scholarly journals Leptin receptor neurons in the dorsomedial hypothalamus regulate diurnal patterns of feeding, locomotion, and metabolism

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Chelsea L Faber ◽  
Jennifer D Deem ◽  
Bao Anh Phan ◽  
Tammy P Doan ◽  
Kayoko Ogimoto ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Cell Types ◽  
Diurnal Rhythms ◽  
Hypothalamic Nucleus ◽  
Light Cycle ◽  
Adult Mice ◽  
Environmental Light ◽  
Normal Increase ◽  
The Brain

The brain plays an essential role in driving daily rhythms of behavior and metabolism in harmony with environmental light–dark cycles. Within the brain, the dorsomedial hypothalamic nucleus (DMH) has been implicated in the integrative circadian control of feeding and energy homeostasis, but the underlying cell types are unknown. Here, we identify a role for DMH leptin receptor-expressing (DMHLepR) neurons in this integrative control. Using a viral approach, we show that silencing neurotransmission in DMHLepR neurons in adult mice not only increases body weight and adiposity but also phase-advances diurnal rhythms of feeding and metabolism into the light cycle and abolishes the normal increase in dark-cycle locomotor activity characteristic of nocturnal rodents. Finally, DMHLepR-silenced mice fail to entrain to a restrictive change in food availability. Together, these findings identify DMHLepR neurons as critical determinants of the daily time of feeding and associated metabolic rhythms.

scholarly journals Leptin-receptor neurons in the dorsomedial hypothalamus regulate the timing of circadian rhythms in feeding and metabolism in mice

2020 ◽  
Author(s):  
Chelsea L. Faber ◽  
Jennifer D. Deem ◽  
Bao Anh Phan ◽  
Tammy P. Doan ◽  
Kayoko Ogimoto ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Cell Types ◽  
Hypothalamic Nucleus ◽  
Light Cycle ◽  
Adult Mice ◽  
Normal Increase ◽  
Time Of Feeding ◽  
The Brain

AbstractAnimal behavior and metabolism are tightly coordinated with sleep-wake cycles governed by the brain in harmony with environmental light:dark cycles. Within the brain, the dorsomedial hypothalamic nucleus (DMH) has been implicated in the integrative control of feeding, energy homeostasis, and circadian rhythms [1], but the underlying cell types are unknown. Here, we identify a role for DMH leptin receptor-expressing neurons (DMHLepR) in these effects. Using a viral approach, we show that silencing DMHLepR neurons in adult mice not only increases body weight and adiposity, but also shifts circadian rhythms in feeding and metabolism into the light-cycle. Moreover, DMHLepR silencing abolishes the normal increase in dark-cycle locomotor activity characteristic of nocturnal rodents. Furthermore, DMHLepR-silenced mice fail to entrain to a restrictive change in food availability. Together, these findings identify DMHLepR neurons as critical determinants of the daily time of feeding and associated metabolic rhythms.

scholarly journals TrkB-expressing neurons in the dorsomedial hypothalamus are necessary and sufficient to suppress homeostatic feeding

2019 ◽  
Vol 116 (8) ◽  
pp. 3256-3261 ◽  
Author(s):  
Guey-Ying Liao ◽  
Clint E. Kinney ◽  
Juan Ji An ◽  
Baoji Xu
Keyword(s):  
Leptin Receptor ◽  
Critical Role ◽  
Light Cycle ◽  
Dark Cycle ◽  
Neuronal Tracing ◽  
Dorsomedial Hypothalamus ◽  
Adult Mice ◽  
Treatment Of Obesity ◽  
Control Body ◽  
Necessary And Sufficient

Genetic evidence indicates that brain-derived neurotrophic factor (BDNF) signaling through the TrkB receptor plays a critical role in the control of energy balance. Mutations in the BDNF or the TrkB-encoding NTRK2 gene have been found to cause severe obesity in humans and mice. However, it remains unknown which brain neurons express TrkB to control body weight. Here, we report that TrkB-expressing neurons in the dorsomedial hypothalamus (DMH) regulate food intake. We found that the DMH contains both glutamatergic and GABAergic TrkB-expressing neurons, some of which also express the leptin receptor (LepR). As revealed by Fos immunohistochemistry, a significant number of TrkB-expressing DMH (DMHTrkB) neurons were activated upon either overnight fasting or after refeeding. Chemogenetic activation of DMHTrkB neurons strongly suppressed feeding in the dark cycle when mice are physiologically hungry, whereas chemogenetic inhibition of DMHTrkB neurons greatly promoted feeding in the light cycle when mice are physiologically satiated, without affecting feeding in the dark cycle. Neuronal tracing revealed that DMHTrkB neurons do not innervate neurons expressing agouti-related protein in the arcuate nucleus, indicating that DMHTrkB neurons are distinct from previously identified LepR-expressing GABAergic DMH neurons that suppress feeding. Furthermore, selective Ntrk2 deletion in the DMH of adult mice led to hyperphagia, reduced energy expenditure, and obesity. Thus, our data show that DMHTrkB neurons are a population of neurons that are necessary and sufficient to suppress appetite and maintain physiological satiation. Pharmacological activation of these neurons could be a therapeutic intervention for the treatment of obesity.

