potentially serve as a model for hypercortisolemia and stress-related obesity.

Topics: Adipose Tissue, White; Adiposity; Adrenal Glands; Animals; Atrophy; Chemical Phenomena; Corticosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Endocrine System; Glucose Intolerance; Hyperphagia; Insulin; Leptin; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Motor Activity; Thymus Gland; Triglycerides; Weight Gain

The purpose of this study was to assess the effects of low-dose ursolic acid (UA) on glycemic regulation and immune responses in streptozotocin-nicotinamide (STZ/NA)-induced diabetic mice. Diabetic mice were supplemented with two different doses of UA (0.01 and 0.05%, w/w) or metformin (0.5%, w/w) for 4 weeks. Compared with the untreated diabetic group, UA and metformin significantly improved blood glucose, glycosylated hemoglobin, glucose tolerance, insulin tolerance and plasma leptin levels as well as aminotransferase activity. The plasma and pancreatic insulin concentrations were significantly higher in both UA groups than in the untreated diabetic group. Supplementation with metformin increased the pancreatic insulin level without a change in the plasma insulin level. The relative thymus weights were lower in the untreated diabetic group compared to the non-diabetic group; however, the UA or metformin group had significantly improved thymus weights. Mice receiving UA or metformin supplementation had increased CD4(+)CD8(+) subpopulations in the thymus compared to the untreated diabetic mice. Concanavalin A-stimulated splenic T-lymphocyte proliferation and single-positive (CD4(+) and CD8(+)) subpopulations were significantly higher in the UA-supplemented diabetic groups than in the untreated diabetic group, but lipopolysaccharide-stimulated B-lymphocyte proliferation and the CD19(+) subpopulation were not significantly different among the groups. In the STZ/NA-induced diabetic mice, metformin increased the splenic T-lymphocyte CD4(+) and CD8(+) cell numbers without any change in T-lymphocyte proliferation. Both doses of UA lowered splenic IL-6 levels, whereas metformin increased IFN-γ, IL-6 and TNF-α levels compared to the untreated diabetic mice. These results suggest that low-dose UA may be used as a hypoglycemic agent and immune modulator in non-obese type 2 diabetic mice.

Topics: Animals; Atrophy; Blood Glucose; Body Weight; Cell Proliferation; Cytokines; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Glucose Tolerance Test; Glycated Hemoglobin; Hyperglycemia; Insulin; Leptin; Lymphocytes; Male; Mice; Mice, Inbred ICR; Niacinamide; Pancreas; Spleen; Thymus Gland; Transaminases; Triterpenes; Ursolic Acid

Protein deficiency is one of the biggest public health problems in the world, accounting for about 30-40% of hospital admissions in developing countries. Nutritional deficiencies lead to alterations in the peripheral nervous system and in the digestive system. Most studies have focused on the effects of protein-deficient diets on the enteric neurons, but not on sympathetic ganglia, which supply extrinsic sympathetic input to the digestive system. Hence, in this study, we investigated whether a protein-restricted diet would affect the quantitative structure of rat coeliac ganglion neurons. Five male Wistar rats (undernourished group) were given a pre- and postnatal hypoproteinic diet receiving 5% casein, whereas the nourished group (n = 5) was fed with 20% casein (normoproteinic diet). Blood tests were carried out on the animals, e.g., glucose, leptin, and triglyceride plasma concentrations. The main structural findings in this study were that a protein-deficient diet (5% casein) caused coeliac ganglion (78%) and coeliac ganglion neurons (24%) to atrophy and led to neuron loss (63%). Therefore, the fall in the total number of coeliac ganglion neurons in protein-restricted rats contrasts strongly with no neuron losses previously described for the enteric neurons of animals subjected to similar protein-restriction diets. Discrepancies between our figures and the data for enteric neurons (using very similar protein-restriction protocols) may be attributable to the counting method used. In light of this, further systematic investigations comparing 2-D and 3-D quantitative methods are warranted to provide even more advanced data on the effects that a protein-deficient diet may exert on sympathetic neurons. (c) 2009 Wiley-Liss, Inc.

