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Leptin signaling adiposity and energy balance – Sixteen years and counting: an update on leptin in energy balance

Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF Am J Physiol.

Matthew Cox
Thursday, May 13, 2021
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  • The ARC is a major site for sensing and integrating peripheral energy balance signals, including hormones leptin, insulin, and ghrelin and nutrients fatty acids, amino acids, and glucose

  • Abstract There is now considerable consensus that the adipocyte hormone leptin and the pancreatic hormone insulin are important regulators of food intake and energy balance.

  • Only few studies have focused on the photoperiod effects to animals fed an obesogenic diet.

  • Rent or Buy article Get time limited or full article access on ReadCube.

  • The exact cellular mechanism of how leptin affects Lepr POA neuron functions is not clear due to small effect sizes and trending but statistically non-significant results for various measurements for energy expenditure.

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During periods of energy deficit, the fall in leptin plasma levels exceeds the rate at which fat stores are decreased. Miroschnikow, A. Leptin and insulin fulfill many of the requirements to be putative adiposity signals to the brain. Affiliations 1 author 1.

However, the precise mechanisms for this control are still not clear. Ozata, M. Abd, A. USA— Fertility was analyzed for female mice at 9 or 18 weeks of age and for male mice at 9 weeks of each indicated genotype, monitored over a period of 6 weeks. Zhang Y, et al.

Anatomic localization of alternatively spliced leptin receptors Ob-R in mouse brain and other tissues. For blood measurements, mice at 10—11 weeks of age were anesthetized and killed, either overnight fasted 16 h or fed ad libitum. Human longevity: the grandmother effect. Frederich, R. Barsh, G. Neuron 49—

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Essential revisions: The biggest issue is noted by the authors leptin signaling adiposity and energy balance to the mechanism of the effects to regulate energy expenditure. After RYGB but before substantial fat loss, postprandial adipositg of PYY 3—36 and GLP-1 increase substantially, whereas ghrelin levels decrease in most but not all studieschanges that should be anorexigenic and may therefore contribute to fat loss. The mechanism by which cholecystokinin promotes satiety is hypothesized to involve both inhibition of gastric emptying, which stimulates vagal afferents sensitive to gastric distention, and direct activation of vagal afferent fibers that terminate in the brainstem. Phone:

Weekly body weight was measured from 3 weeks before viral injections to 10 weeks post-injections. Differential expression of mRNA for leptin receptor isoforms in the rat brain. Am J Clin Nutr 60 : — Nat Med 10 : — Comments By submitting a comment you agree to abide by our Terms and Community Guidelines. Through this mechanism, body fuel stored in the form of adipose tissue tends to remain constant despite short-term mismatches in energy balance. This is consistent with our earlier data showing decreased expression of thermogenic BAT genes in LeprbPOA KD mice, which nevertheless did not reach statistical significance.

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TrpC5 mediates acute leptin and serotonin effects via Pomc neurons. Abstract Leptin regulates energy balance and glucose metabolism by activation of multiple signaling cascades mediated by the long-form leptin receptor Ob-Rb. Betley, J. Published by Elsevier Inc. Cite this article Friedman, J.

Zeng, W. This article has been cited by other articles in PMC. Leptin regulates the reward value of nutrient. Domest Anim Endocrinol21 401 Nov The food-insecurity obesity paradox: A resource scarcity hypothesis.

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Arch JR. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. New York : Basic Books: 63 — Am J Physiol ; : R — 6. In support of this, recent insulin-clamp studies revealed that leptin can modify hepatic glucose production by simultaneously increasing gluconeogenesis and decreasing glycogenolysis in rats and mice 42 — 44suggesting that leptin has antidiabetic actions.

Recent Activity. Kennedy, G. Miroschnikow, A. Buy or subscribe. Leinninger, G.

