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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>
Matagne, V.,Kim, J. G.,Ryu, B. J.,Hur, M. K.,Kim, M. S.,Kim, K.,Park, B. S.,Damante, G.,Smiley, G.,Lee, B. J.,Ojeda, S. R. Blackwell Publishing Ltd 2012 Journal of neuroendocrinology Vol.24 No.6
<P>Thyroid transcription factor 1 (TTF1), a member of the Nkx family of transcription factors required for basal forebrain morphogenesis, functions in the postnatal hypothalamus as a transcriptional regulator of genes encoding neuromodulators and hypophysiotrophic peptides. One of these peptides is gonadotrophin‐releasing hormone (GnRH). In the present study, we show that <I>Ttf1</I> mRNA abundance varies in a diurnal and melatonin‐dependent fashion in the preoptic area of the rat, with maximal <I>Ttf1</I> expression attained during the dark phase of the light/dark cycle, preceding the nocturnal peak in <I>GnRH</I> mRNA content. <I>GnRH</I> promoter activity oscillates in a circadian manner in GT1‐7 cells, and this pattern is enhanced by TTF1 and blunted by small interfering RNA‐mediated <I>Ttf1</I> gene silencing. TTF1 transactivates <I>GnRH</I> transcription by binding to two sites in the GnRH promoter. Rat GnRH neurones <I>in situ</I> contain key proteins components of the positive (BMAL1, CLOCK) and negative (PER1) limbs of the circadian oscillator, and these proteins repress <I>Ttf1</I> promoter activity <I>in vitro</I>. By contrast, <I>Ttf1</I> transcription is activated by CRY1, a clock component required for circadian rhythmicity. In turn, TTF1 represses transcription of <I>Rev‐erbα</I>, a heme receptor that controls circadian transcription within the positive limb of the circadian oscillator. These findings suggest that TTF1 is a component of the molecular machinery controlling circadian oscillations in <I>GnRH</I> gene transcription.</P>