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Kim, Jae Geun,Park, Byong Seo,Yun, Chang Ho,Kim, Hyun Jun,Kang, Sang Soo,D’Elia, Angela Valentina,Damante, Giuseppe,Lee, Ki-Up,Park, Jeong Woo,Kim, Eun Sook,Namgoong, Il Seong,Kim, Young Il,Lee, Byung American Diabetes Association 2011 Diabetes Vol.60 No.3
<P><B>OBJECTIVE</B></P><P>α-Melanocyte–stimulating hormone (α-MSH) and agouti-related peptide (AgRP) control energy homeostasis by their opposing actions on melanocortin receptors (MC3/4R) in the hypothalamus. We previously reported that thyroid transcription factor-1 (TTF-1) controls feeding behavior in the hypothalamus. This study aims to identify the function of TTF-1 in the transcriptional regulation of AgRP and α-MSH synthesis for the control of feeding behavior.</P><P><B>RESEARCH DESIGN AND METHODS</B></P><P>TTF-1 activity in AgRP and pro-opiomelanocortin (POMC) transcription was examined using gel-shift and promoter assays and an in vivo model of TTF-1 synthesis inhibition by intracerebroventricular injection of an antisense (AS) oligodeoxynucleotide (ODN). Double immunohistochemistry was performed to colocalize TTF-1 and AgRP or α-MSH in the hypothalamic arcuate nucleus (ARC). To determine whether TTF-1 action on food intake is mediated through MC3/4R, we measured changes in food intake upon intracerebroventricular injection of MC3/4R antagonists (SHU9119 and AgRP) into rat brain preinjected with the AS ODN.</P><P><B>RESULTS</B></P><P>TTF-1 stimulated AgRP but inhibited POMC transcription by binding to the promoters of these genes. TTF-1 was widely distributed in the hypothalamus, but we identified some cells coexpressing TTF-1 and AgRP or α-MSH in the ARC. In addition, intracerebroventricular administration of leptin decreased TTF-1 expression in the hypothalamus, and AS ODN-induced inhibition of TTF-1 expression decreased food intake and AgRP expression but increased α-MSH expression. Anorexia induced by the AS ODN was attenuated by the administration of MC3/4R antagonists.</P><P><B>CONCLUSIONS</B></P><P>TTF-1 transcriptionally regulates synthesis of AgRP and α-MSH in the ARC and affects feeding behavior via the melanocortin pathway.</P>