Given the central importance of leptin function in metabolic control through actions in the hypothalamus and in the periphery 33 — 35further molecular dissection of the detailed interplay between these multiple signaling components, especially under pathophysiologic conditions, will lead us to understand better the molecular impairments responsible for the occurrence of leptin resistance that underlie the pathogenesis of human obesity and type 2 diabetes. Comparison of dietary assessment methods in nutritional epidemiology: weighed records v Bingham 24 h recalls, food-frequency questionnaires, and estimated-diet records. Miroschnikow, A. The rate of leptin production is related to adiposity, but a large portion of the interindividual variability in plasma leptin concentration is independent of body fatness.

Short-Term, Meal-Related Determinants of Food Intake

The paraventricular hypothalamus PVH is a possible candidate, as it sends a direct projection to pre-ganglionic autonomic neurons. Open in new tab. Endocrinology : — Abstract Leptin has a central role in the maintenance of energy homeostasis, and its sensitivity is influenced by both the photoperiod and dietary polyphenols. Cell Metab.

Brown adipose tissue balancw diet-induced thermogenesis. The hypothesis that adipocytes secrete an adiposity-related negative feedback signal was first advanced by Kennedy 13 46 y ago and the recent discovery of leptin has confirmed this hypothesis. Diabetes 53, — Pharmacol Biochem Behav 97 : 15 — IRS1 is sparsely expressed in the ventral hypothalamus and IRS1-deficient mice do not express abnormal metabolic phenotype Araki et al. The reviewers have opted to remain anonymous.

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Signalin mechanisms that may account for leptin resistance in human obesity include a limitation of the blood-brain-barrier transport system for leptin and an inhibition of the leptin signaling pathways in leptin-responsive hypothalamic neurons. As mentioned before, new applications for leptin therapy have been suggested based on animal research, including the treatment of type 1 diabetes Despite steady research progress, mechanisms underlying the resistance to fat loss once obesity is established remain incompletely understood. Of the 5 melanocortin receptor subtypes identified to date, 2 are expressed primarily in the brain MC3 and MC4 receptors Quantification of the relationship between insulin sensitivity and B-cell function in human subjects: evidence for a hyperbolic function.

  • Both lean and obese subjects eventually reach energy balance and their body weight regulation implies that the adipose tissue mass is "sensed", leading to appropriate responses of energy intake and energy expenditure.

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  • Grape seed-derived procyanidins have an antihyperglycemic effect in streptozotocin-induced diabetic rats and insulinomimetic activity in insulin-sensitive cell lines. Physiol Behav : —

Saper, C. Glucocorticoids are required for food deprivation-induced increases in hypothalamic neuropeptide Y expression. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Conditioned preferences: young children prefer flavors associated with high dietary fat.

Show 10 more leptin signaling adiposity and energy balance 10 of Unger RH. The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box. The genetic landscape of type 2 diabetes in mice. Leptin and the endocrine control of energy balance. Boucher, J. Both lean and obese subjects eventually reach energy balance and their body weight regulation implies that the adipose tissue mass is "sensed", leading to appropriate responses of energy intake and energy expenditure.

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Steppan CM, et al. Keywords: adiposity; energy homeostasis; leptin; neuropeptide Y. Bence, K. Read article at publisher's site DOI :

Rent or Buy article Get time addiposity or full article access on ReadCube. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. The mechanisms that may account for leptin resistance in human obesity include a limitation of the blood-brain-barrier transport system for leptin and an inhibition of the leptin signaling pathways in leptin-responsive hypothalamic neurons. Evidence for a non-leptin system that defends against weight gain in overfeeding. Get the most important science stories of the day, free in your inbox.

A historical perspective on leptin. Together, these studies clearly support the key role of ARH siggnaling in mediating the action of leptin to regulate glucose homeostasis and insulin levels Figure 1. This was primarily due to a failure to properly lower energy expenditure in response to a negative energy state during fasting Figure 4G. Front Neuroendocrinol ; 14 : —

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Towards a molecular understanding of adaptive thermogenesis. Further reading Countering adipose tissue dysfunction could underlie the superiority of telmisartan in the treatment of obesity-related hypertension Yahya M. This website requires cookies, and the limited processing of your personal data in order to function.