Topics: Analysis of Variance; Animals; Animals, Newborn; Atrophy; Blood Glucose; Cell Count; Cell Size; Female; Ganglia, Sympathetic; Leptin; Male; Maternal-Fetal Exchange; Nerve Degeneration; Neurons; Organ Size; Pregnancy; Protein Deficiency; Rats; Rats, Wistar; Triglycerides

Leptin is a member of the IL-6 cytokine family and is primarily produced by adipose tissue. At high enough concentration, leptin engages leptin receptors expressed in the hypothalamus that regulate a variety of functions, including induction of weight loss. Mice deficient in leptin (ob/ob) or leptin receptor (db/db) function exhibit thymic atrophy associated with a reduction in double-positive (DP) thymocytes. However, the mediator of such thymic atrophy remains to be identified, and the extent to which leptin acts in the periphery vs. the hypothalamus to promote thymocyte cellularity is unknown. In the present study, we first demonstrate that thymic cellularity and composition is fully restored in ob/ob mice subjected to adrenalectomy. Second, we observe that ob/ob mice treated with low-dose leptin peripherally but not centrally exhibit increased thymocyte cellularity in the absence of any weight loss or significant reduction in systemic corticosterone levels. Third, we demonstrate that reconstitution of db/db mice with wild-type bone marrow augments thymocyte cellularity and restores DP cell frequency despite elevated corticosterone levels. These and additional data support a mode of action whereby leptin acts in the periphery to reduce the sensitivity of DP thymocytes to glucocorticoid-mediated apoptosis in vivo. Strikingly, our data reveal that leptin's actions on thymic cellularity in the periphery can be uncoupled from its anorectic actions in the hypothalamus.

Topics: Adrenalectomy; Age Factors; Animals; Apoptosis; Atrophy; Chimera; Corticosterone; Flow Cytometry; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Receptors, Leptin; Thymus Gland; Weight Loss

To determine the cross-section area of adrenal medulla and the percentage of Ki-67 (a proliferation marker) of the adrenal gland in diabetic rats after leptin injection.. Twenty-nine male Wistar rats were randomly divided into 3 groups: control (C) group (n = 9), diabetes mellitus (DM) group (n = 10) and leptin-injected diabetes mellitus (DM+L) group (n = 10). Experimental DM was induced by a single intraperitoneal dose of streptozotocin (40 mg/kg). After this, leptin (100 microg/kg) was injected subcutaneously for a period of 2 weeks in the diabetic group.. An atrophy of adrenal medulla in the DM group was observed, and this atrophy returned to normal morphology after injection of leptin. In addition, an increase in the Ki-67 percentage was demonstrated in the zona reticularis layers in the DM+L group.. Our study indicated that leptin stimulates the sympathoadrenal system and the androgen producing adrenal cortex in DM rats.

Topics: Adrenal Glands; Adrenal Medulla; Animals; Atrophy; Diabetes Mellitus, Experimental; Leptin; Male; Rats; Rats, Wistar

The thymus is a lymphoid organ that selects T cells for release to the peripheral immune system. Unfortunately, thymopoiesis is highly susceptible to damage by physiologic stressors and can contribute to immune deficiencies that occur in a variety of clinical settings. No treatment is currently available to protect the thymus from stress-induced involution. Leptin-deficient (ob/ob) mice have severe thymic atrophy and this finding suggests that this hormone is required for normal thymopoiesis. In this study, the ability of leptin to promote thymopoiesis in wild-type C57BL/6 and BALB/c mice, as well as in leptin-deficient (ob/ob) and endotoxin-stressed (Escherichia coli LPS) mice, was determined. Leptin administration induced weight loss and stimulated thymopoiesis in ob/ob mice, but did not stimulate thymopoiesis in wild-type C57BL/6 nor BALB/c mice. In endotoxin-stressed mice, however, leptin prevented LPS-induced thymus weight loss and stimulated TCRalpha gene rearrangement. Coadministration of leptin with LPS blunted endotoxin-induced systemic corticosterone response and production of proinflammatory cytokines. Thus, leptin has a selective thymostimulatory role in settings of leptin deficiency and endotoxin administration, and may be useful for protecting the thymus from damage and augmenting T cell reconstitution in these clinical states.

