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 Norepinephrine Regulation of Ventromedial Hypothalamic Nucleus Astrocyte Glycogen Metabolism

2021 ◽  
Vol 22 (2) ◽  
pp. 759
Author(s):  
Karen P. Briski ◽  
Mostafa M. H. Ibrahim ◽  
A. S. M. Hasan Mahmood ◽  
Ayed A. Alshamrani
Keyword(s):  
Alternative Energy ◽  
Glycogen Synthase ◽  
Glycogen Metabolism ◽  
Receptor Expression ◽  
Hypothalamic Nucleus ◽  
Control Structures ◽  
Ventromedial Hypothalamic Nucleus ◽  
Glycogen Reserve ◽  
Noradrenergic Modulation ◽  
The Brain

The catecholamine norepinephrine (NE) links hindbrain metabolic-sensory neurons with key glucostatic control structures in the brain, including the ventromedial hypothalamic nucleus (VMN). In the brain, the glycogen reserve is maintained within the astrocyte cell compartment as an alternative energy source to blood-derived glucose. VMN astrocytes are direct targets for metabolic stimulus-driven noradrenergic signaling due to their adrenergic receptor expression (AR). The current review discusses recent affirmative evidence that neuro-metabolic stability in the VMN may be shaped by NE influence on astrocyte glycogen metabolism and glycogen-derived substrate fuel supply. Noradrenergic modulation of estrogen receptor (ER) control of VMN glycogen phosphorylase (GP) isoform expression supports the interaction of catecholamine and estradiol signals in shaping the physiological stimulus-specific control of astrocyte glycogen mobilization. Sex-dimorphic NE control of glycogen synthase and GP brain versus muscle type proteins may be due, in part, to the dissimilar noradrenergic governance of astrocyte AR and ER variant profiles in males versus females. Forthcoming advances in the understanding of the molecular mechanistic framework for catecholamine stimulus integration with other regulatory inputs to VMN astrocytes will undoubtedly reveal useful new molecular targets in each sex for glycogen mediated defense of neuronal metabolic equilibrium during neuro-glucopenia.

Abstinence from chronic methylphenidate exposure modifies cannabinoid receptor 1 levels in the brain in a dose-dependent manner

2021 ◽  
Vol 27 ◽  
Author(s):  
Carly Connor ◽  
John Hamilton ◽  
Lisa Robison ◽  
Michael Hadjiargyrou ◽  
David Komatsu ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
High Dose ◽  
Dependent Manner ◽  
Water Control ◽  
Cannabinoid Receptor 1 ◽  
The Brain ◽  
Abstinence Period

Introduction: Methylphenidate (MP) is a widely used psychostimulant prescribed for Attention Deficit Hyperactivity Disorder, and is also used illicitly by healthy individuals. Chronic exposure to MP has been shown to affect physiology, behavior, and neurochemistry. Methods: The present study examined its effect on the endocannabinoid system. Adolescent rats had daily oral access to either water (control), low dose MP (4/10 mg/kg), or high dose MP (30/60 mg/kg). After 13 weeks of exposure, half of the rats in each group were euthanized, however the remaining rats underwent a four-week long abstinence period. Cannabinoid receptor 1 binding (CB1) was measured with in vitro autoradiography using [3H] SR141716A. Results: Rats who underwent a 4-week abstinence period after exposure to chronic HD MP showed increased binding compared to rats with no abstinence period in several cortical and basal ganglia regions of the brain. In contrast to this, rats who underwent a 4-week abstinence period after exposure to chronic LD MP showed lower binding compared to rats with no abstinence period in mainly the basal ganglia regions and in the hindlimb region of the somatosensory cortex. Following 4 weeks of drug abstinence, rats who were previously given HD MP showed higher [ 3H] SR141716A binding than rats given LD MP in many of the cortical and basal ganglia regions examined. These results highlight biphasic effects of MP treatment on cannabinoid receptor levels. Abstinence from HD MP seemed to increase CB1 receptor levels while abstinence from LD MP seemed to decrease CB1 levels. Conclusion: Given the prolific expression of cannabinoid receptors throughout the brain, many types of behaviors may be affected as a result of MP abstinence. Further research will be needed to help identify these behavioral changes.