scholarly journals Collective and Individual Functions of Leptin Receptor Modulated Neurons Controlling Metabolism and Ingestion

Endocrinology ◽  
2007 ◽  
Vol 149 (4) ◽  
pp. 1773-1785 ◽  
Author(s):  
Esther van de Wall ◽  
Rebecca Leshan ◽  
Allison W. Xu ◽  
Nina Balthasar ◽  
Roberto Coppari ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Normal Glucose Tolerance ◽  
Adult Mice ◽  
Normal Glucose ◽  
High Doses ◽  
Agouti Gene

Two known types of leptin-responsive neurons reside within the arcuate nucleus: the agouti gene-related peptide (AgRP)/neuropeptide Y (NPY) neuron and the proopiomelanocortin (POMC) neuron. By deleting the leptin receptor gene (Lepr) specifically in AgRP/NPY and/or POMC neurons of mice, we examined the several and combined contributions of these neurons to leptin action. Body weight and adiposity were increased by Lepr deletion from AgRP and POMC neurons individually, and simultaneous deletion in both neurons (A+P LEPR-KO mice) further increased these measures. Young (periweaning) A+P LEPR-KO mice exhibit hyperphagia and decreased energy expenditure, with increased weight gain, oxidative sparing of triglycerides, and increased fat accumulation. Interestingly, however, many of these abnormalities were attenuated in adult animals, and high doses of leptin partially suppress food intake in the A+P LEPR-KO mice. Although mildly hyperinsulinemic, the A+P LEPR-KO mice displayed normal glucose tolerance and fertility. Thus, AgRP/NPY and POMC neurons each play mandatory roles in aspects of leptin-regulated energy homeostasis, high leptin levels in adult mice mitigate the importance of leptin-responsiveness in these neurons for components of energy balance, suggesting the presence of other leptin-regulated pathways that partially compensate for the lack of leptin action on the POMC and AgRP/NPY neurons.

scholarly journals 20 YEARS OF LEPTIN: Insights into signaling assemblies of the leptin receptor

2014 ◽  
Vol 223 (1) ◽  
pp. T9-T23 ◽  
Author(s):  
Frank Peelman ◽  
Lennart Zabeau ◽  
Kedar Moharana ◽  
Savvas N Savvides ◽  
Jan Tavernier
Keyword(s):  
Electron Microscopy ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Structural Information ◽  
Cell Types ◽  
Activation Mechanism ◽  
Peripheral Cell ◽  
X Ray ◽  
X Ray Crystallography ◽  
X Ray Scattering

Leptin plays a central role in the control of body weight and energy homeostasis, but is a pleiotropic cytokine with activities on many peripheral cell types. In this review, we discuss the interaction of leptin with its receptor, and focus on the structural and mechanistic aspects of the extracellular aspects of leptin receptor (LR) activation. We provide an extensive overview of all structural information that has been obtained for leptin and its receptor via X-ray crystallography, electron microscopy, small-angle X-ray scattering, homology modeling, and mutagenesis studies. The available knowledge is integrated into putative models toward a recapitulation of the LR activation mechanism.

scholarly journals Tanycyte-independent control of hypothalamic leptin signaling

2019 ◽  
Author(s):  
Sooyeon Yoo ◽  
David Cha ◽  
Dong Won Kim ◽  
Thanh V. Hoang ◽  
Seth Blackshaw
Keyword(s):  
Gene Expression ◽  
Single Molecule ◽  
Leptin Receptor ◽  
Cell Types ◽  
Leptin Signaling ◽  
And Function ◽  
Induced Changes ◽  
The Brain ◽  
Specific Deletion

AbstractLeptin is secreted by adipocytes to regulate appetite and body weight. Recent studies have reported that tanycytes actively transport circulating leptin across the brain barrier into the hypothalamus, and are required for normal levels of hypothalamic leptin signaling. However, direct evidence for leptin receptor (LepR) expression is lacking, and the effect of tanycyte-specific deletion of LepR has not been investigated. In this study, we analyze the expression and function of the tanycytic LepR in mice. Using single-molecule fluorescent in situ hybridization (smfISH), RT-qPCR, single-cell RNA sequencing (scRNA-Seq), and selective deletion of the LepR in tanycytes, we are unable to detect expression of LepR in the tanycytes. Tanycyte-specific deletion of LepR likewise did not affect leptin-induced pSTAT3 expression in hypothalamic neurons, regardless of whether leptin was delivered by intraperitoneal or intracerebroventricular injection. Finally, we use activity-regulated scRNA-Seq (act-Seq) to comprehensively profile leptin-induced changes in gene expression in all cell types in mediobasal hypothalamus. Clear evidence for leptin signaling is only seen in endothelial cells and subsets of neurons, although virtually all cell types show leptin-induced changes in gene expression. We thus conclude that LepR expression in tanycytes is either absent or undetectably low, that tanycytes do not directly regulate hypothalamic leptin signaling through a LepR-dependent mechanism, and that leptin regulates gene expression in diverse hypothalamic cell types through both direct and indirect mechanisms.