  • Belgardt, B.

  • Wan for creating figures and I. Intracellular signalling: Key enzyme in leptin-induced anorexia.

  • The mechanisms underlying the regulation of these MCH and orexin neurons, however, are unknown, and the possibility that both neuropeptides are expressed within the same neurons has yet to be explored.

  • Impairment in glucose homeostasis is highly correlated with obesity, and leptin has been proposed to regulate glucose metabolism through both adiposity-dependent and -independent pathways

Long-term measurements of energy expenditure in humans using a respiration chamber. Transient increase in obese gene expression after food intake or insulin administration. Moreover, this work underscores the metabolic importance of tyrosine-independent actions by Ob-Rb in exerting the broad physiological functions of leptin, of which the exact molecular signaling events remain to be delineated. Farooqi, I.

Lancet— This is particularly evident in the treatment of uncontrolled insulin-dependent diabetes, whereby the normalization of blood glucose concentrations with insulin treatment causes weight gain despite reduced food intake Grape seed proanthocyanidin extract-mediated regulation of STAT3 proteins contributes to Treg differentiation and attenuates inflammation in a murine model of obesity-associated arthritis. All the aforementioned physiological parameters are under the control of the sympathetic nervous system, and observed changes in these parameters are often considered to be indirect measures of sympathetic outflow. In addition, leptin directly injected into the dorsal vagal complex enhances CCK-induced anorectic effects 89and knocking down leptin receptor expression in the dorsal vagal complex of rats eliminates CCK-induced feeding suppression

Brain Res Bull ; 12 : — 5. The long form of the leptin receptor OB-Rb is widely expressed in the human brain. Sleep, feeding, and neuropeptides: roles of orexins and orexin receptors. This result proposes that the manipulation of POA neural circuits can affect body weight. Autonomic and endocrine factors in the regulation of food intake.

To gain further mechanistic insight into energgy effect of insulin on the DA signaling, there is need to carry out more studies using an experimental model in which balance insulin signaling has been disrupted specifically in the DA neurons. Effect of force-feeding upon basal insulin levels in rats. Article Navigation. WAT stores chemical energy as triacylglycerols for use during periods of fasting or starvation. Growing evidence suggests that interacting genetic and possibly developmental factors play an important role to determine obesity susceptibility when human populations are confronted with an obesogenic environment Fig. Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. J Neurosci —

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Lee GH, et al. Leptin action via neurotensin neurons controls orexin, the mesolimbic dopamine system and energy balance. Reis, B. Development of beta 3-adrenoceptor agonists for the treatment of obesity and diabetes--an update. Glucose concentrations were likewise measured by venous bleeding at 0, 15, 30, 60, and min after i. Obesity is genetic.

  • Leptin transport across the BBB has been reported to be gradually impaired during high-fat feeding

  • CAS Google Scholar Similar Articles To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

  • Implicit in our model of energy homeostasis is a mechanism for integrating input from short-term, meal-related signals into the long-term control of energy balance.

  • This hypothesis is supported by the observation that mice with impaired SNS activity due to genetic deficiency of either norepinephrine 86 or UCP-1 87 do not develop obesity, despite unambiguous defects in thermogenesis. Acquired flavor acceptance and intake facilitated by monosodium glutamate in humans.

Its role in the etiology of human obesity is only demonstrated in the very rare situations of absence of the leptin signal mutations of the leptin gene or of the oeptin receptor genewhich produces an internal perception of starvation and results in a chronic stimulation of excessive food intake. USA 93— Hyperleptinemia is required for the development of leptin resistance. Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. Prentice, A. Heterozygote mice were subsequently intercrossed to yield homozygotes and WT littermates, and the mutation sites were confirmed again by direct sequencing of Ob-Rb RT-PCR products derived from hypothalamic RNA data not shown. Per institutional policy, J.

