CRTC1 in Mc4r-Expressing Cells Is Required for Peripheral Metabolism and Systemic Energy Homeostasis

Melanocortin-4 receptor (Mc4r) is a G protein–coupled receptor that controls systemic energy balance by regulating food intake and energy expenditure. Although the detailed molecular mechanism remains unclear, the activation of cAMP signaling in Mc4r-expressing cells reportedly suppresses food intake and increases energy expenditure. CREBP-regulated transcriptional coactivator-1 (CRTC1) is selectively expressed in neuronal cells and participates in transcriptional control, thereby contributing to neuronal plasticity and energy homeostasis. Considering the cAMP-dependent regulation of CRTC1 activity, CRTC1 in Mc4r-expressing cells may contribute to energy balance regulation through the melanocortin pathway. In this context, we examined the physiological contribution of CRTC1 in Mc4r-expressing cells to energy metabolism. In this study, mice with CRTC1 deficiency in Mc4r-expressing cells exhibited 1) modest obesity, glucose intolerance, insulin resistance, hyperinsulinemia, and hyperlipidemia; 2) decreased systemic energy expenditure and thermogenesis; 3) suppression of melanocortin agonist–induced adaptation of energy expenditure and food intake; 4) impaired thermogenic programs and oxidative pathway in brown adipose tissue and skeletal muscle; and 5) enhanced lipogenic programs in the liver and white adipose tissue. These results provide novel insights into the molecular mechanisms underlying the regulation of energy balance by the melanocortin system.

• The detailed molecular mechanisms by which Mc4r and CRTC1 regulate energy homeostasis remain unclear.

• CRTC1 deficiency in Mc4r-expressing cells elicits obesity and decreases energy expenditure.

• CRTC1 deficiency in Mc4r-expressing cells perturbs peripheral metabolism.

• CRTC1 in Mc4r-expressing cells contributes to systemic energy homeostasis.