How does leptin contribute to homeostasis

On average, some subjects lost weight, but the extent of weight loss and the variability between subjects has led many to conclude that the leptin resistance of common obesity cannot be usefully overcome by leptin supplementation, at least when administered peripherally.

However, it is of interest that there was a significant effect on weight in some subjects with low serum leptin concentrations 50 , which suggests that leptin can continue to have a dose-response effect on energy homeostasis across a wide serum concentration range. Recent studies of leptin in combination with other agents suggest that leptin may yet find a role in the treatment of more common forms of obesity Although it had been recognized for a long time that the hypothalamus plays a key role in the regulation of energy homeostasis 52 and that body fat status plays an important role in regulating immune and reproductive function in many species 53 , the precise molecular mechanisms by which energy availability is translated into a physiologic signal became apparent only with the discovery of leptin 1.

Subsequent work showing the mechanisms involved in leptin signaling and the physiologic responses mediated by leptin has provided a robust framework on which our current understanding of the mechanisms involved in energy homeostasis has been built Although congenital leptin deficiency is rare, the characterization of these disorders has provided insights into the role of leptin in human physiology and shown that, for the most part, leptin-mediated responses are highly conserved in mammalian species.

Importantly, administration of recombinant human leptin in leptin deficiency represents the first mechanistically based targeted therapy for obesity and has provided immense clinical benefits for the patients concerned. In subsequent years, we and others have continued to show that human obesity can result from a multiplicity of defects in the pathways downstream of leptin signaling within the brain. Interestingly, all of these disorders are characterized by hyperphagia and have allowed us to demonstrate equivocally that human appetite and eating behavior is in part biologically determined.

Our growing understanding that human appetite varies markedly between individuals as does interindividual susceptibility to obesity should lead to a more enlightened and sympathetic approach toward obese patients and the problems that they endure.

Finally, the discovery of leptin and the central pathways involved in energy homeostasis will contribute to the development of more rationale pharmacologic approaches toward the prevention and treatment of obesity and its complications.

Other articles in this supplement to the Journal include references 66— Both authors contributed to the writing of this manuscript.

Neither author had a conflict of interest. Positional cloning of the mouse obese gene and its human homologue. Nature ; : — Google Scholar. Weight-reducing effects of the plasma protein encoded by the obese gene. Science ; : — 6. Science ; : — 3. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science ; : — 9. Role of leptin in the neuroendocrine response to fasting. Nature ; : — 2. Identification and expression cloning of a leptin receptor, OB-R.

Cell ; 83 : — Cell ; 84 : — 5. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB leptin receptor.

Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology ; : — Endocrinology ; : — 6. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes ; 46 : — Independent and additive effects of central POMC and leptin pathways on murine obesity. Science ; : — 4. Melanocortin receptors in leptin effects. Nature ; : Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein.

Science ; : — 8. Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol ; : — Central nervous system control of food intake. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med ; 1 : — Congenital leptin deficiency is associated with severe early-onset obesity in humans.

Nature ; : — 8. Truncated human leptin delta associated with extreme obesity undergoes proteasomal degradation after defective intracellular transport. J Clin Invest ; : — A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet ; 18 : — 5. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med ; : — The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight.

Recombinant human leptin in women with hypothalamic amenorrhea. Leptin-replacement therapy for lipodystrophy. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects.

J Clin Endocrinol Metab ; 84 : — Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Leptin regulates striatal regions and human eating behavior. Science ; : Leptin reverses weight loss-induced changes in regional neural activity responses to visual food stimuli. Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones.

J Clin Endocrinol Metab ; 87 : — 4. Synchronicity of frequently sampled thyrotropin TSH and leptin concentrations in healthy adults and leptin-deficient subjects: evidence for possible partial TSH regulation by leptin in humans.

J Clin Endocrinol Metab ; 86 : — Congenital leptin deficiency due to homozygosity for the DeltaG mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab ; 89 : — 6. Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling.

Neuroendocrinology ; 68 : 89 — Leptin regulates prothyrotropin-releasing hormone biosynthesis. Evidence for direct and indirect pathways. J Biol Chem ; : — Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor.

Novel form of lipolysis induced by leptin. J Biol Chem ; : — 4. Leptin directly alters lipid partitioning in skeletal muscle. Diabetes ; 46 : — 3. Maintenance of a reduced body weight is associated with integrated autonomic and neuroendocrine changes that reduce energy expenditure and increase food intake in a manner that is similar to that seen in rodents and humans who are deficient in, or resistant to, the adipocyte-derived hormone leptin.

