Thyroid transcription factor-1 regulates feeding behavior via melanocortin pathway in the hypothalamus.

Abstract

OBJECTIVE:

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.

RESEARCH DESIGN AND METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

TTF-1 transcriptionally regulates synthesis of AgRP and α-MSH in the ARC and affects feeding behavior via the melanocortin pathway.

• Authors: Jae Geun Kim, Byong Seo Park, Chang Ho Yun, Hyun Jun Kim, Sang Soo Kang, Angela Valentina D'Elia, Giuseppe Damante, Ki-Up Lee, Jeong Woo Park, Eun Sook Kim, Il Seong Namgoong, Young Il Kim, Byung Ju Lee
• Journal: Diabetes (Diabetes) Vol. 60 Issue 3 Pg. 710-9 (Mar 2011) ISSN: 1939-327X [Electronic] United States
• PMID: 21282365 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Agouti-Related Protein
• Nkx2-1 protein, mouse
• Nkx2-1 protein, rat
• Nuclear Proteins
• Oligodeoxyribonucleotides, Antisense
• RNA, Messenger
• Thyroid Nuclear Factor 1
• Transcription Factors
• SHU 9119
• alpha-MSH
• Melanocyte-Stimulating Hormones

Topics

• Agouti-Related Protein (genetics, metabolism, pharmacology)
• Analysis of Variance
• Animals
• Arcuate Nucleus of Hypothalamus (drug effects, physiology)
• Blotting, Western
• Cell Line
• Cells, Cultured
• Eating (drug effects, physiology)
• Electrophoretic Mobility Shift Assay
• Feeding Behavior (drug effects, physiology)
• Immunohistochemistry
• In Situ Hybridization
• Melanocyte-Stimulating Hormones (pharmacology)
• Mice
• Nuclear Proteins (genetics, metabolism)
• Oligodeoxyribonucleotides, Antisense
• Promoter Regions, Genetic
• RNA, Messenger (genetics, metabolism)
• Rats
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (physiology)
• Thyroid Nuclear Factor 1
• Transcription Factors (genetics, metabolism)
• alpha-MSH (genetics, metabolism)