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Frontiers in Endocrinology 2021The peptide hormone leptin regulates food intake, body mass, and reproductive function and plays a role in fetal growth, proinflammatory immune responses, angiogenesis... (Review)
Review
The peptide hormone leptin regulates food intake, body mass, and reproductive function and plays a role in fetal growth, proinflammatory immune responses, angiogenesis and lipolysis. Leptin is a product of the obese () gene and, following synthesis and secretion from fat cells in white adipose tissue, binds to and activates its cognate receptor, the leptin receptor (LEP-R). LEP-R distribution facilitates leptin's pleiotropic effects, playing a crucial role in regulating body mass a negative feedback mechanism between adipose tissue and the hypothalamus. Leptin resistance is characterized by reduced satiety, over-consumption of nutrients, and increased total body mass. Often this leads to obesity, which reduces the effectiveness of using exogenous leptin as a therapeutic agent. Thus, combining leptin therapies with leptin sensitizers may help overcome such resistance and, consequently, obesity. This review examines recent data obtained from human and animal studies related to leptin, its role in obesity, and its usefulness in obesity treatment.
Topics: Animals; Energy Metabolism; Humans; Hypothalamus; Leptin; Obesity; Risk Factors; Satiety Response; Signal Transduction
PubMed: 34084149
DOI: 10.3389/fendo.2021.585887 -
Endocrine Reviews Jan 2021The discovery of leptin was intrinsically associated with its ability to regulate body weight. However, the effects of leptin are more far-reaching and include profound... (Review)
Review
The discovery of leptin was intrinsically associated with its ability to regulate body weight. However, the effects of leptin are more far-reaching and include profound glucose-lowering and anti-lipogenic effects, independent of leptin's regulation of body weight. Regulation of glucose metabolism by leptin is mediated both centrally and via peripheral tissues and is influenced by the activation status of insulin signaling pathways. Ectopic fat accumulation is diminished by both central and peripheral leptin, an effect that is beneficial in obesity-associated disorders. The magnitude of leptin action depends upon the tissue, sex, and context being examined. Peripheral tissues that are of particular relevance include the endocrine pancreas, liver, skeletal muscle, adipose tissues, immune cells, and the cardiovascular system. As a result of its potent metabolic activity, leptin is used to control hyperglycemia in patients with lipodystrophy and is being explored as an adjunct to insulin in patients with type 1 diabetes. To fully understand the role of leptin in physiology and to maximize its therapeutic potential, the mechanisms of leptin action in these tissues needs to be further explored.
Topics: Animals; Body Weight; Glucose; Humans; Insulin; Leptin; Lipid Metabolism; Organ Specificity
PubMed: 33150398
DOI: 10.1210/endrev/bnaa027 -
Nature Reviews. Endocrinology Jun 2017Obesity, a major risk factor for the development of diabetes mellitus, cardiovascular diseases and certain types of cancer, arises from a chronic positive energy balance... (Review)
Review
Obesity, a major risk factor for the development of diabetes mellitus, cardiovascular diseases and certain types of cancer, arises from a chronic positive energy balance that is often due to unlimited access to food and an increasingly sedentary lifestyle on the background of a genetic and epigenetic vulnerability. Our understanding of the humoral and neuronal systems that mediate the control of energy homeostasis has improved dramatically in the past few decades. However, our ability to develop effective strategies to slow the current epidemic of obesity has been hampered, largely owing to the limited knowledge of the mechanisms underlying resistance to the action of metabolic hormones such as leptin and ghrelin. The development of resistance to leptin and ghrelin, hormones that are crucial for the neuroendocrine control of energy homeostasis, is a hallmark of obesity. Intensive research over the past several years has yielded tremendous progress in our understanding of the cellular pathways that disrupt the action of leptin and ghrelin. In this Review, we discuss the molecular mechanisms underpinning resistance to leptin and ghrelin and how they can be exploited as targets for pharmacological management of obesity.