Leptin was obtained from Dr. Please leave this field empty. This lptin metabolic behavior described in mammals has been recently considered an evolutionary mechanism for survival 9. An extensive body of evidence has demonstrated that endocrine regulators such as insulin and leptin mainly act on the hypothalamus of the central nervous system CNS to regulate food intake and body weight. IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates. Mol Cell Neurosci ; 1 : 41 — 8.

MINI REVIEW article

Banks, W. Differing severity of glucose intolerance and insulin resistance in YF and Y3F mice. Institute of Physiology, University of Lausanne, Switzerland.

  • After its binding to LRb in the hypothalamus, leptin stimulates a specific signaling cascade that results in the inhibition of several orexigenic neuropeptides, while stimulating several anorexigenic peptides.

  • Publication types Research Support, N. Download citation.

  • Nat Genet 19 : — Some candidate signaling molecules used by central effector pathways involved in the hypothalamic control of energy balance 1.

  • Positional cloning of the mouse obese gene and its human homologue.

  • Cocaine- and amphetamine-regulated transcript CART is widely expressed in the brain, including hypothalamic areas such as the arcuate nucleus, paraventricular nucleus, and dorsomedial hypothalamic nucleus 7677and encodes a neuropeptide with potent, but short-lived anorexic effects after intracerebroventricular administration 76 ,

  • Positional cloning of the mouse obese gene and its human homologue. Hetherington, A.

Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. Mechanism by which lose weight acids inhibit insulin activation of insulin receptor substrate-1 IRS-1 -associated phosphatidylinositol 3-kinase activity in muscle. Total — sognaling of viruses were injected. Belgardt, B. Open in new tab Download slide. Body weight and food intake were measured weekly. We confirmed that this leptin effect was not due to the leptin leakage to other areas, especially the arcuate nucleus of the hypothalamus ARCby staining for the phosphorylation of signal-transducer-and-activator-of-transcription-3 pSTAT3a marker for functional Lepr signaling Figure 2—figure supplement 1B.

Low leptin levels can also be the result of rare genetic disorders such as lipodystrophies and congenital leptin deficiency 23 In red is the newly discovered NSAPP pathway that we showed to be essential for producing an intracellular burst of H 2 O 2 that inhibits key protein tyrosine phosphatases PTPasesthereby allowing canonical leptin signaling to propagate. One of the factors contributing to increased incidences of obesity is diet composition especially in this modern era where most people opt for processed or instant foods. Raw electrophysiological data for individually recorded neurons are available in the laboratory of Dr. Relationship of body weight to the lateral hypothalamic feeding syndrome. Cell Signal.

This work provides an in vivo and energy showing the physiological contributions of signaling through Tyr and Tyre. Towards a molecular understanding of adaptive thermogenesis. Long-term measurements of energy expenditure in snergy using a respiration chamber. Leptin and the regulation of body weight in mammals. 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. Weight-reducing effects of the plasma protein encoded by the obese gene. Of note, both male and female YF mice at 10 weeks of age exhibited slightly higher BW gain than their Y3F counterparts.

Long-Term Regulation of Food Intake and Energy Balance

The food-insecurity obesity paradox: A resource scarcity hypothesis. Elias, C. Human leptin adiposify 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. Adolph, E. Cell84—94

  • Thus, cherry intake modulated the central leptin system when consumed out-of-season in both obese animals and non-obese animals. A receptor subtype involved in neuropeptide-Y-induced food intake.

  • Download citation. Incidence trends of type 1 and type 2 diabetes among youths,

  • Glucocorticoids as counterregulatory hormones of leptin. JAMA : —

  • You are using a browser version with limited support for CSS. Vong, L.

  • Physiol Behav 55 : — Intraventricular insulin reduces food intake and body weight of lean but not obese Zucker rats.

Prog Brain Res, 01 Jan Effects of Ob-Rb intracellular tyrosine mutations on energy expenditure and adaptive thermogenesis. The Y3F knockin mice were likewise generated. Obesity is genetic. Int J Obes,

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  • Thus, obesity susceptibility may be a polygenic trait. This picture is further complicated by evidence of discrepancies between endogenous and exogenous leptin sensitivity

  • Needless to say, food reward cannot be dissociated from satiety, taste, and homeostatic needs, and numerous psychological and environmental factors may also influence food reward.

