Regulation of hypothalamic gene expression by glucocorticoid: implications for energy homeostasis

Abstract

Using the serial analysis of gene expression (SAGE) method, we studied the effects of adrenalectomy (ADX) and GC on the transcriptomes of mouse hypothalamus. Approximately 180,000 SAGE tags, which correspond to 50,000 tag species, were isolated from each group of intact or adrenalectomized mice as well as 1, 3, and 24 h after GC injection. ADX upregulated diazepam binding inhibitor gene expression while downregulating vomeronasal 1 receptor D4, genes involved in mitochondrial phosphorylation (cytochrome-c oxidase 1 and NADH dehydrogenase 3), 3␤-hydroxysteroid dehydrogenase-1, and prostaglandin D2 synthase. GC increased the gene expression levels of dehydrogenase/reductase member 3, prostaglandin D2 synthase, solute carrier family 4 member 4, and five cytoskeletal proteins including myosin light chain phosphorylatable fast and troponin C2 fast. On the other hand, GC reduced the mRNA levels of calmodulin 1 and expressed sequence tag similar to calmodulin 2, ATP synthase F0 subunit 6, and solute carrier family 4 member 3. Moreover, 7 uncharacterized and 43 novel transcripts were modulated by ADX and GC. The present study has identified genes that may regulate hypothalamic systems governing energy balance in response to ADX and GC.transcriptome; serial analysis of gene expression; adrenalectomy; obesity CLINICAL FEATURES OF ANOREXIA and weight loss in patients with adrenal insufficiency as well as increased food intake and weight gain in patients with glucocorticoid (GC) excess implicate adrenal GC in energy homeostasis (18). Obesity is dependent on GC action, because rodent models of obesity with pathologies of genetic (13), dietary (65), and hypothalamic (38) origins are normalized by adrenalectomy (ADX) and restored by GC replacement (27). In normal rodents and humans, GC increases food intake and body weight, as well as inducing metabolic features of obesity, such as insulin resistance, hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia (30, 76). Interestingly, an administration of leptin, which barely affects body weight and food intake, becomes powerful and long-lasting in ADX rats, suggesting that GC antagonizes the central action of leptin (75). GC not only increases food intake but also decreases energy expenditure by suppressing thermogenesis in mouse brown adipose tissue (63). Thus GC promotes positive energy balance, whereas a lack of GC is linked to hypophagia and reduced body weight.The hypothalamus is a brain center that regulates energy homeostasis by integrating peripheral signals such as leptin, insulin, and GC. Thus the effects of ADX and GC on hypothalamic gene expression have been a major focus of many previous studies (45,54,60,73). However, no study has previously investigated effects of ADX and GC in the transcriptome of the hypothalamus. The serial analysis gene expression (SAGE) method accurately measures the expression levels of tens of thousands of genes, previously known or not, and finds the genes related to diseases or the effects of stimuli (59,68). Although other techniques ...

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