scholarly journals Cross-Species Analysis Defines the Conservation of Anatomically-Segregated VMH Neuron Populations

2021 ◽  
Author(s):  
Alison H Affinati ◽  
Paul V Sabatini ◽  
Cadence True ◽  
Abigail J Tomlinson ◽  
Melissa Kirigiti ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Affinity Purification ◽  
Species Conservation ◽  
Hypothalamic Nucleus ◽  
Ventromedial Hypothalamic Nucleus ◽  
Neuron Populations ◽  
Starting Point ◽  
Species Analysis ◽  
And Function ◽  
Lepr Expression

The ventromedial hypothalamic nucleus (VMH) controls diverse behaviors and physiologic functions, suggesting the existence of multiple VMH neural subtypes with distinct functions. Combing Translating Ribosome Affinity Purification with RNA sequencing (TRAP-seq) data with snRNA-seq data, we identified 24 mouse VMH neuron clusters. Further analysis, including snRNA-seq data from macaque tissue, defined a more tractable VMH parceling scheme consisting of 6 major genetically- and anatomically-differentiated VMH neuron classes with good cross-species conservation. In addition to two major ventrolateral classes, we identified three distinct classes of dorsomedial VMH neurons. Consistent with previously-suggested unique roles for leptin receptor (Lepr)-expressing VMH neurons, Lepr expression marked a single dorsomedial class. We also identified a class of glutamatergic VMH neurons that resides in the tuberal region, anterolateral to the neuroanatomical core of the VMH. This atlas of conserved VMH neuron populations provides an unbiased starting point for the analysis of VMH circuitry and function.

scholarly journals Cross-Species analysis defines the conservation of anatomically-segregated VMH neuron populations

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Alison H Affinati ◽  
Paul V Sabatini ◽  
Cadence True ◽  
Abigail J Tomlinson ◽  
Melissa Kirigiti ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Leptin Receptor ◽  
Affinity Purification ◽  
Species Conservation ◽  
Hypothalamic Nucleus ◽  
Ventromedial Hypothalamic Nucleus ◽  
Neuron Populations ◽  
Starting Point ◽  
Species Analysis ◽  
And Function

The ventromedial hypothalamic nucleus (VMH) controls diverse behaviors and physiologic functions, suggesting the existence of multiple VMH neural subtypes with distinct functions. Combing Translating Ribosome Affinity Purification with RNA sequencing (TRAP-seq) data with snRNA-seq data, we identified 24 mouse VMH neuron clusters. Further analysis, including snRNA-seq data from macaque tissue, defined a more tractable VMH parceling scheme consisting of 6 major genetically- and anatomically-differentiated VMH neuron classes with good cross-species conservation. In addition to two major ventrolateral classes, we identified three distinct classes of dorsomedial VMH neurons. Consistent with previously-suggested unique roles for leptin receptor (Lepr)-expressing VMH neurons, Lepr expression marked a single dorsomedial class. We also identified a class of glutamatergic VMH neurons that resides in the tuberal region, anterolateral to the neuroanatomical core of the VMH. This atlas of conserved VMH neuron populations provides an unbiased starting point for the analysis of VMH circuitry and function.

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.

Cloning and sequence analysis of the human gene encoding steroidogenic factor 1

1996 ◽  
Vol 17 (2) ◽  
pp. 139-147 ◽  
Author(s):  
M Wong ◽  
M S Ramayya ◽  
G P Chrousos ◽  
P H Driggers ◽  
K L Parker
Keyword(s):  
Gonadal Development ◽  
Hypothalamic Nucleus ◽  
Endocrine Disorders ◽  
Orphan Nuclear Receptor ◽  
Gene Encoding ◽  
Steroidogenic Factor 1 ◽  
Ventromedial Hypothalamic Nucleus ◽  
And Function ◽  
Steroid Hydroxylases

ABSTRACT The orphan nuclear receptor steroidogenic factor 1 (SF-1) plays key roles in endocrine development and function. Initially identified as a positive regulator of the cytochrome P450 steroid hydroxylases, analyses of knockout mice deficient in SF-1 revealed that SF-1 is essential for adrenal and gonadal development, pituitary gonadotropin expression and formation of the ventromedial hypothalamic nucleus. Although more limited in scope, analyses of SF-1 in humans similarly have suggested that SF-1 is important for differentiated function in adrenocortical and gonadotrope adenomas. In the hope of extending our understanding of SF-1 function by identifying possible roles of SF-1 in clinical endocrine disorders, we isolated the FTZ-F1 gene encoding human SF-1 and mapped it to chromosome 9q33. In this report, we characterize the sequence and structural organization of the human cDNA and gene encoding SF-1, providing new insights into comparative aspects of SF-1 structure that will facilitate efforts to study the role of this transcription factor in human endocrine disorders.

