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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 -
Comprehensive Physiology Dec 2017We summarize the biological impact of leptin signaling as well as the molecular and cellular characteristics of leptin action. Our focus is principally in the central... (Review)
Review
We summarize the biological impact of leptin signaling as well as the molecular and cellular characteristics of leptin action. Our focus is principally in the central nervous system and we describe the properties of the neuronal networks that are mediators of leptin's effects on ingestive behavior, energy balance, and the reproductive system. The molecular targets of leptin's effects are also responsible for the attenuation and termination of the intracellular signal transduction pathway for leptin, providing a clear understanding of the mechanisms leading to leptin resistance or insensitivity. Using the tools of comparative biology, we explore the potential functions of leptin in fish and birds. Based on the highly variable expression of leptin in multiple tissues, a clear lack of expression of leptin in adipocytes in numerous species of fish and birds and an absence of changes of leptin concentrations in blood that are correlated with changes in nutritional status, it is clear that leptin is unlikely to function as a signal for triglyceride stores in nonmammalian species. This comparative survey serves to highlight the unique function of leptin in mammalian biology as a modulator of energy balance, sexual development, and fertility. © 2018 American Physiological Society. Compr Physiol 8:351-369, 2018.
Topics: Animals; Biological Availability; Brain; Energy Metabolism; Fertility; Gene Expression Regulation; Hormones; Humans; Leptin; Nutritional Physiological Phenomena; Receptors, Leptin; Reproduction
PubMed: 29357132
DOI: 10.1002/cphy.c160041 -
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 -
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 -
Endocrine Reviews Apr 2020Animals that lack the hormone leptin become grossly obese, purportedly for 2 reasons: increased food intake and decreased energy expenditure (thermogenesis). This review... (Review)
Review
Animals that lack the hormone leptin become grossly obese, purportedly for 2 reasons: increased food intake and decreased energy expenditure (thermogenesis). This review examines the experimental evidence for the thermogenesis component. Analysis of the data available led us to conclude that the reports indicating hypometabolism in the leptin-deficient ob/ob mice (as well as in the leptin-receptor-deficient db/db mice and fa/fa rats) derive from a misleading calculation artefact resulting from expression of energy expenditure per gram of body weight and not per intact organism. Correspondingly, the body weight-reducing effects of leptin are not augmented by enhanced thermogenesis. Congruent with this, there is no evidence that the ob/ob mouse demonstrates atrophied brown adipose tissue or diminished levels of total UCP1 mRNA or protein when the ob mutation is studied on the inbred C57BL/6 mouse background, but a reduced sympathetic nerve activity is observed. On the outbred "Aston" mouse background, brown adipose tissue atrophy is seen, but whether this is of quantitative significance for the development of obesity has not been demonstrated. We conclude that leptin is not a thermogenic hormone. Rather, leptin has effects on body temperature regulation, by opposing torpor bouts and by shifting thermoregulatory thresholds. The central pathways behind these effects are largely unexplored.
Topics: Animals; Energy Metabolism; Humans; Leptin; Mice; Obesity; Rats; Thermogenesis
PubMed: 31774114
DOI: 10.1210/endrev/bnz016 -
Vitamins and Hormones 2005Leptin is an adipocyte-derived hormone that acts as a major regulator for food intake and energy homeostasis. Leptin deficiency or resistance can result in profound... (Comparative Study)
Comparative Study Review
Leptin is an adipocyte-derived hormone that acts as a major regulator for food intake and energy homeostasis. Leptin deficiency or resistance can result in profound obesity, diabetes, and infertility in humans. Since its discovery, our understanding of leptin's biological functions has expanded from anti-obesity to broad effects on reproduction, hematopoiesis, angiogenesis, blood pressure, bone mass, lymphoid organ homeostasis, and T lymphocyte systems. Leptin orchestrates complex biological effects through its receptors, expressed both centrally and peripherally. Leptin receptor belongs to the class I cytokine receptor superfamily. At least five isoforms of leptin receptor exist, primarily because of alternate splicing. The longest form is capable of full signal transduction. The short forms may serve as leptin binding proteins and play a role in leptin transporting across the blood-brain barrier. In this review, we present the crystal structure of leptin and the structural comparison with other four-helical cytokines, discuss the leptin-receptor binding models based on other cytokine-receptor complex structures, and summarize the most recent progress on leptin signal transduction pathways--especially its link to peripheral lipid metabolism through AMP-activated protein kinase and hepatic stearoyl-CoA desaturase-1 pathways. Furthermore, we propose the structure based design of leptin analogs with increased stability, improved potency, enhanced blood-brain barrier transport, and extended time action for future therapeutic application.