  • Reed, A. Calcium channel CaV2.

STAT3 signalling is required for leptin regulation of energy balance but not reproduction. SOCS3 mediates adiposty inhibition of the leptin receptor via Tyr Farooqi, I. The effects of lesions in the hypothalamus in parabiotic rats. Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. Neuron 23—

During the acclimation, body weight of the mice was monitored daily and we ensured stabilization of the body weight before using mice for experiments. About this article. Nature —2. Zfp maintains white adipocyte identity through suppression of the beige cell thermogenic gene program.

Introduction

Minokoshi Y, et al. Institute of Physiology, University of Lausanne, Switzerland. The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box. Ioffe, E. Psychiatry 2—

During periods of energy deficit, the fall in leptin plasma levels exceeds the rate at which fat stores are decreased. Berthoud, H. Dhillon, H. Reduced rate of energy expenditure as a risk factor for body-weight gain. Obese humans have high plasma leptin concentrations related to the size of adipose tissue, but this elevated leptin signal does not induce the expected responses i.

Neuropeptide regulation of appetite and weight. In humans, leptin concentrations do not change acutely with meal consumption and do not fluctuate with acute changes in endogenous insulin or glucose concentrations A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Because agouti antagonizes MC4 receptors as well as MC1 receptors, this form of obesity appears to result from antagonism of melanocortin receptors in the brain, whereas the yellow coat color arises from antagonism of the melanocortin receptors in the hair follicle

INTRODUCTION

Diabetes 50— Obesity Silver Spring 14 Suppl. Bates SH, et al.

  • In addition, cherry consumption in the SD photoperiod significantly decreased RQ values in obese animals. We agree with the reviewers that the body weight phenotype without a clear effect on energy expenditure is puzzling.

  • Neuron 95—

  • Address correspondence to: Joel K.

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  • CAS Google Scholar The evolution of body fatness: trading off disease and predation risk.

Lancet ; : — 8. We have further blance in the Discussion that due to the small non-significant changes, we are unable to pinpoint the exact mechanism for the increased body weight, but that several experimental outcomes suggest a combination of a blunted BAT thermogenesis and thyroid axis Discussion, fourth paragraph. Melanin concentrating hormone 3. Qu, D. J Biol Chem —

The central actions of leptin signaliing insulin are essential adiposity and energy the regulation of energy and glucose homeostasis. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Hypothalamic reactive oxygen species are required for insulin-induced food intake inhibition: an NADPH oxidase-dependent mechanism. The endocannabinoid system includes the ligands anandamide and 2-arachydonlyglycerol that can act on either of two cannabinoid receptor subtypes CB1 and CB2. Saper, C. Effects of intracerebroventricular injection of neuropeptide Y on energy metabolism.

J Neurosci 19 : — Keesey RE. Diabetes ; 38 : — 7. Leptin receptor OB-R signaling.

Open leptkn new tab. Bruijnzeel, A. Although these inputs can exert potent effects on meal initiation, meal size, and meal frequency, their balance on body fat content is limited by compensatory changes in the level of adiposity signals. Harris, G. This effect may result from SNS activation, because intravenous leptin infusion increases the firing rate of SNS nerves, which innervate muscle, BAT, kidney, and adrenal gland in anesthetized rats Although these studies are provocative, the importance of leptin in glucose homeostasis in normal animals remains uncertain.

To understand fully the physiological contributions of phosphotyrosine-mediated signaling actions of Ob-Rb, we generated 2 lines of knockin mice by introducing tyrosine-to-phenylalanine substitution mutations simultaneously at all 3 intracellular tyrosine sites or at Tyr alone. The rate of leptin production is related to adiposity, but a large portion of the interindividual variability in plasma leptin concentration is independent of body fatness. Lee GH, et al. Thank you for visiting nature. Published online Nov Bouret, S. Science—

Bray, G. BoxRahway, NJ Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behaviour in leptin-deficient adults. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. Modern science versus the stigma of obesity.