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 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.

scholarly journals IL-6 ameliorates defective leptin sensitivity in DIO ventromedial hypothalamic nucleus neurons

2016 ◽  
Vol 311 (4) ◽  
pp. R764-R770 ◽  
Author(s):  
Louise Larsen ◽  
Christelle Le Foll ◽  
Ambrose A. Dunn-Meynell ◽  
Barry E. Levin
Keyword(s):  
Leptin Receptor ◽  
Cellular Level ◽  
Leptin Resistance ◽  
Hypothalamic Nucleus ◽  
Reduce Food Intake ◽  
Bardet Biedl Syndrome ◽  
Diet Induced Obesity ◽  
Leptin Sensitivity ◽  
Ventromedial Hypothalamic Nucleus ◽  
Pancreatic Peptide

Rats selectively bred to develop diet-induced obesity (DIO) have an early onset reduction in the sensitivity of their ventromedial hypothalamic nucleus (VMN) neurons to leptin compared with diet-resistant (DR) rats. This reduced sensitivity includes decreased leptin receptor (Lepr-b) mRNA expression, leptin receptor binding, leptin-induced phosphorylation of STAT3 (pSTAT3), and impaired leptin excitation (LepE) of VMN neurons. When administered exogenously, the pancreatic peptide, amylin, acts synergistically to reduce food intake and body weight in obese, leptin-resistant DIO rats by increasing VMN leptin signaling, likely by stimulation of microglia IL-6, which acts on its receptor to increase leptin-induced pSTAT3. Here, we demonstrate that incubation of cultured VMN neurons of outbred rats with IL-6 increases their leptin sensitivity. Control, dissociated DIO VMN neurons express 66% less Lepr-b and 75% less Bardet Biedl Syndrome-6 (BBS6) mRNA and have reduced leptin-induced activation of LepE neurons compared with DR neurons. Incubation for 4 days with IL-6 increased DIO neuron Lepr-b expression by 77% and BBS6 by 290% and corrected their defective leptin activation of LepE neurons to DR levels. Since BBS6 enhances trafficking of Lepr-b to the cell membrane, the increases in Lepr-b and BBS6 expression appear to account for correction of the reduced leptin excitation of DIO LepE neurons to that of control DR rats. These data support prior findings suggesting that IL-6 mediates the leptin-sensitizing effects of amylin on VMN neurons and that the inherent leptin resistance of DIO rats can be effectively reversed at a cellular level by IL-6.

scholarly journals The metabolic hormone leptin promotes the function of TFH cells and supports vaccine responses

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jun Deng ◽  
Qian Chen ◽  
Zhian Chen ◽  
Kaili Liang ◽  
Xin Gao ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Serum Levels ◽  
Affinity Maturation ◽  
Antibody Responses ◽  
Vaccine Failure ◽  
Vaccine Responses ◽  
Follicular Helper ◽  
B Virus ◽  
And Function ◽  
Metabolic Hormone

AbstractFollicular helper T (TFH) cells control antibody responses by supporting antibody affinity maturation and memory formation. Inadequate TFH function has been found in individuals with ineffective responses to vaccines, but the mechanism underlying TFH regulation in vaccination is not understood. Here, we report that lower serum levels of the metabolic hormone leptin associate with reduced vaccine responses to influenza or hepatitis B virus vaccines in healthy populations. Leptin promotes mouse and human TFH differentiation and IL-21 production via STAT3 and mTOR pathways. Leptin receptor deficiency impairs TFH generation and antibody responses in immunisation and infection. Similarly, leptin deficiency induced by fasting reduces influenza vaccination-mediated protection for the subsequent infection challenge, which is mostly rescued by leptin replacement. Our results identify leptin as a regulator of TFH cell differentiation and function and indicate low levels of leptin as a risk factor for vaccine failure.

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