Circadian clock control of MRTF/SRF pathway suppresses beige adipocyte thermogenic recruitment

Area of Science:

• Metabolic regulation
• Circadian biology
• Cellular differentiation

Background:

• Adipocyte differentiation involves actin cytoskeleton remodeling and MRTF/SRF signaling.
• The circadian clock regulates the timing of adipogenesis.
• Extracellular physical cues are transduced by the actin cytoskeleton-MRTF/SRF pathway.

Purpose of the Study:

• To define a novel circadian transcriptional control mechanism in the actin cytoskeleton-MRTF/SRF signaling cascade.
• To investigate the role of this axis in modulating beige fat thermogenic function.
• To understand the contribution to systemic metabolic homeostasis.

Main Methods:

• Analysis of circadian regulation of actin dynamics and MRTF/SRF pathway components in beige fat.
• Investigating the direct transcriptional control of Bmal1 on the actin dynamic-MRTF/SRF cascade.
• Utilizing beige fat-selective gene-targeting models and pharmacological interventions in vivo.

Main Results:

• Key components of the actin dynamic-MRTF/SRF pathway exhibit circadian regulation in beige fat.
• Bmal1 directly controls genes in this cascade, influencing actin organization and SRF activity.
• Bmal1 inhibition of beige adipogenesis and thermogenic capacity was confirmed in vivo via MRTF/SRF.
• Bmal1 ablation induced beigeing and improved glucose homeostasis; Bmal1 overexpression led to obesity.

Conclusions:

• The clock-MRTF/SRF regulatory axis acts as an inhibitory mechanism for beige fat thermogenic recruitment.
• This pathway significantly contributes to systemic metabolic homeostasis.
• Targeting the Bmal1-MRTF/SRF axis offers potential therapeutic strategies for metabolic disorders.