Topics: Acute Disease; Adjuvants, Immunologic; Animals; Atrophy; Corticosterone; Cytokines; Inflammation Mediators; Injections, Intraperitoneal; Leptin; Lipopolysaccharides; Lymphopoiesis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Obese; Species Specificity; Thymus Gland

Extensive loss of adipose tissue is a hallmark of cancer cachexia but the cellular and molecular basis remains unclear. This study has examined morphologic and molecular characteristics of white adipose tissue in mice bearing a cachexia-inducing tumour, MAC16. Adipose tissue from tumour-bearing mice contained shrunken adipocytes that were heterogeneous in size. Increased fibrosis was evident by strong collagen-fibril staining in the tissue matrix. Ultrastructure of 'slimmed' adipocytes revealed severe delipidation and modifications in cell membrane conformation. There were major reductions in mRNA levels of adipogenic transcription factors including CCAAT/enhancer binding protein alpha (C/EBPalpha), CCAAT/enhancer binding protein beta, peroxisome proliferator-activated receptor gamma, and sterol regulatory element binding protein-1c (SREBP-1c) in adipose tissue, which was accompanied by reduced protein content of C/EBPalpha and SREBP-1. mRNA levels of SREBP-1c targets, fatty acid synthase, acetyl CoA carboxylase, stearoyl CoA desaturase 1 and glycerol-3-phosphate acyl transferase, also fell as did glucose transporter-4 and leptin. In contrast, mRNA levels of peroxisome proliferators-activated receptor gamma coactivator-1alpha and uncoupling protein-2 were increased in white fat of tumour-bearing mice. These results suggest that the tumour-induced impairment in the formation and lipid storing capacity of adipose tissue occurs in mice with cancer cachexia.

Topics: Adenocarcinoma; Adipose Tissue; Animals; Atrophy; Blotting, Western; Body Weight; Cachexia; CCAAT-Enhancer-Binding Protein-alpha; CCAAT-Enhancer-Binding Protein-beta; Female; Gene Expression; Glucose Transporter Type 4; Ion Channels; Leptin; Male; Mice; Mice, Inbred Strains; Microscopy, Electron; Mitochondrial Proteins; PPAR gamma; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Uncoupling Protein 2

Leptin-deficient ob/ob mice exhibit several metabolic and immune abnormalities, including thymus atrophy and markedly reduced inflammatory responses. We evaluated whether transplantation of wild-type (WT) white adipose tissue (WAT) into ob/ob mice could mimic the effect of recombinant leptin administration in normalizing metabolic, immune and inflammatory abnormalities. Female ob/ob mice received a subcutaneous transplantation of WAT obtained from WT littermates. A separate group of ob/ob mice was sham-operated. Despite raising leptin levels to only 15% of those observed in WT mice, WAT transplantation normalized metabolic abnormalities (glycemia, ALT, liver weight) in ob/ob mice and prevented further body weight gain. The transplanted group demonstrated normalization of thymus and spleen cellularity, thymocyte subpopulations and rates of thymocyte apoptosis. In the model of dextran sulfate sodium-induced colitis, WAT transplantation restored inflammation to levels equivalent to those of WT mice. Colonic production of IL-6 and MIP-2 was markedly reduced in the non-transplanted ob/ob group compared to transplanted ob/ob and WT mice. Our data indicate that WAT transplantation is an effective way to normalize metabolic as well as immune and inflammatory parameters in ob/ob mice. The threshold of leptin sufficient to normalize metabolic, immune and inflammatory function is significantly lower than levels present in lean WT mice. Finally, leptin derived exclusively from WAT is sufficient to normalize metabolic, immune and inflammatory parameters in ob/ob mice.

