Brain-Specific Homeobox Factor as a Target Selector for Glucocorticoid Receptor in Energy Balance

Lee, Bora; Kim, Sun Gyun; Kim, Juhee; Choi, Kwan Yong; Lee, Seung‐Hee; Lee, Soo Kyung; Lee, Jae Woo

doi:10.1128/mcb.00094-13

Cited by 37 publications

(36 citation statements)

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“…In terms of food intake, the orexigenic function of GCs appear to be under the control of GR action in the nervous system [18]. In particular, these functions are largely localised to specialised neuronal populations in the hypothalamus and involve a complex interplay between regulated expression of orexigenic neuropeptides agouti-related peptide (AgRP) and neuropeptide Y (NPY) in response to peripheral signals [18][19][20][21]. In terms of the effects of GC on energy expenditure, several explanations have emerged.…”

Section: Gcs In Whole-body Energy Balancementioning

confidence: 99%

Glucocorticoid hormones and energy homeostasis

Guia

Rose

Herzig³

2014

Hormone Molecular Biology and Clinical Investigation

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Glucocorticoids (GC) and their cognate intracellular receptor, the glucocorticoid receptor (GR), have been characterised as critical checkpoints in the endocrine control of energy homeostasis in mammals. Indeed, aberrant GC action has been linked to a variety of severe metabolic diseases, including obesity, insulin resistance and type 2 diabetes. As a steroid-binding member of the nuclear receptor superfamily of transcription factors, the GR translocates into the cell nucleus upon GC binding where it serves as a transcriptional regulator of distinct GC-responsive target genes that are - in many cases - associated with glucose and lipid regulatory pathways and thereby intricately control both physiological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of GC/GR function in energy metabolism and systemic metabolic dysfunction, particularly focusing on glucose and lipid metabolism.

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Section: Gcs In Whole-body Energy Balancementioning

confidence: 99%

Glucocorticoid hormones and energy homeostasis

Guia

Rose

Herzig³

2014

Hormone Molecular Biology and Clinical Investigation

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“…Similarly agouti-related protein ( Agrp ) expression follows this inconsistency in response to Cort treatment (7, 8). Although the Gc-response elements (GREs) are present within the promotor regions of Agrp (9), Pomc (10), and neuropeptide Y ( Npy ) (11), the effect of chronic Gc treatment is still unclear.…”

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confidence: 99%

Elevated Hypothalamic Glucocorticoid Levels Are Associated With Obesity and Hyperphagia in Male Mice

et al. 2016

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Glucocorticoid (Gc) excess, from endogenous overproduction in disorders of the hypothalamic-pituitary-adrenal axis or exogenous medical therapy, is recognized to cause adverse metabolic side effects. The Gc receptor (GR) is widely expressed throughout the body, including brain regions such as the hypothalamus. However, the extent to which chronic Gcs affect Gc concentrations in the hypothalamus and impact on GR and target genes is unknown. To investigate this, we used a murine model of corticosterone (Cort)-induced obesity and analyzed Cort levels in the hypothalamus and expression of genes relevant to Gc action. Mice were administered Cort (75 μg/mL) or ethanol (1%, vehicle) in drinking water for 4 weeks. Cort-treated mice had increased body weight, food intake, and adiposity. As expected, Cort increased plasma Cort levels at both zeitgeber time 1 and zeitgeber time 13, ablating the diurnal rhythm. Liquid chromatography dual tandem mass spectrometry revealed a 4-fold increase in hypothalamic Cort, which correlated with circulating levels and concentrations of Cort in other brain regions. This occurred despite decreased 11β-hydroxysteroid dehydrogenase (Hsd11b1) expression, the gene encoding the enzyme that regenerates active Gcs, whereas efflux transporter Abcb1 mRNA was unaltered. In addition, although Cort decreased hypothalamic GR (Nr3c1) expression 2-fold, the Gc-induced leucine zipper (Tsc22d3) mRNA increased, which indicated elevated GR activation. In keeping with the development of hyperphagia and obesity, Cort increased Agrp, but there were no changes in Pomc, Npy, or Cart mRNA in the hypothalamus. In summary, chronic Cort treatment causes chronic increases in hypothalamic Cort levels and a persistent elevation in Agrp, a mediator in the development of metabolic disturbances.