Topics: Animals; Cyclic AMP; Drug Resistance; Energy Metabolism; Ghrelin; Homeostasis; Humans; Hypothalamus; Leptin; Obesity; Receptors, Ghrelin; Receptors, Leptin; Signal Transduction
PubMed: 28232667
DOI: 10.1038/nrendo.2016.222 -
Journal of the American College of... Feb 2021Leptin has emerged over the past 2 decades as a key hormone secreted by adipose tissue that conveys information on energy stores. Leptin is considered an important... (Review)
Review
Leptin has emerged over the past 2 decades as a key hormone secreted by adipose tissue that conveys information on energy stores. Leptin is considered an important regulator of both neuroendocrine function and energy homeostasis. Numerous studies (mainly preclinical and much less in humans) have investigated the mechanisms of leptin's actions both in the healthy state as well as in a wide range of metabolic diseases. In this review, the authors present leptin physiology and review the main findings from animal studies, observational and interventional studies, and clinical trials in humans that have investigated the role of leptin in metabolism and cardiometabolic diseases (energy deficiency, obesity, diabetes, cardiovascular diseases, nonalcoholic fatty liver disease). The authors discuss the similarities and discrepancies between animal and human biology and present clinical applications of leptin, directions for future research, and current approaches for the development of the next-generation leptin analogs.
Topics: Animals; Clinical Trials as Topic; Humans; Leptin; Obesity; Thinness
PubMed: 33573745
DOI: 10.1016/j.jacc.2020.11.069 -
Metabolism: Clinical and Experimental Jan 2015The cloning of leptin in 1994 was an important milestone in obesity research. In those days obesity was stigmatized as a condition caused by lack of character and... (Review)
Review
The cloning of leptin in 1994 was an important milestone in obesity research. In those days obesity was stigmatized as a condition caused by lack of character and self-control. Mutations in either leptin or its receptor were the first single gene mutations found to cause morbid obesity, and it is now appreciated that obesity is caused by a dysregulation of central neuronal circuits. From the first discovery of the leptin deficient obese mouse (ob/ob), to the cloning of leptin (ob aka lep) and leptin receptor (db aka lepr) genes, much has been learned about leptin and its action in the central nervous system. The initial high hopes that leptin would cure obesity were quickly dampened by the discovery that most obese humans have increased leptin levels and develop leptin resistance. Nevertheless, leptin target sites in the brain represent an excellent blueprint for distinct neuronal circuits that control energy homeostasis. A better understanding of the regulation and interconnection of these circuits will further guide and improve the development of safe and effective interventions to treat obesity. This review will highlight our current knowledge about the hormone leptin, its signaling pathways and its central actions to mediate distinct physiological functions.
Topics: Animals; Central Nervous System; Humans; Leptin; Mutation; Receptors, Leptin; Signal Transduction
PubMed: 25305050
DOI: 10.1016/j.metabol.2014.09.010 -
Cell Metabolism Mar 2023Until menopause, women have a lower propensity to develop metabolic diseases than men, suggestive of a protective role for sex hormones. Although a functional synergy...
Until menopause, women have a lower propensity to develop metabolic diseases than men, suggestive of a protective role for sex hormones. Although a functional synergy between central actions of estrogens and leptin has been demonstrated to protect against metabolic disturbances, the underlying cellular and molecular mechanisms mediating this crosstalk have remained elusive. By using a series of embryonic, adult-onset, and tissue/cell-specific loss-of-function mouse models, we document an unprecedented role of hypothalamic Cbp/P300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 1 (Cited1) in mediating estradiol (E2)-dependent leptin actions that control feeding specifically in pro-opiomelanocortin (Pomc) neurons. We reveal that within arcuate Pomc neurons, Cited1 drives leptin's anorectic effects by acting as a co-factor converging E2 and leptin signaling via direct Cited1-ERα-Stat3 interactions. Together, these results provide new insights on how melanocortin neurons integrate endocrine inputs from gonadal and adipose axes via Cited1, thereby contributing to the sexual dimorphism in diet-induced obesity.
