Bsx, a novel hypothalamic factor linking feeding with locomotor activity, is regulated by energy availability

Ruben Nogueiras, Miguel Lopez, Ricardo Lage, Diego Perez-Tilve, Paul T Pfluger, Hugo Mendieta-Zeron, Maria Sakkou, Petra Wiedmer, Stephen C Benoit, Rakesh Datta, Jesse Z Dong, Michael D Culler, Mark W Sleeman, Antonio Vidal-Puig, Tamas L Horvath, Mathias Treier, Carlos Dieguez, Matthias H Tschop

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Abstract

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.
Original languageEnglish
Pages (from-to)3009 - 3015
Number of pages7
JournalEndocrinology
Volume149
Issue number6
DOIs
Publication statusPublished - 2008
Externally publishedYes

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