Researchers revealed the mechanism of the obesity gene

Professor Shigenobu Matsumura from the Graduate School of Human Life and Ecology and his research team studied to understand how CRTC1 suppresses the obesity mechanism. They focused on neurons expressing the melanocortin-4 receptor (MC4R).

They postulated that because MC4R gene mutations are known to produce obesity, CRTC1 expression in MC4R-expressing neurons will reduce obesity. In order to investigate the impact that losing CRTC1 in those neurons had on obesity and diabetes, they developed a line of mice that expresses CRTC1 normally aside from in MC4R-expressing neurons where it is blocked.

The animals lacking CRTC1 in MC4R-expressing neurons did not differ from control mice in terms of body weight when given a regular diet. The CRTC1-deficient animals who overate were noticeably more obese than the control mice and eventually acquired diabetes when they were fed a high-fat diet.

“This study has revealed the role that the CRTC1 gene plays in the brain, and part of the mechanism that stops us from overeating high-calorie, fatty, and sugary foods,” said Professor Matsumura. “We hope this will lead to a better understanding of what causes people to overeat.”

The research results were published in the FASEB Journal on November 9.

Study abstract:

Melanocortin-4 receptor (MC4R) is a critical regulator of appetite and energy expenditure in rodents and humans. MC4R deficiency causes hyperphagia, reduced energy expenditure, and impaired glucose metabolism. Ligand binding to MC4R activates adenylyl cyclaseincreasinged levels of intracellular cyclic adenosine monophosphate (cAMP), a secondary messenger that regulates several cellular processes. Cyclic adenosine monophosphate responsive element-binding protein-1-regulated transcription coactivator-1 (CRTC1) is a cytoplasmic coactivator that translocates to the nucleus in response to cAMP and is reportedly involved in obesity. However, the precise mechanism through which CRTC1 regulates energy metabolism remains unknown. Additionally, there are no reports linking CRTC1 and MC4R, although both CRTC1 and MC4R are known to be involved in obesity. Here, we demonstrate that mice lacking CRTC1, specifically in MC4R cells, are sensitive to high-fat diet (HFD)-induced obesity and exhibit hyperphagia and increased body weight gain. Moreover, the loss of CRTC1 in MC4R cells impairs glucose metabolism. MC4R-expressing cell-specific CRTC1 knockout mice did not show changes in body weight gain, food intake, or glucose metabolism when fed a normal-chow diet. Thus, CRTC1 expression in MC4R cells is required for metabolic adaptation to HFD with respect to appetite regulation. Our results revealed an important protective role of CRTC1 in MC4R cells against dietary adaptation.