Topics: Adiponectin; Adipose Tissue, White; Animals; Atrophy; Body Weight; Colitis; Dextran Sulfate; Female; Leptin; Mice; Mice, Obese; Obesity; Resistin; Spleen; Thymus Gland

Both diabetes (db/db) and obese (ob/ob) genotype mutations induce a hyperglycemic-hyperinsulinemic endometabolic state in C57BL mice, manifesting a type II NIDDM diabetes-obesity syndrome (DOS) in these leptin ligand/receptor-deficient models. The severity of the DOS induced by these single gene, homozygous-recessive mutations may be moderated by the background genome on which the mutation is expressed. The current studies define the phenotypic, systemic, cytochemical and cellular metabolic responses to db/db and ob/ob mutation expression when modified by /KsJ (severe DOS expression) or /6 (modified DOS expression) background strain influences as compared to littermate control (+/?) indices. Both db/db and ob/ob mutations induced dramatic increases in body weights, blood glucose and serum insulin concentrations relative to +/? indices when expressed on either the C57BL/KsJ (-/KsJ) or C57BL/6 (-/6) backgrounds. However, the -/KsJ background enhanced the severity of expression of these DOS indices relative to the -/6 strain. Similarly, the -/KsJ genome suppressed cellular glucose uptake rates, pancreatic tissue weights and insulin concentrations in both db/db and ob/ob mutants relative to /6 background strain influences or +/? indices. Concurrent enhancement of tissue and cellular lipogenic metabolism and islet cytolipid depositions were exaggerated when the mutations were expressed on the -/KsJ background relative to the -/6 genome. Pancreatic islet B-cell lipodeposition was markedly enhanced in ob/ob and db/db mutants expressed on either the -/KsJ or -/6 background. In both ob/ob and db/db models, B-cell insulin granulation was prominent in mildly hypertrophic pancreatic islets when the mutations were expressed on the -/6 background. In contrast, the severity of the DOS state expressed on the -/KsJ background resulted in pronounced B-cell atrophy, characterized by insulin degranulation, cellular hypertrophy and hypercytolipidemia associated with tissue involution, in both ob/ob and db/db mutants. Dramatic alterations in tissue norephinephrine (NE) and alpha-1-receptor populations in ob/ob and db/db mutants were exaggerated by the -/KsJ genome as compared to -/6 or control indices. The influences of the -/KsJ genome on the progressive expression of tissue NE counter-regulatory responses to enhanced cytolipidemic indices were inversely related, with cytochemical lipodeposition occurring under conditions of diminished adrenergic responses to the DOS indices.

Topics: Animals; Atrophy; Blood Glucose; Body Weight; Cell Size; Diabetes Mellitus, Type 2; Female; Genotype; Hyperinsulinism; Hypertrophy; Insulin; Islets of Langerhans; Leptin; Lipid Metabolism; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Norepinephrine; Obesity; Organ Size; Oxidative Stress; Phenotype; Receptors, Cell Surface; Receptors, Leptin; Species Specificity

The relationship between the adipocyte-derived hormone leptin, insulin resistance, and fat redistribution in patients with human immunodeficiency virus (HIV) infection has not been established. We classified a cohort of HIV type 1 (HIV-1)-infected patients with >or=6 months of antiretroviral exposure as having no lipodystrophy (51 patients [43% of the cohort]), lipoatrophy (23 patients [19% of the cohort]), mixed lipodystrophy (29 patients [24% of the cohort]), or lipohypertrophy (17 patients [14% of the cohort]), on the basis of physical examination, anthropometric measurements, and the findings of dual-emission x-ray absorptiometry and computed tomography. Measurements of insulin resistance were higher for patients with each category of lipodystrophy, compared with those observed for patients with no lipodystrophy (P<.001). Mean leptin levels (+/- standard deviation) were lowest in patients with lipoatrophy (1.76+/-1.20 ng/mL), highest in patients with lipohypertrophy (9.10+/-6.86 ng/mL), and significantly different from those in patients without lipodystrophy (3.14+/-2.30 ng/mL; both P<.01). In this cohort of antiretroviral-experienced HIV-infected patients, a low serum level of leptin was independently associated with insulin resistance in patients with lipoatrophy, after controlling for total and regional body fat.

