CREB coactivator CRTC1 in melanocortin-4 receptor-expressing cells regulate dietary fat intake.

Abstract

Cyclic adenosine monophosphate-response element-binding protein-1-regulated transcription coactivator-1 (CRTC1), a cytoplasmic coactivator that translocates to the nucleus in response to cAMP, is associated with obesity. We previously reported that CRTC1 deficiency in melanocortin-4 receptor (MC4R)-expressing neurons, which regulate appetite and energy metabolism in the brain, causes hyperphagia and obesity under a high-fat diet (HFD). HFD is preferred for mice, and the dietary fat in HFD is the main factor contributing to its palatability. These findings, along with our previous results, suggest that CRTC1 regulates the appetite for dietary fat. Therefore, in this study, we aimed to investigate the dietary fat intake behavior and energy metabolism of MC4R neuron-specific CRTC1 knockout mice fed soybean oil or lard. CRTC1 deficiency increased the intake of soybean oil and significantly increased body weight gain. Furthermore, obesity induced by soybean oil intake was partially due to leptin resistance. No significant changes in soybean oil intake were observed between young CRTC1-deficient and wild-type mice; however, soybean oil intake increased with age. Moreover, lard intake did not significantly affect the body weight. Overall, our findings highlighted the crucial role of CRTC1 in the regulation of spontaneous dietary fat intake. Furthermore, the role of CRTC1 becomes increasingly significant with age.