Topics: Mice; Animals; Female; Leptin; Arcuate Nucleus of Hypothalamus; Estradiol; Pro-Opiomelanocortin; Hypothalamus; Obesity
PubMed: 36889283
DOI: 10.1016/j.cmet.2023.02.004 -
Biomolecules Dec 2021Leptin is a 16-kDa multifunctional, neuroendocrine peptide hormone secreted by adipocytes in proportion to total adipose tissue mass, known to control food intake,...
Leptin is a 16-kDa multifunctional, neuroendocrine peptide hormone secreted by adipocytes in proportion to total adipose tissue mass, known to control food intake, energy homeostasis, immune response, and reproductive processes [...].
Topics: Gene Expression Regulation, Neoplastic; Humans; Leptin; Neoplasms
PubMed: 34944480
DOI: 10.3390/biom11121836 -
Aging Feb 2014
Topics: Aging; Animals; Humans; Leptin
PubMed: 24561396
DOI: 10.18632/aging.100637 -
Nutrients Feb 2020Leptin is a hormone released by adipose tissue that plays a key role in the control of energy homeostasis through its binding to leptin receptors (LepR), mainly... (Review)
Review
Leptin is a hormone released by adipose tissue that plays a key role in the control of energy homeostasis through its binding to leptin receptors (LepR), mainly expressed in the hypothalamus. Most scientific evidence points to leptin's satiating effect being due to its dual capacity to promote the expression of anorexigenic neuropeptides and to reduce orexigenic expression in the hypothalamus. However, it has also been demonstrated that leptin can stimulate (i) thermogenesis in brown adipose tissue (BAT) and (ii) the browning of white adipose tissue (WAT). Since the demonstration of the importance of BAT in humans 10 years ago, its study has aroused great interest, mainly in the improvement of obesity-associated metabolic disorders through the induction of thermogenesis. Consequently, several strategies targeting BAT activation (mainly in rodent models) have demonstrated great potential to improve hyperlipidemias, hepatic steatosis, insulin resistance and weight gain, leading to an overall healthier metabolic profile. Here, we review the potential therapeutic ability of leptin to correct obesity and other metabolic disorders, not only through its satiating effect, but by also utilizing its thermogenic properties.
Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Energy Metabolism; Humans; Hypothalamus; Leptin; Obesity; Receptors, Leptin; Satiation; Thermogenesis
PubMed: 32069871
DOI: 10.3390/nu12020472 -
Neuron Jul 2011Leptin acts in the brain to prevent obesity. The underlying neurocircuitry responsible for this is poorly understood, in part because of incomplete knowledge regarding...
Leptin acts in the brain to prevent obesity. The underlying neurocircuitry responsible for this is poorly understood, in part because of incomplete knowledge regarding first-order, leptin-responsive neurons. To address this, we and others have been removing leptin receptors from candidate first-order neurons. While functionally relevant neurons have been identified, the observed effects have been small, suggesting that most first-order neurons remain unidentified. Here we take an alternative approach and test whether first-order neurons are inhibitory (GABAergic, VGAT⁺) or excitatory (glutamatergic, VGLUT2⁺). Remarkably, the vast majority of leptin's antiobesity effects are mediated by GABAergic neurons; glutamatergic neurons play only a minor role. Leptin, working directly on presynaptic GABAergic neurons, many of which appear not to express AgRP, reduces inhibitory tone to postsynaptic POMC neurons. As POMC neurons prevent obesity, their disinhibition by leptin action on presynaptic GABAergic neurons probably mediates, at least in part, leptin's antiobesity effects.
Topics: Agouti-Related Protein; Animals; Brain; Disease Models, Animal; Excitatory Postsynaptic Potentials; Glutamic Acid; Inhibitory Postsynaptic Potentials; Leptin; Mice; Mice, Transgenic; Neurons; Obesity; Pro-Opiomelanocortin; Receptors, Leptin; gamma-Aminobutyric Acid
PubMed: 21745644
DOI: 10.1016/j.neuron.2011.05.028