Recently, it has become clear that the human gene CREB-Regulated Transcription Coactivator 1 (CRTC1) is related to obesity. Mice lacking CRTC1 develop obesity, suggesting that CRTC1 prevents obesity when used normally. However, the specific neurons that reduce obesity and the mechanism they contain are still unclear, as CRTC1 is found in all brain neurons.
A research team led by Associate Professor Shigenobu Matsumura of the Graduate School of Human Life and Ecology at Osaka Metropolitan University focused on neurons expressing the melanocortin-4 receptor (MC4R) to elucidate the mechanism by which CRTC1 suppresses obesity. They hypothesized that because MC4R gene mutations are known to cause obesity, CRTC1 expression in MC4R-expressing neurons will reduce obesity. To investigate the impact that the loss of CRTC1 in those neurons had on obesity and diabetes, they developed a line of mice that express CRTC1 normally, except in MC4R-expressing neurons where it is blocked.
The mice lacking CRTC1 in MC4R-expressing neurons did not differ from control mice in terms of body weight when fed a normal diet. The CRTC1-deficient animals were noticeably more obese than the control mice and eventually developed diabetes when fed a high-fat diet.
Professor Matsumura said: “This study has revealed the role the CRTC1 gene plays in the brain and part of the mechanism that keeps us from eating too many high-calorie, fatty and sugary foods. We hope this will lead to a better understanding of why people overeat.”
- Shigenobu Matsumura, Motoki Miyakita, Haruka Miyamori, et al. CRTC1 deficiency, particularly in cells expressing melanocortin-4 receptor, causes hyperphagia, obesity and insulin resistance. FASEB journal. DOI: 10.1096/fj.202200617R