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

Abstract

The molecular basis underlying the physiologically well-defined orexigenic function of glucocorticoid (Gc) is unclear. Brain-specific 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.

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SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00094-13.

ACKNOWLEDGMENTS

This work was supported by grants from the NIH (DK064678 to J.W.L. and NS054941 to S.K.L.); March of Dimes and Christopher Reeve Foundation (S.K.L.); Research Institute of Pharmaceutical Sciences, Research Settlement Fund for the new faculty of SNU, POSCO TJ Park Science Fellowship, Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Education, Science, and Technology (2012R1A1A1001749), and National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1220120) (S.L.); and the World Class University program through the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (R31-10105) (J.W.L. and K.Y.C.).

We thank Dan Marks and Roger Cone for help with intracerebroventricular injection and reagents and Karen Thiebes for critical reading of the manuscript.