Angiopoietin-Like Growth Factor Controls Appetite Via Leptin Signaling in the Hypothalamus

Hypothalamic regulation of appetite governs whole-body energy balance. Satiety is regulated by endocrine factors, including leptin, and impaired leptin induction causes obesity. Angiopoietin-like growth factor (AGF) promotes energy expenditure in the periphery, and systemic reconstitution of AGF antagonizes obesity. However, whether hypothalamic AGF plays a role in controlling food intake remains unknown. Here, we demonstrated that AGF is expressed in proopiomelanocortin (POMC)-positive neurons located in the arcuate nucleus (ARC) of the hypothalamus. AGF expression was stimulated by leptin-induced STAT3 phosphorylation. Notably, intracerebroventricular injection of AGF significantly reduced food intake by stimulating phosphorylation of CREB in the POMC and increasing α-melanocyte-stimulating hormone (α-MSH) content in the hypothalamus. We also found that hypothalamic injection of AGF significantly suppressed food intake and decreased body weight in high-fat-diet-induced obese mice, which exhibit leptin insensitivity. Collectively, our findings demonstrate that hypothalamic AGF provokes the anorectic melanocortin pathway and mediates leptin signaling to prevent obesity. Funding: This work was supported by the National Research Foundation of South of Korea (NRF) grant funded by the Ministry of Science, ICT & Future Planning (MSIP) (2017R1E1A1A01075126, 2014R1A6A1029617, 2016R1A2B4010398, 2016R1D1A1B03932766, 2017R1A5A201538, 2017R1A6A3A11029367) and research fund of Chungnam National University Declaration of Interest: The authors have declared that no conflict of interests existed. Ethical Approval: Animal experiments were approved by the Institutional Animal Care and Use Committee of Chungnam National University (ethical approval number, CNU-00912). The hypothalamus was obtained from postmortem brains of otherwise healthy individuals at the University of Miyazaki, Japan, with the approval of institutional review board (approval number, C-0037; May 11, 2018). Written informed consent was acquired from each outpatient, and the study was conducted according to provisions of the Declaration of Helsinki.