Sirtuin1-Mediated Deacetylation of Hypothalamic TTF-1 Contributes to the Energy Deficiency Response

Author:

Kang Dasol1,Yang Hye Rim2,Kim Dong Hee1,Kim Kwang Kon13,Jeong Bora1ORCID,Park Byong Seo2ORCID,Park Jeong Woo1,Kim Jae Geun2,Lee Byung Ju1

Affiliation:

1. Department of Biological Sciences, College of Natural Sciences, University of Ulsan, Ulsan 44610, Republic of Korea

2. Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Republic of Korea

3. Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Stanford, CA 94305, USA

Abstract

TTF-1 stimulates appetite by regulating the expression of agouti-related peptide (AgRP) and proopiomelanocortin (POMC) genes in the hypothalamus of starving animals. However, the mechanism underlying TTF-1’s response to decreased energy levels remains elusive. Here, we provide evidence that the NAD+-dependent deacetylase, sirtuin1 (Sirt1), activates TTF-1 in response to energy deficiency. Energy deficiency leads to a twofold increase in the expression of both Sirt1 and TTF-1, leading to the deacetylation of TTF-1 through the interaction between the two proteins. The activation of Sirt1, induced by energy deficiency or resveratrol treatment, leads to a significant increase in the deacetylation of TTF-1 and promotes its nuclear translocation. Conversely, the inhibition of Sirt1 prevents these Sirt1 effects. Notably, a point mutation in a lysine residue of TTF-1 significantly disrupts its deacetylation and thus nearly completely hinders its ability to regulate AgRP and POMC gene expression. These findings highlight the importance of energy-deficiency-induced deacetylation of TTF-1 in the control of AgRP and POMC gene expression.

Funder

National Research Foundation of Korea

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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