Altered expression of hypothalamic neuropeptide mRNAs in food restricted and food-deprived rats. Choi, Y. Although it seems counterintuitive that Lepr POA KD mice have higher energy expenditure during fasting than control mice, a similar discordance of leptin-linked physiology was reported for female reproduction. Mouse ob protein: evidence for a peripheral signal linking adiposity and central neural networks. Additionally, numerous studies report the metabolic protective effects of grapes, grape by-products, cherries or their pure compounds 141516171819and thus, we chose red grape and cherry as representative polyphenol-rich fruits for autumn and spring, respectively. However, neither stimulation nor ablation of POA Lepr affected temperature-dependent adaptive changes in energy expenditure and food intake. Radioimmunological measurement of leptin in plasma of obese and diabetic human subjects.

Abnormal splicing of the leptin receptor in diabetic mice. Balthasar, Fnergy. Diabetes, a new mutation in the mouse. Collectively, these findings support the notion that Lepr-expressing NPY neurones act as the key relay point where peripheral adipose storage information is sensed, and corresponding responses are initiated to protect adipose reserves. Notably, when normalized to or adjusted by covariate analysis for their respective body fat contents, HOMA assessment indicated appreciably improved insulin sensitivity in Y3F mice than YF animals Fig.

Consistent with this hypothesis, leptin is present signalint human cerebrospinal fluid in concentrations that are strongly correlated with plasma leptin concentrationsand leptin signaling adiposity and energy balance receptors also termed OB-R are present in various brain regions including the hypothalamus 34, Hypothalamic CART is a new anorectic peptide regulated by leptin. Although these inputs can exert potent effects on meal initiation, meal size, and meal frequency, their effect on body fat content is limited by compensatory changes in the level of adiposity signals. Studies in the hypothalamus have provided a basis for understanding the molecular mechanism of insulin and leptin in the CNS even though the entire mechanism remains to be elucidated. J Clin Invest ; 88 : —

Harris, R. FPrime Rep. Scott, M. Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. Ser or from the variability of AgRP expression measured in animals fed ad libitum. Gao, Y. Open in a separate window.

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Thank you for visiting nature. Close banner Close. Publication types Research Support, Non-U. Zhang, Y. Cell Metab. Abnormal splicing of the leptin receptor in diabetic mice. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis.

This mechanism was forwarded to explain obesity in mice with transgenic ablation of BAT Oxford University Press is a department of the University of Oxford. Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, beta3-adrenergic agonists, and leptin. However, for reasons that are not fully understood, obese individuals do not show diminished appetite and increased energy expenditure, as would be predicted based on their increased leptin levels 6 We and others have shown that leptin normally induces a transient burst in reactive oxygen species ROS in neurons and other cell types 2260 — The recruitment of JAK2 in turn activates diverse signal transduction cascades through autophosphorylation and phosphorylation of LepRb and signal transducer and activator of transcription 3 STAT3 blue in Figure 1.

Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. The discovery of leptin changed the view of adipose tissue from that of a passive vessel that stores fat to that of a dynamic endocrine organ that actively regulates behaviour and metabolism. Pinto, S. Published by Elsevier Inc. Insufficiency of Janus kinase 2-autonomous leptin receptor signals for most physiologic leptin actions.

Nature73—76 Correspondence to Jeffrey M. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. Effects of Ob-Rb intracellular tyrosine mutations on energy expenditure and adaptive thermogenesis. Leptin receptor signaling in T cells is required for Th17 differentiation.

Jequier iphysiol. Miroschnikow, A. However, the whole spectrum of signaling actions through the 3 cytoplasmic tyrosines of mouse Ob-Rb remains to be completely defined in vivo. Ser or from the variability of AgRP expression measured in animals fed ad libitum.

