Hypothalamic TTF-1 orchestrates the sensitivity of leptin

• Huvudupphovsmän: Byong Seo Park (Författare, medförfattare), Dasol Kang (Författare, medförfattare), Kwang Kon Kim (Författare, medförfattare), Bora Jeong (Författare, medförfattare), Tae Hwan Lee (Författare, medförfattare), Jeong Woo Park (Författare, medförfattare), Shioko Kimura (Författare, medförfattare), Jung-Yong Yeh (Författare, medförfattare), Gu Seob Roh (Författare, medförfattare), Chang-Joong Lee (Författare, medförfattare), Sungchil Yang (Författare, medförfattare), Sunggu Yang (Författare, medförfattare), Jae Geun Kim (Författare, medförfattare), Byung Ju Lee (Författare, medförfattare)
• Materialtyp: Bok
• Publicerad: Elsevier, 2022-12-01T00:00:00Z.
• Ämnen: article
• Länkar: Connect to this object online.
• Notes: 2212-8778; 10.1016/j.molmet.2022.101636
• Keywords: Thyroid transcription factor-1; Leptin receptor; Leptin sensitivity; Leptin resistance; Obesity; Internal medicine; RC31-1245
• Source: Molecular Metabolism, Vol 66, Iss , Pp 101636- (2022)

Objective: Thyroid transcription factor-1 (TTF-1), a homeodomain-containing transcription factor, is predominantly expressed in discrete areas of the hypothalamus, which acts as the central unit for the regulation of whole-body energy homeostasis. Current study designed to identify the roles of TTF-1 on the responsiveness of the hypothalamic circuit activity to circulating leptin and the development of obesity linked to the insensitivity of leptin. Methods: We generated conditional knock-out mice by crossing TTF-1flox/flox mice with leptin receptor (ObRb)Cre or proopiomelanocortin (POMC)Cre transgenic mice to interrogate the contributions of TTF-1 in leptin signaling and activity. Changes of food intake, body weight and energy expenditure were evaluated in standard or high fat diet-treated transgenic mice by using an indirect calorimetry instrument. Molecular mechanism was elucidated with immunohistochemistry, immunoblotting, quantitative PCR, and promoter assays. Results: The selective deletion of TTF-1 gene expression in cells expressing the ObRb or POMC enhanced the anorexigenic effects of leptin as well as the leptin-induced phosphorylation of STAT3. We further determined that TTF-1 inhibited the transcriptional activity of the ObRb gene. In line with these findings, the selective deletion of the TTF-1 gene in ObRb-positive cells led to protective effects against diet-induced obesity via the amelioration of leptin resistance. Conclusions: Collectively, these results suggest that hypothalamic TTF-1 participates in the development of obesity as a molecular component involved in the regulation of cellular leptin signaling and activity. Thus, TTF-1 may represent a therapeutic target for the treatment, prevention, and control of obesity.