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“…The region between nucleotides Ϫ127 and ϩ29 of the mouse NOR1 promoter was amplified using the following primers: ACC CTC GCA CAC GCG GAA C (forward) and TTC GCT CGC TCT CTC GGC AC (reverse). The primers for the AgRP-GRE were as reported previously (7).…”

Section: Methodsmentioning

confidence: 99%

“…An actin ␤-galactosidase plasmid was cotransfected as a control for transfection efficiency, and empty vectors were used to equalize the total amount of DNA. The luciferase assays were done as described previously (7).…”

Section: Methodsmentioning

confidence: 99%

“…Interestingly, the hypothalamic mTOR pathway has been shown to mediate the T3-induced hyperphagia in hyperthyroidism by triggering the increased expression of AgRP and NPY and the decreased expression of ␣MSH, likely through the arcuate thyroid hormone receptor ␣ (6). In addition, we have found that the well-defined peripheral orexigenic signal glucocorticoid (Gc) directly upregulates the expression of AgRP in AgRP neurons by triggering the Gc receptor (GR) to functionally bind to a novel Gc response element (GRE) located in the promoter region of AgRP that we named the AgRP-GRE (7). Overall, increasing our knowledge of gene regulatory networks of NRs in the CNS control of energy balance remains an interesting challenge.…”

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confidence: 99%

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Control of Energy Balance by Hypothalamic Gene Circuitry Involving Two Nuclear Receptors, Neuron-Derived Orphan Receptor 1 and Glucocorticoid Receptor

Kim

Lee

Kim

et al. 2013

Molecular and Cellular Biology

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e Nuclear receptors (NRs) regulate diverse physiological processes, including the central nervous system control of energy balance. However, the molecular mechanisms for the central actions of NRs in energy balance remain relatively poorly defined. Here we report a hypothalamic gene network involving two NRs, neuron-derived orphan receptor 1 (NOR1) and glucocorticoid receptor (GR), which directs the regulated expression of orexigenic neuropeptides agouti-related peptide (AgRP) and neuropeptide Y (NPY) in response to peripheral signals. Our results suggest that the anorexigenic signal leptin induces NOR1 expression likely via the transcription factor cyclic AMP response element-binding protein (CREB), while the orexigenic signal glucocorticoid mobilizes GR to inhibit NOR1 expression by antagonizing the action of CREB. Also, NOR1 suppresses glucocorticoid-dependent expression of AgRP and NPY. Consistently, relative to wild-type mice, NOR1-null mice showed significantly higher levels of AgRP and NPY and were less responsive to leptin in decreasing the expression of AgRP and NPY. These results identify mutual antagonism between NOR1 and GR to be a key rheostat for peripheral metabolic signals to centrally control energy balance.T he first group of neurons that encounters peripheral metabolic signals, such as leptin, insulin, and ghrelin, thereby transducing their action to control energy balance to the rest of the central nervous system (CNS), is clustered in the arcuate nucleus region of the hypothalamus (ARC) (1, 2). Two types of metabolic neurons in the ARC have been particularly well characterized, i.e., neurons that express the orexigenic neuropeptides agouti-related peptide (AgRP) and neuropeptide Y (NPY), herein named AgRP neurons, and neurons expressing the anorexigenic neuropeptides ␣-melanocyte-stimulating hormone (␣MSH), a proteolytic product of pro-opiomelanocortin (POMC), and cocaine-and amphetamine-regulated transcript (CART), herein named POMC neurons. The anorexigenic signals insulin and leptin, which are critical adiposity signals that circulate in proportion to the body fat mass, stimulate POMC neurons and inactivate AgRP neurons to inhibit food intake and increase energy expenditure (1, 2). In contrast, the orexigenic signal ghrelin, a circulating peptide secreted from the stomach, activates AgRP neurons, thereby stimulating food intake. Thus, interplays among leptin, insulin, ghrelin, and AgRP and POMC neurons play important roles in maintaining normal energy balance, and deregulation of these communications leads to obesity and type II diabetes (1, 2).Nuclear receptors (NRs) have been extensively studied as critical regulators of a diverse array of physiological processes in the human body, including the CNS control of energy balance (3). In particular, recent progress has uncovered the roles of NRs in energy balance that involve the arcuate POMC and AgRP neurons. For example, it has been suggested that estrogen exerts its anorexigenic function through AgRP neurons and that, interestingly, this ...

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Brain-Specific Homeobox Factor as a Target Selector for Glucocorticoid Receptor in Energy Balance

Cited by 37 publications

References 36 publications

Glucocorticoid hormones and energy homeostasis

Glucocorticoid hormones and energy homeostasis

Elevated Hypothalamic Glucocorticoid Levels Are Associated With Obesity and Hyperphagia in Male Mice

Control of Energy Balance by Hypothalamic Gene Circuitry Involving Two Nuclear Receptors, Neuron-Derived Orphan Receptor 1 and Glucocorticoid Receptor

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