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 Knockout Mice Lacking Steroidogenic Factor 1 Are a Novel Genetic Model of Hypothalamic Obesity

Endocrinology ◽  
2002 ◽  
Vol 143 (2) ◽  
pp. 607-614 ◽  
Author(s):  
Gregor Majdic ◽  
Morag Young ◽  
Elise Gomez-Sanchez ◽  
Paul Anderson ◽  
Lidia S. Szczepaniak ◽  
...  
Keyword(s):  
Genetic Model ◽  
Late Onset ◽  
Ventromedial Hypothalamus ◽  
Hypothalamic Nucleus ◽  
Weight Regulation ◽  
Wild Type ◽  
Hypothalamic Obesity ◽  
Steroidogenic Factor 1 ◽  
Ventromedial Hypothalamic Nucleus

Abstract Knockout (KO) mice lacking steroidogenic factor 1 (SF-1) exhibit a phenotype that includes adrenal and gonadal agenesis, impaired gonadotropin expression, and abnormalities of the ventromedial hypothalamic nucleus (VMH). Studies in rodents with lesions of the ventromedial hypothalamus have implicated the VMH in body weight regulation, suggesting that SF-1 KO mice may provide a genetic model of obesity. To prevent death, SF-1 KO mice were rescued with corticosteroid injections, followed by syngeneic adrenal transplants from wild-type (WT) littermates. Corticosterone and ACTH levels in WT and SF-1 KO mice were indistinguishable, documenting restoration of hypothalamic-pituitary-adrenal function. Although weights at earlier ages did not differ significantly from WT littermates, SF-1 KO mice were significantly heavier by 8 wk of age and eventually weighed almost twice as much as WT controls. Obesity in SF-1 KO mice predominantly resulted from decreased activity rather than increased food intake. Leptin was increased markedly, insulin was modestly elevated, and glucose was indistinguishable from WT mice. Although sex steroids in rodents affect weight, ovariectomy did not abolish the weight difference between WT and SF-1 KO mice. These SF-1 KO mice are a genetic model of late-onset obesity that may help elucidate the role of the VMH in weight regulation.

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 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 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.

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