scholarly journals The type I interferon system protects mice from Semliki Forest virus by preventing widespread virus dissemination in extraneural tissues, but does not mediate the restricted replication of avirulent virus in central nervous system neurons

2007 ◽  
Vol 88 (12) ◽  
pp. 3373-3384 ◽  
Author(s):  
Rennos Fragkoudis ◽  
Lucy Breakwell ◽  
Clive McKimmie ◽  
Amanda Boyd ◽  
Gerald Barry ◽  
...  
Keyword(s):  
Virus Infection ◽  
Semliki Forest Virus ◽  
Type I Interferon ◽  
Cell Types ◽  
Ependymal Cells ◽  
Type I ◽  
Type I Ifn ◽  
Adult Mice ◽  
Vector Systems ◽  
The Brain

Semliki Forest virus (SFV) infection of the mouse provides a powerful model to study the pathogenesis of virus encephalitis. SFV and other alphavirus-based vector systems are increasingly used in biotechnology and medicine. This study analysed the strong susceptibility of this virus to type I interferon (IFN) responses. Following intraperitoneal infection of adult mice, SFV strain A7(74) was efficiently (100 %) neuroinvasive. In contrast, SFV4 was poorly (21 %) neuroinvasive. Upon entry into the brain, both viruses activated type I IFN responses. As determined by quantitative RT-PCR, activation of the IFN-α gene was proportional to virus RNA load. An intact type I IFN system was required for protection against both strains of SFV. IFN strongly curtailed virus spread in many cell types and in many tissues. In mice with an intact type I IFN system, infected cells were rarely observed and tissue tropism was difficult to determine. In the absence of a functional type I IFN system, the tropism and the potential for rapid and widespread infection of this virus was revealed. Virus infection was readily observed in the myocardium, endocardium, exocrine pancreas, adipose tissue, smooth muscle cells and in the brain in meningeal cells, ependymal cells and oligodendrocytes. In the brains of mice with and without type I IFN responses, virus infection of neurons remained rare and focal, indicating that the previously described restricted replication of SFV A7(74) in neurons is not mediated by type I IFN responses.

scholarly journals Steroidogenic Factor 1 Regulates Expression of the Cannabinoid Receptor 1 in the Ventromedial Hypothalamic Nucleus

2008 ◽  
Vol 22 (8) ◽  
pp. 1950-1961 ◽  
Author(s):  
Ki Woo Kim ◽  
Young-Hwan Jo ◽  
Liping Zhao ◽  
Nancy R. Stallings ◽  
Streamson C. Chua ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Cannabinoid Receptor ◽  
Hypothalamic Nucleus ◽  
Cannabinoid Receptor 1 ◽  
Steroidogenic Factor 1 ◽  
Ventromedial Hypothalamic Nucleus ◽  
Hypothalamic Slice ◽  
Responsive Element ◽  
And Function ◽  
The Brain

Abstract The nuclear receptor steroidogenic factor 1 (SF-1) plays essential roles in the development and function of the ventromedial hypothalamic nucleus (VMH). Considerable evidence links the VMH and SF-1 with the regulation of energy homeostasis. Here, we demonstrate that SF-1 colocalizes in VMH neurons with the cannabinoid receptor 1 (CB1R) and that a specific CB1R agonist modulates electrical activity of SF-1 neurons in hypothalamic slice preparations. We further show that SF-1 directly regulates CB1R gene expression via a SF-1-responsive element at −101 in its 5′-flanking region. Finally, we show that knockout mice with selective inactivation of SF-1 in the brain have decreased expression of CB1R in the region of the VMH and exhibit a blunted response to systemically administered CB1R agonists. These studies suggest that SF-1 directly regulates the expression of CB1R, which has been implicated in the regulation of energy homeostasis and anxiety-like behavior.

scholarly journals Selective Loss of Leptin Receptors in the Ventromedial Hypothalamic Nucleus Results in Increased Adiposity and a Metabolic Syndrome

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2138-2148 ◽  
Author(s):  
Nathan C. Bingham ◽  
Kimberly K. Anderson ◽  
Anne L. Reuter ◽  
Nancy R. Stallings ◽  
Keith L. Parker
Keyword(s):  
Metabolic Syndrome ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Artificial Chromosome ◽  
Hypothalamic Nucleus ◽  
Steroidogenic Factor 1 ◽  
Low Fat Diet ◽  
Ventromedial Hypothalamic Nucleus