Systemic leptin administration to leptin-deficient rodents and humans reverses the metabolic hypometabolism, hyperphagia , autonomic increased parasympathetic and decreased sympathetic nervous system tone , and neuroendocrine changes that characterize the leptin-deficient state. The proposed studies focus on the neuroendocrine, autonomic, and metabolic changes that characterize the reduced-obese individual, and the effects on these phenotypes of restoration of circulating concentrations of leptin to levels present prior to weight loss.

Healthy lean and overweight subjects are admitted to the General Clinical Research Center at Columbia University Medical College and placed on a liquid formula diet.

Calories are adjusted until weight is stable and then subjects undergo testing of neuroendocrine, autonomic, and metabolic function. During each of these study periods, subjects will undergo detailed evaluation of 1 energy expenditure; 2 autonomic nervous system tone serial blockade of sympathetic and parasympathetic inputs, heart rate variability analyses, and urinary catecholamine excretion ; 3 hypothalamic-pituitary-thyroid, -adrenal and -gonadal, axis function; 4 adipose tissue gene expression; 5 other molecules e.

The results of these studies will further delineate the physiology of body weight regulation and of leptin. Layout table for study information Study Type : Interventional Clinical Trial Actual Enrollment : 22 participants Allocation: Randomized Intervention Model: Crossover Assignment Intervention Model Description: Randomized, single-blind, crossover study: half of the subjects had placebo first and half had leptin first.

The order does not affect data analysis. Drug: Subcutaneous Placebo Twice daily injections of saline in the same volume as will be used for leptin injections. Drug: Leptin Leptin will be given as twice daily subcutaneous injections in doses titrated to replicate 8 a. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Hide glossary Glossary Study record managers: refer to the Data Element Definitions if submitting registration or results information. Search for terms. Save this study. Warning You have reached the maximum number of saved studies Leptin in Human Energy and Neuroendocrine Homeostasis The safety and scientific validity of this study is the responsibility of the study sponsor and investigators.

Listing a study does not mean it has been evaluated by the U. Federal Government. Read our disclaimer for details. Lack of funding. First Posted : December 15, Results First Posted : September 18, Last Update Posted : September 18, Study Description. Previous work in our laboratory, and many others, has shown that body weight is regulated.

When anyone, fat or thin, tries to maintain a reduced body weight, many systems affecting energy balance skeletal muscle, neuroendocrine, and autonomic systems conspire to slow metabolic rate thus favoring the regain of lost weight.

Individuals with leptin deficiency are remarkably similar to weight-reduced individuals. Their metabolism, thyroid hormones, and sympathetic nervous system activity are all low despite their obesity.

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Leptin action through hypothalamic nitric oxide synthaseexpressing neurons controls energy balance. Rezai-Zadeh, K. Leptin receptor neurons in the dorsomedial hypothalamus are key regulators of energy expenditure and body weight, but not food intake.

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Evidence that the caudal brainstem is a target for the inhibitory effect of leptin on food intake. Hayes, M. Endogenous leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation. Scott, M. Leptin targets in the mouse brain. Patterson, C. Molecular mapping of mouse brain regions innervated by leptin receptor-expressing cells. Brain Res. Yadav, V. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure.

Cell , — Lam, D. Leptin does not directly affect CNS serotonin neurons to influence appetite. Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance. A leptin-regulated circuit controls glucose mobilization during noxious stimuli. Kanoski, S. Hippocampus contributions to food intake control: mnemonic, neuroanatomical, and endocrine mechanisms.

Psychiatry 81 , — El-Haschimi, K. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. Jameson, J. Hormone Resistance Syndromes. Region-specific leptin resistance within the hypothalamus of diet-induced obese mice.

Identification of SOCS-3 as a potential mediator of central leptin resistance. Cell 1 , — The role of SOCS-3 in leptin signaling and leptin resistance. Bjornholm, M. Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function.

Mori, H. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Zabolotny, J. PTP1B regulates leptin signal transduction in vivo. Cell 2 , — White, C. HF diets increase hypothalamic PTP1B and induce leptin resistance through both leptin-dependent and -independent mechanisms. AJP Endocrinol. Bence, K. Neuronal PTP1B regulates body weight, adiposity and leptin action. Loh, K. Lumeng, C. Inflammatory links between obesity and metabolic disease.

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