e The molecular basis underlying the physiologically well-defined orexigenic function of glucocorticoid (Gc) is unclear. Brainspecific homeobox factor (Bsx) is a positive regulator of the orexigenic neuropeptide, agouti-related peptide (AgRP), in AgRP neurons of the hypothalamic arcuate nucleus. Here, we show that in response to fasting-elevated Gc levels, Gc receptor (GR) and Bsx synergize to direct activation of AgRP transcription. This synergy is dictated by unique sequence features in a novel Gc response element in AgRP (AgRP-GRE). In contrast to AgRP-GRE, Bsx suppresses transactivation directed by many conventional GREs, functioning as a gene context-dependent modulator of GR actions or a target selector for GR. Consistent with this finding, AgRP-GRE drives fasting-dependent activation of a target gene specifically in GR ؉ Bsx ؉ AgRP neurons. These results define AgRP as a common orexigenic target gene of GR and Bsx and provide an opportunity to identify their additional common targets, facilitating our understanding of the molecular basis underlying the orexigenic activity of Gc and Bsx.

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 ...