Topics: Adult; Atrophy; Female; HIV Infections; HIV-1; Humans; Hypertrophy; Leptin; Male; Middle Aged; Regression Analysis

Acyl CoA:diacylglycerol acyltransferase (DGAT) is a ubiquitously expressed enzyme that catalyzes the final reaction in the major pathways of triglyceride synthesis. Mice lacking DGAT1 (Dgat(-/-)) demonstrate significant changes in lipid metabolism in several tissues, including the skin. Here we report the effects of DGAT1 deficiency on fur and sebaceous glands. Adult Dgat(-/-) mice had dry fur and hair loss, which were associated with atrophic sebaceous glands and fur lipid abnormalities. As a result, Dgat(-/-) mice had impaired water repulsion and defective thermoregulation after water immersion. These phenotypes were mostly absent in Dgat(-/-) mice with leptin deficiency, indicating an unexpected role for leptin in modulating the skin phenotype. Our findings indicate that DGAT1 plays an important role in normal fur and sebaceous gland physiology and provide evidence that leptin modulates these processes in the skin.

Topics: Acyltransferases; Agouti Signaling Protein; Androgens; Animals; Atrophy; Diacylglycerol O-Acyltransferase; Hair; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Proteins; Sebaceous Glands; Skin; Up-Regulation; Water

Sustained hyperleptinemia in normal rats induced by infusing a recombinant adenovirus containing the rat leptin cDNA (AdCMV-leptin) exhibited a remarkable reduction in food intake (AdCMV-leptin, 9.3 +/- 2.6 vs untreated, 20.6 +/- 1.0 g/day) and ablated body fat without any significant changes in wet weight of liver and left ventricle. In those hyperleptinemic rats, we found a 52% reduction in wet weight of salivary gland compared with that in the pair-fed AdCMV-beta-gal-treated rats, which received a recombinant virus containing the beta-galactosidase gene (AdCMV-beta-gal) and were fed on the same amount of food as had been consumed by the AdCMV-leptin-treated group on the previous day. Microscopic examination with hematoxylin-eosin staining revealed that atrophic change was induced in both serous and mucous gland only in the AdCMV-leptin-treated group, but not in the pair-fed controls. Thus, the atrophic changes in hyperleptinemic rats were due to neither a decrease of food intake nor disuse of the salivary gland related with anorexia. Our data suggested that size of the salivary gland was controlled, at lease in part, by "non-anorexic" effect of leptin.

Topics: Adenoviridae; Adipose Tissue; Animals; Atrophy; Eating; Epididymis; Genetic Vectors; Heart Ventricles; Kinetics; Leptin; Liver; Male; Organ Size; Rats; Rats, Zucker; Salivary Gland Diseases; Salivary Glands

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

Excess or loss of body fat can be associated with infertility, suggesting that adequate fat mass is essential for proper reproductive function. Leptin is an adipocyte-derived hormone that is involved in the regulation of food intake and energy expenditure, and its synthesis and secretion are markedly increased in obesity. Short-term administration of leptin accelerates the onset of puberty in normal mice and corrects the sterility of leptin-deficient ob/ob mice. These findings suggest a role for leptin as an endocrine signal between fat depots and the reproductive axis, but the effect of hyperleptinemia on the initiation and maintenance of reproductive function has not been elucidated. To address this issue, we examined the reproductive phenotypes of female transgenic skinny mice with elevated plasma leptin concentrations comparable to those in obese subjects. With no apparent adipose tissue, female transgenic skinny mice exhibit accelerated puberty and intact fertility at younger ages followed by successful delivery of healthy pups. However, at older ages, they develop hypothalamic hypogonadism characterized by prolonged menstrual cycles, atrophic ovary, reduced hypothalamic gonadotropin releasing hormone contents, and poor pituitary luteinizing hormone secretion. This study has demonstrated for the first time to our knowledge that accelerated puberty and late-onset hypothalamic hypogonadism are associated with chronic hyperleptinemia, thereby leading to a better understanding of the pathophysiological and therapeutic implication of leptin.

