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Bsx, a Novel Hypothalamic Factor Linking Feeding with Locomotor Activity, Is Regulated by Energy Availability

Department of Psychiatry (R.N., D.P.-T., P.P., S.C.B., M.H.T.), Obesity Research Centre, University of Cincinnati, Cincinnati, Ohio 45237; Department of Physiology (M.L., R.L., H.M.-Z., C.D.), Centro de Investigación Biomédica en Red, Fisiopatologia de la Obesidad y Nutrición, Instituto de Salud Carlos III, Faculty of Medicine, University of Santiago de Compostela, 15 782 Santiago de Compostela, Spain; Developmental Biology Unit (M.Sa., M.T.), European Molecular Biology Laboratory, 69117 Heidelberg, Germany; Department of Pharmacology (P.W.), German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany; Biomeasure Incorporated/Ipsen (R.D., J.Z.D., M.C.), Milford, Massachusetts 01757; Regeneron Pharmaceuticals (M.Sl.), Tarrytown, New York 10591; Department of Clinical Biochemistry (A.V.-P.), Addenbrooke’s Hospital, University of Cambridge, CB2 2SP Cambridge, United Kingdom; and Department of Obstetrics (T.H.), Yale University School of Medicine, New Haven, Connecticut 06510

Address all correspondence and requests for reprints to: Matthias H. Tschöp, M.D., Department of Psychiatry, Obesity Research Center, University of Cincinnati-Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237. E-mail: tschoemh{at}ucmail.uc.edu.

We recently reported that the hypothalamic homeobox domain transcription factor Bsx plays an essential role in the central nervous system control of spontaneous physical activity and the generation of hyperphagic responses. Moreover, we found Bsx to be a master regulator for the hypothalamic expression of key orexigenic neuropeptide Y and agouti gene-related protein. We now hypothesized that Bsx, which is expressed in the dorsomedial and arcuate nucleus (ARC) of the hypothalamus, is regulated by afferent signals in response to peripheral energy balance. Bsx expression was analyzed using in situ hybridization in fed vs. fasted (24 h) and ghrelin vs. leptin-treated rats, as well as in mice deficient for leptin or the ghrelin signaling. Ghrelin administration increased, whereas ghrelin receptor antagonist decreased ARC Bsx expression. Leptin injection attenuated the fasting-induced increase in ARC Bsx levels but had no effect in fed rats. Dorsomedial hypothalamic nucleus Bsx expression was unaffected by pharmacological modifications of leptin or ghrelin signaling. Obese leptin-deficient (ob/ob) mice, but not obese melanocortin 4 receptor-knockout mice, showed higher expression of Bsx, consistent with dependency from afferent leptin rather than increased adiposity per se. Interestingly, exposure to a high-fat diet triggered Bsx expression, consistent with the concept that decreased leptin signaling due to a high-fat diet induced leptin resistance. Our data indicate that ARC Bsx expression is specifically regulated by afferent energy balance signals, including input from leptin and ghrelin. Future studies will be necessary to test if Bsx may be involved in the pathogenesis of leptin resistance.