Positional cloning of the mouse obese gene and its human signa,ing. Int J Eat Disord 44 : — Pubmed Abstract Pubmed Full And energy balance. This possibility is further supported by studies showing that leptin is required for ambient temperature-dependent food intake adjustment Kaiyala et al. Specifically, a recent study showed that direct administration of insulin into the VTA reduced food intake and repressed feeding of sweetened high-fat diet in the sated condition hedonic feeding; Bruijnzeel et al.

Knockdown of leptin receptors selectively in midbrain augmented progressive ratio responding for sucrose and restored high-fat, diet-induced suppression of dopamine content in the nucleus accumbens. Abstract Leptin signalig energy balance and glucose metabolism by activation of multiple signaling cascades mediated by the long-form leptin receptor Ob-Rb. Positional cloning of the mouse obese gene and its human homologue. Bray, G. Here, we show that the NPY neurone subpopulation that is directly responsive to leptin is not required for the inhibition of fasting-induced hyperphagia by leptin, although it is essential for the regulation of adiposity independent of changes in energy balance or diet composition.

In addition to the crucial effects signaliing the hypothalamus, emerging evidence suggests that the leptin and insulin signaling can act on other brain regions to mediate the reward value of nutrients. You can also search for this author in PubMed Google Scholar. Here, we review several well-known hypotheses that have been proposed to explain impaired central responsiveness to the appetite-suppressing effects of leptin in obesity. Several aspects of cholecystokinin action exemplify the distinction between short-term, meal-related factors and long-term hormonal signals that regulate adiposity.

Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. The relative expression of each gene was calculated referring to Ppia and Rplp0 housekeeping genes and normalized to the control group. Interestingly, melatonin reduces the energy expenditure induced by cold exposure in the Siberian hamster placed at LD 50 and stimulates Pomc expression in mice Central opioids and consumption of sweet tastants: when reward outweighs homeostasis. Leptin action in the forebrain regulates the hindbrain response to satiety signals. Protein tyrosine phosphatases: from genes, to function, to disease. Several hypothalamic nuclei have been shown to be involved in activation of BAT and browning of WAT by leptin and other factors [reviewed in 29 ].

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Google Balance. Effect on food intake. Consistent with our findings, NOX4-deficient mice are unusually daiposity to diet-induced obesity and early-onset insulin resistance for handling glucose Previous Figure 5—figure supplement 1B-J are now separated as Figure 5—figure supplement 2. Reductions of body fat stores and total plasma cholesterol and triglyceride concentrations in several species by bromocriptine treatment. Accordingly, abnormal increases in the abundance and possibly activity of hypothalamic PTPases have been implicated in high-fat diet-induced obesity and central leptin resistance 56 Based on the work of Ahima RS et al.

Peng, Y. To understand fully the physiological contributions of phosphotyrosine-mediated signaling actions of Aadiposity, we generated 2 lines of knockin mice by introducing tyrosine-to-phenylalanine substitution mutations simultaneously at all 3 intracellular tyrosine sites or at Tyr alone. Recombinant mouse OB protein: Evidence for a peripheral signal linking adiposity and central neural networks. Making insulin-deficient type 1 diabetic rodents thrive without insulin. Zucker, L.

Toward a wiring diagram understanding of appetite control. Unger RH. Pup delivery was monitored as the fertility score for a period of 6 weeks. Abnormal splicing of the leptin receptor in diabetic mice. Cite this article Friedman, J.

Metreleptin-mediated improvements in insulin sensitivity are independent of food intake in humans with lipodystrophy. Hypothalamic mTOR signaling regulates food intake. Leptin signaling. Publication types Review. The adiposity hormone leptin has been identified as a potential modulator of reward-induced feeding. Analysis of protein-coding genetic variation in 60, humans.

  • First, neither the fasting plasma glucose concentration nor the rate of whole-body glucose utilization vary with differences in body adiposity in normal humans ,

  • Leptin triggers activation of Janus kinase 2 JAK2 by binding to Ob-Rb 7 and elicits an array of subsequent intracellular tyrosyl-phosphorylation-dependent signaling actions, thought to be mediated through the 3 cytoplasmic tyrosine residues TyrTyrand Tyr within mouse Ob-Rb. Calcium channel CaV2.

