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

Area of Science:

• Metabolic regulation
• Neuroendocrinology
• Molecular biology

Background:

• Melanocortin-4 receptor (Mc4r) regulates energy balance via cAMP signaling.
• CREBP-regulated transcriptional coactivator-1 (CRTC1) influences neuronal plasticity and energy homeostasis.
• CRTC1 activity is cAMP-dependent, suggesting a role in the melanocortin pathway.

Purpose of the Study:

• To investigate the physiological role of CRTC1 in Mc4r-expressing cells in regulating energy metabolism.
• To elucidate the contribution of CRTC1 to the melanocortin system's control of energy balance.

Main Methods:

• Generation of mice with CRTC1 deficiency specifically in Mc4r-expressing cells.
• Assessment of metabolic parameters including body weight, glucose tolerance, insulin resistance, and lipid profiles.
• Measurement of systemic energy expenditure, thermogenesis, and adaptation to melanocortin agonists.
• Analysis of gene expression related to thermogenic and lipogenic programs in key metabolic tissues.

Main Results:

• CRTC1 deficiency in Mc4r-expressing cells led to modest obesity, glucose intolerance, insulin resistance, hyperinsulinemia, and hyperlipidemia.
• Mice showed decreased systemic energy expenditure and impaired thermogenesis.
• Adaptation of energy expenditure and food intake in response to melanocortin agonists was suppressed.
• Thermogenic and oxidative pathways in brown adipose tissue and skeletal muscle were impaired.
• Lipogenic programs in the liver and white adipose tissue were enhanced.

Conclusions:

• CRTC1 in Mc4r-expressing cells plays a significant role in regulating systemic energy balance.
• CRTC1 deficiency disrupts energy expenditure, thermogenesis, and metabolic homeostasis.
• These findings offer new insights into the molecular mechanisms of energy balance controlled by the melanocortin system.