Topics: Adipose Tissue; Age Factors; Animals; Atrophy; Female; Fertility; Gene Expression Regulation; Gonadotropin-Releasing Hormone; Hypogonadism; Hypothalamic Diseases; Leptin; Luteinizing Hormone; Male; Mice; Mice, Mutant Strains; Organ Size; Ovary; Pituitary Gland, Anterior; Promoter Regions, Genetic; Recombinant Fusion Proteins; Serum Amyloid P-Component; Sexual Maturation

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

Lipoatropic diabetes (LD) designates a group of syndromes characterized by diabetes mellitus with marked insulin resistance and either a localized or generalized absence of adipose tissue. In this study, we evaluated plasma leptin levels in subjects with congenital generalized lipoatropic diabetes (CGLD, n = 11) or acquired generalized lipoatropic diabetes (AGLD, n = 11), and assessed correlations between leptin levels and estimations of insulin secretion and insulin sensitivity using homeostasis model assessment (HOMA). Leptin levels were 0.86 +/- 0.32, 1.76 +/- 0.78, and 6.9 +/- 4.4 ng/mL in subjects with CGLD, AGLD, and controls (n = 19), respectively (ANOVA P < 0.0001). Specific insulin levels were 154 +/- 172, 177 +/- 137 and 43 +/- 22 pmol/L, respectively (P < 0.0001). Insulin sensitivity was significantly decreased in both groups with LD (P < 0.0001), whereas HOMA beta-cell function was not significantly different when compared with controls. Leptin levels were significantly correlated with body mass index, insulin levels, and HOMA beta-cell function, and inversely correlated with insulin sensitivity in control subjects but not in subjects with generalized LD. In conclusion, decreased leptin levels were observed in subjects with generalized LD, with a trend towards lower levels in the acquired than in the congenital form (P = 0.06). The temporal relationship between the decrease in leptin levels and the development of lipoatrophy should be investigated in at-risk young relatives of subjects with the acquired forms to assess the usefulness of leptin levels as a marker of lipoatrophy.

Topics: Adipose Tissue; Adolescent; Adult; Atrophy; Body Mass Index; Child; Diabetes Mellitus; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Leptin; Male; Middle Aged; Proteins

Leptin is a 16-kd protein synthesized and secreted by adipose tissue, which regulates adiposity and body weight. To investigate the peripheral effects of recombinant human leptin, lean C57BL/6 mice were treated with subcutaneous injections of vehicle or 20 mg/kg/day leptin for 1 to 14 days. Groups of animals were killed on Days 1, 2, 3, 4, 7, or 8 and 15 to evaluate the time course of clinical chemistry, morphologic, and molecular changes in white (WAT) and brown adipose tissue (BAT) depots. There was a progressive daily reduction in the body weight of mice receiving leptin. By Day 15, the body weight of leptin-treated groups decreased by 6% to 8% relative to base-line weight. Clinical chemistry changes in treated mice included decreased cholesterol and triglyceride levels. At necropsy, the mice had rapidly progressive atrophy of subcutaneous, intra-abdominal, and retroperitoneal WAT and interscapular BAT depots, with complete depletion of fat stores by Days 3 to 4 in most females and by Days 7 to 14 in male mice. Histologically, white and brown adipocytes underwent marked atrophy with loss of lipid droplets and activation of BAT cells in WAT depots. Ultrastructurally, white and brown adipocytes contained numerous, enlarged mitochondria. Molecular analysis of key adipose tissue genes in brown and white fat depots revealed a rapid, selective increase in the mRNA expression of thermogenic proteins and lipolytic enzymes, including uncoupling proteins 1 and 2, lipoprotein lipase, and hormone-sensitive lipase, with decreases in the lipogenic enzyme fatty acid synthase, endogenous leptin, and cytochrome c oxidase. These data suggest that the peripheral effects of leptin include increased thermogenesis and lipid oxidation in brown fat coupled with increased lipolysis and decreased fat synthesis in white and brown fat, which lead to a rapid reduction in the body weight and adiposity of mice.

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Atrophy; Blood; Body Weight; Female; Humans; In Situ Hybridization; Leptin; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron; Molecular Sequence Data; Nucleic Acid Hybridization; Proteins; Recombinant Proteins; Ribonucleases