Leptin, an adipocyte-derived hormone, has emerged as a critical regulator of energy homeostasis. The leptin receptor (Lepr) is expressed in discrete regions of the brain; among the sites of highest expression are several mediobasal hypothalamic nuclei known to play a role in energy homeostasis, including the arcuate nucleus, the ventromedial hypothalamic nucleus (VMH), and the dorsomedial hypothalamic nucleus. Although most studies have focused on leptin’s actions in the arcuate nucleus, the role of Lepr in these other sites has received less attention. To explore the role of leptin signaling in the VMH, we used bacterial artificial chromosome transgenesis to target Cre recombinase to VMH neurons expressing steroidogenic factor 1, thereby inactivating a conditional Lepr allele specifically in steroidogenic factor 1 neurons of the VMH. These knockout (KO) mice, designated Lepr KOVMH, exhibited obesity, particularly when challenged with a high-fat diet. On a low-fat diet, Lepr KOVMH mice exhibited significantly increased adipose mass even when their weights were comparable to wild-type littermates. Furthermore, these mice exhibited a metabolic syndrome including hepatic steatosis, dyslipidemia, and hyperleptinemia. Lepr KOVMH mice were hyperinsulinemic from the age of weaning and eventually developed overt glucose intolerance. These data define nonredundant roles of the Lepr in VMH neurons in energy homeostasis and provide a model system for studying other actions of leptin in the VMH.

scholarly journals 20 YEARS OF LEPTIN: Human disorders of leptin action

2014 ◽  
Vol 223 (1) ◽  
pp. T63-T70 ◽  
Author(s):  
I Sadaf Farooqi ◽  
Stephen O'Rahilly
Keyword(s):  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Eating Behaviour ◽  
Human Obesity ◽  
Genes Encoding ◽  
Human Disorders ◽  
Clinical Benefits ◽  
The Brain ◽  
Robust Framework

The discovery of leptin has provided a robust framework upon which our current understanding of the mechanisms involved in energy homeostasis has been built. In this review, we describe how the identification of humans with mutations in the genes encoding leptin and the leptin receptor and the characterisation of the associated clinical phenotypes have provided insights into the role of leptin-responsive pathways in the regulation of eating behaviour, intermediary metabolism and the onset of puberty. 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 shown that human obesity can result from a multiplicity of defects in the pathways downstream of leptin signalling within the brain.

scholarly journals Voluntary Exercise Improves High-Fat Diet-Induced Leptin Resistance Independent of Adiposity

Endocrinology ◽  
2011 ◽  
Vol 152 (7) ◽  
pp. 2655-2664 ◽  
Author(s):  
Kimberly A. Krawczewski Carhuatanta ◽  
Giovanna Demuro ◽  
Matthias H. Tschöp ◽  
Paul T. Pfluger ◽  
Stephen C. Benoit ◽  
...  
Keyword(s):  
Fat Mass ◽  
High Fat Diet ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Voluntary Exercise ◽  
Leptin Resistance ◽  
Hypothalamic Nucleus ◽  
High Fat ◽  
Ventromedial Hypothalamic Nucleus ◽  
Obesity In Mice

The efficacy of exercise as primary prevention of obesity is the subject of intense investigation. Here, we show that voluntary exercise in a mouse strain susceptible to diet-induced obesity (C57B6J) decreases fat mass and increases energy expenditure. In addition, exercise attenuates obesity in mice fed a high-fat diet (HFD). Using FosB immunoreactivity as a marker of chronic neuronal activation, we found that exercise activates leptin receptor-positive neurons in the ventromedial hypothalamic nucleus, involved in homeostatic control of energy balance. FosB immunoreactivity in the ventromedial hypothalamic nucleus is decreased in sedentary mice exposed to HFD but is increased in exercised mice independent of adiposity. To determine whether the antiobesity effects of voluntary exercise improve central nervous system (CNS) leptin action, we measured the anorectic and weight reducing effects of intracerebroventricular (ICV) leptin in sedentary and exercised mice exposed to HFD (EH), as well as in sedentary mice that have been calorie restricted (SR) to match the fat mass of EH mice. ICV leptin was ineffective in lowering food intake and body weight (BW) in sedentary mice exposed to HFD mice. The anorectic potency of leptin was partially restored in EH and SR groups. However, ICV leptin significantly lowered BW in EH but not SR mice. Thus, exercise leads to the maintenance of a lower BW and leaner composition, as well as to improved CNS leptin action, independent of fat mass. These results support the notion that physical exercise directly influences the responsiveness of the CNS circuits involved in energy homeostasis by allowing the defense of a lowered BW.

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