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

• Published in: International journal of molecular sciences 2023-08, Vol.24 (15), p.12530
• Main Authors: Kang, Dasol, Yang, Hye Rim, Kim, Dong Hee, Kim, Kwang Kon, Jeong, Bora, Park, Byong Seo, Park, Jeong Woo, Kim, Jae Geun, Lee, Byung Ju
• Format: Article
• Language: English
• Subjects: Adenosine; Brain; Energy; Gene expression; Gene mutations; Hypothalamus; Lee, B.J; Metabolites; Resveratrol; Scientific equipment and supplies industry; Thyroid gland; Transcription factors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241512530

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.