scholarly journals Novel Role for the Nuclear Phosphoprotein SET in Transcriptional Activation of P450c17 and Initiation of Neurosteroidogenesis

2000 ◽  
Vol 14 (6) ◽  
pp. 875-888 ◽  
Author(s):  
Nathalie A. Compagnone ◽  
Peilin Zhang ◽  
Jean-Louis Vigne ◽  
Synthia H. Mellon
Keyword(s):  
Transcriptional Activation ◽  
Neuronal Morphology ◽  
Steroidogenic Factor 1 ◽  
Mouse Fetus ◽  
Neuronal Precursor Cells ◽  
Endogenous Regulators ◽  
Nuclear Phosphoprotein ◽  
Inducible Protein ◽  
And Function ◽  
The Brain

Abstract Neurosteroids are important endogenous regulators of γ-aminobutryic acid (GABAA) and N-methyl-d-aspartate (NMDA) receptors and also influence neuronal morphology and function. Neurosteroids are produced in the brain using many of the same enzymes found in the adrenal and gonad. The crucial enzyme for the synthesis of DHEA (dehydroepiandrosterone) in the brain is cytochrome P450c17. The transcriptional strategy for the expression of P450c17 is clearly different in the brain from that in the adrenal or gonad. We previously characterized a novel transcriptional regulator from Leydig MA-10 cells, termed StF-IT-1, that binds at bases −447/−399 of the rat P450c17 promoter, along with the known transcription factors COUP-TF (chicken ovalbumin upstream promoter transcription factor), NGF-IB (nerve growth factor inducible protein B), and SF-1 (steroidogenic factor-1). We have now purified and sequenced this protein from immature porcine testes, identifying it as the nuclear phosphoprotein SET; a role for SET in transcription was not established previously. Binding of bacterially expressed human and rat SET to the DNA site at −418/−399 of the rat P450c17 gene transactivates P450c17 in neuronal and in testicular Leydig cells. We also found SET expressed in human NT2 neuronal precursor cells, implicating a role in neurosteroidogenesis. Immunocytochemistry and in situ hybridization in the mouse fetus show that the ontogeny and distribution of SET in the developing nervous system are consistent with SET being crucial for initiating P450c17 transcription. SET’s developmental pattern of expression suggests it may participate in the early ontogenesis of the nervous, as well as the skeletal and hematopoietic, systems. These studies delineate an important new factor in the transcriptional regulation of P450c17 and consequently, in the production of DHEA and sex steroids.

scholarly journals Metabolic Sensing and the Brain: Who, What, Where, and How?

Endocrinology ◽  
2011 ◽  
Vol 152 (7) ◽  
pp. 2552-2557 ◽  
Author(s):  
Barry E. Levin ◽  
Christophe Magnan ◽  
Ambrose Dunn-Meynell ◽  
Christelle Le Foll
Keyword(s):  
Energy Homeostasis ◽  
Distributed Network ◽  
Metabolic Substrates ◽  
Hepatic Portal Vein ◽  
Metabolic Sensing ◽  
Hepatic Portal ◽  
And Function ◽  
The Brain ◽  
Local Brain ◽  
Brain Barriers

Unique subpopulations of specialized metabolic sensing neurons reside in a distributed network throughout the brain and respond to alterations in ambient levels of various metabolic substrates by altering their activity. Variations in local brain substrate levels reflect their transport across the blood- and cerebrospinal-brain barriers as well as local production by astrocytes. There are a number of mechanisms by which such metabolic sensing neurons alter their activity in response to changes in substrate levels, but it is clear that these neurons cannot be considered in isolation. They are heavily dependent on astrocyte and probably tanycyte metabolism and function but also respond to hormones (e.g. leptin and insulin) and cytokines that cross the blood-brain barrier from the periphery as well as hard-wired neural inputs from metabolic sensors in peripheral sites such as the hepatic portal vein, gastrointestinal tract, and carotid body. Thus, these specialized neurons are capable of monitoring and integrating multiple signals from the periphery as a means of regulating peripheral energy homeostasis.

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.

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