Topics: AMP-Activated Protein Kinase Kinases; Animals; Biological Transport; Crystallization; DNA-Binding Proteins; Drug Resistance; Humans; Leptin; Mitogen-Activated Protein Kinases; Molecular Structure; Phosphatidylinositol 3-Kinases; Protein Binding; Protein Isoforms; Protein Kinases; Protein-Tyrosine Kinases; Receptors, Cell Surface; Receptors, Leptin; STAT3 Transcription Factor; Sequence Analysis, DNA; Signal Transduction; Solubility; Tissue Distribution; Trans-Activators
PubMed: 16112274
DOI: 10.1016/S0083-6729(05)71012-8 -
Biomolecules Jul 2021Leptin, a multifunctional hormone primarily, but not exclusively, secreted in adipose tissue, is implicated in a wide range of biological functions that control... (Review)
Review
Leptin, a multifunctional hormone primarily, but not exclusively, secreted in adipose tissue, is implicated in a wide range of biological functions that control different processes, such as the regulation of body weight and energy expenditure, reproductive function, immune response, and bone metabolism. In addition, leptin can exert angiogenic and mitogenic actions in peripheral organs. Leptin biological activities are greatly related to its interaction with the leptin receptor. Both leptin excess and leptin deficiency, as well as leptin resistance, are correlated with different human pathologies, such as autoimmune diseases and cancers, making leptin and leptin receptor important drug targets. The development of leptin signaling modulators represents a promising strategy for the treatment of cancers and other leptin-related diseases. In the present manuscript, we provide an update review about leptin-activity modulators, comprising leptin mutants, peptide-based leptin modulators, as well as leptin and leptin receptor specific monoclonal antibodies and nanobodies.
Topics: Animals; Binding Sites; Humans; Leptin; Peptides; Receptors, Leptin; Single-Domain Antibodies
PubMed: 34356668
DOI: 10.3390/biom11071045 -
Annual Review of Physiology 2000The discovery of the adipose-derived hormone leptin has generated enormous interest in the interaction between peripheral signals and brain targets involved in the... (Review)
Review
The discovery of the adipose-derived hormone leptin has generated enormous interest in the interaction between peripheral signals and brain targets involved in the regulation of feeding and energy balance. Plasma leptin levels correlate with fat stores and respond to changes in energy balance. It was initially proposed that leptin serves a primary role as an anti-obesity hormone, but this role is commonly thwarted by leptin resistance. Leptin also serves as a mediator of the adaptation to fasting, and this role may be the primary function for which the molecule evolved. There is increasing evidence that leptin has systemic effects apart from those related to energy homeostasis, including regulation of neuroendocrine and immune function and a role in development.
Topics: Adipose Tissue; Animals; Humans; Leptin
PubMed: 10845097
DOI: 10.1146/annurev.physiol.62.1.413 -
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 -
Cytokine Sep 2019Metabolic syndrome poses a major threat on human health affecting the quality of life. Adipose tissue is an important organ which plays a crucial role in the... (Review)
Review
Metabolic syndrome poses a major threat on human health affecting the quality of life. Adipose tissue is an important organ which plays a crucial role in the pathogenesis of metabolic syndrome. Adipocytokines secreted by the adipose tissue plays a critical role in storage, food intake, energy expenditure, lipid and glucose metabolism. Leptin is primarily involved in regulating food intake, body weight and energy homeostasis through neuroendocrine functions. Contemporary research suggests that leptin also influences insulin sensitivity and lipid metabolism. High leptin concentrations are directly associated with the obesity subsequent development of metabolic disease sequelae such as insulin resistance, type 2 diabetes and cardiovascular diseases. Elucidation of the mechanism of action of leptin would help to develop novel therapeutic approaches for there metabolic disorders like obesity and diabetes. This review provides an updated 'state-of-the-art' about the leptin and its role in the pathophysiology of metabolic syndrome at the molecular level.
Topics: Animals; Biomarkers; Ethnicity; Humans; Leptin; Metabolic Syndrome; Models, Biological; Receptors, Leptin
PubMed: 31154250
DOI: 10.1016/j.cyto.2019.154735