Enhancement of Hypothalamic STAT3 Acetylation by Nuclear Receptor Nur77 Dictates Leptin Sensitivity

Abstract

Leptin, an anorexigenic hormone in the hypothalamus, suppresses food intake and increases energy expenditure. Failure to respond to leptin will lead to obesity. Here, we discovered that nuclear receptor Nur77 expression is lower in the hypothalamus of obese mice compared with normal mice. Injection of leptin results in significant reduction in body weight in wild-type mice but not in Nur77 knockout (KO) littermates or mice with specific Nur77 knockdown in the hypothalamus. Hypothalamic Nur77 not only participates in leptin central control of food intake but also expands leptin's reach to liver and adipose tissues to regulate lipid metabolism. Nur77 facilitates signal transducer and activator of transcription 3 (STAT3) acetylation by recruiting acetylase p300 and disassociating deacetylase histone deacetylase 1 (HDAC1) to enhance the transcriptional activity of STAT3 and consequently modulates the expression of downstream gene Pomc in the hypothalamus. Nur77 deficiency compromises response to leptin in mice fed a high-fat diet. Severe leptin resistance in Nur77 KO mice with increased appetite, lower energy expenditure, and hyperleptinemia contributes to aginginduced obesity. Our study opens a new avenue for regulating metabolism with Nur77 as the positive modulator in the leptin-driven antiobesity in the hypothalamus.The hypothalamus is the major center for regulating energy homeostasis by sensing and responding to input from hormonal and nutrient-related signals (1). Among various signals sensed by the hypothalamus, leptin is an important hormone derived from adipocytes with a key role in representing nutritional status to the hypothalamus for the regulation of energy balance (2). This regulation is mostly mediated by several well-structured nuclei in the hypothalamus, especially in arcuate nucleus (ARC) (3). Two distinct populations of neurons in ARC, proopiomelanocortin (Pomc) neurons and agouti-related protein (AgRp) neurons, are regulated by leptin in completely different fashions. Leptin suppresses the expression of orexigenic neuropeptide AgRp and neuropeptide Y (NPY) in AgRp neurons but upregulates the expression of anorexigenic neuropeptide Pomc in Pomc neurons (3). Leptin's function in these neurons is critical to normal food intake and body weight, and its dysregulation would break energy homeostasis. Leptin signaling ablation from the mutations of db or ob genes in mice would result in severe obesity and diabetes (4). Administration of leptin greatly reduces body weight and food intake in normal mice but not in obese mice. This phenomenon, together with higher circulating leptin level in the obese, is the so-called leptin resistance.Signal transducer and activator of transcription 3 (STAT3) is an important downstream component in leptin signaling on energy balance for the regulation of body weight and food intake (5). Mouse models with neural deletion of STAT3 develop hyperphagia and obesity, as well as severe diabetes (6). As Tyr 1138 of OB-Rb (the long form of leptin receptor) is specific for STAT3 ...

Effects of Leptin on Na+/Ca2+ Exchanger in PC12 Cells

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Leptin-Sensitive JAK2 Activation in the Regulation of Tau Phosphorylation in PC12 Cells

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Effects of glyceollin on mRNA expression in the female mouse brain.

“…In contrast, the previous study used only 4 h serum starvation prior to E2 treatment (Friedman 2013 In addition to ERs, of special interest was the finding that these mouse hypothalamic cell lines express the orphan nuclear receptor, Nr4a1. Nr4a1 is induced in the hypothalamus in response to stress (Helbling et al 2014), and it plays a role in leptin's central control of food intake (Chen et al 2015) and in learning and memory (McNulty et al 2012). This is the first report demonstrating Nr4a1 expression in a murine hypothalamic cell line.…”

“…Nr4a1 is moderately expressed in various hypothalamic nuclei (Saucedo-Cardenas and Conneely 1996). Nr4a1 is downregulated by E2 in the mouse hypothalamus (Lundholm et al 2008) and plays a functional role in stress responses (Helbling et al 2014), food intake (Chen et al 2015), and cognition (McNulty et al 2012). Nr4a1 is also highly expressed in the hippocampus, with highest expression in the CA1 region (McNulty et al 2012;Saucedo-Cardenas and Conneely 1996).…”

“…Kiss1 expression was reported in all cell lines tested in this study (Friedman 2013;Kim 2010), whereas this is the first examination of Gh and Prl expression in these cell lines. In addition, we examined the expression of Nr4a1, an orphan nuclear receptor, which is expressed in the hypothalamus, is regulated by E2 (Lundholm et al 2008;Saucedo-Cardenas and Conneely 1996) and plays a functional role in stress responses (Helbling et al 2014), food intake (Chen et al 2015), and …”