  • Metabolic control of eating, energy expenditure and bioenergetics of obesity. Neuron 69 : —

The psychobiology of meals. Moderate red-wine consumption partially prevents body weight gain in rats fed a hyperlipidic diet. Food intake. About this article. Brobeck JR Food and temperature. Ritter RC Gastrointestinal mechanisms of satiation for food.

About this article. Adiopsity, D. Furthermore, leptin is not a satiety factor in humans because changes in food intake do not induce short-term increases in plasma leptin levels. Download citation. Because all 3 tyrosines within the intracellular domain of Ob-Rb are phosphorylated upon leptin activation, the triple-knockin mice devoid of tyrosine phosphorylation can provide critical insights on the role of tyrosine phosphorylation-independent actions of Ob-Rb in mediating the biological effects of leptin.

Physiol Behav 91 : — The neuroendocrinology of postprandial satiety. Cumulative effects and predictive value of common obesity-susceptibility variants identified by genome-wide association studies. Melanin concentrating hormone 3. Traveling from the hypothalamus to the adipose tissue: the thermogenic pathway.

Neurosci Biobehav Rev 11 : — Although the mechanistic underpinnings of this effect remain poorly understood, plausible explanations involving adiposity and energy in gut-brain communication have emerged. In addition, the POA was further implicated in food intake modulation under a changing thermal environment Brobeck, ; Andersson and Larsson, Your article has been favorably evaluated by Mark McCarthy Senior Editor and three reviewers, one of whom is a member of our Board of Reviewing Editors. Download references. Perry, M.

Its role in the etiology of human obesity is only demonstrated in the very rare situations of absence of the leptin signal mutations of the leptin gene or adiposity and the leptin receptor genewhich produces an internal perception of starvation and results in a chronic stimulation of excessive food intake. Neuron 42— In conclusion, in humans, the leptin signaling system appears to be mainly involved in maintenance of adequate energy stores for survival during periods of energy deficit. Leptin as a therapeutic agent: Trials and tribulations. Wu, Q. Interestingly, YF and Y3F mice had similar circulating levels of resistin another adipokine thought to play a causal role in insulin resistance 22largely correlating with their extents of adiposity Table 1.

To understand fully the physiological contributions of phosphotyrosine-mediated signaling actions of Ob-Rb, we generated 2 lines leptinn knockin mice by introducing tyrosine-to-phenylalanine substitution mutations simultaneously at all 3 intracellular tyrosine sites or at Tyr alone. Furthermore, under obesogenic conditions such as a high-fat diet, a lack of Lepr signalling on NPY neurones results in significant increases in food intake and concomitant reductions in energy expenditure, leading to accelerated accumulation of fat mass. Neurons for hunger and thirst transmit a negative-valence teaching signal. The BW of animals was monitored weekly for each genotype and sex of mice from 4 to 28 weeks of age.

A lightly leptinn version of the letter sent to the authors after peer review is shown, indicating the most substantive concerns; minor comments are not usually included. Moreover, leptin signaling adiposity and energy balance overlap might also exist in the molecular pathways that provide negative effects to the insulin and leptin signaling such as the phosphatase protein tyrosine phosphatase 1B PTP1B and the suppressor of cytokine signaling 3 SOCS3. Email alerts Article activity alert. Grape seed proanthocyanidin supplementation reduces adipocyte size and increases adipocyte number in obese rats. Brain image: Patrick J.

Towards a molecular understanding of adaptive thermogenesis. Wu, Q. Nature— Wang MY, et al. Positional cloning of the lfptin obese gene and its human homologue. Pup delivery was monitored as the fertility score for a period of 6 weeks. Glucose concentrations were measured in blood collected by venous bleeding from tail vein, immediately before and 30, 60, and min after a bolus i.

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