PPARγ Acetylation Orchestrates Adipose Plasticity and Metabolic Rhythms

Area of Science:

• Metabolic Regulation
• Chronobiology
• Adipose Tissue Biology

Background:

• Systemic glucose metabolism and insulin activity exhibit diurnal oscillations crucial for metabolic homeostasis.
• Adipose tissue plays a key role in maintaining metabolic balance.
• The intrinsic regulatory mechanisms within adipose tissue governing these rhythms are not fully understood.

Purpose of the Study:

• To investigate the role of Peroxisome proliferator-activated receptor gamma (PPARγ) acetylation in orchestrating diurnal metabolic rhythms within adipose tissue.
• To elucidate how PPARγ acetylation dynamics are affected by physiological conditions like obesity, aging, and circadian disruption.

Main Methods:

• Analysis of diurnal rhythms of PPARγ acetylation in young healthy mice.
• Generation and study of adipocyte-specific acetylation-mimetic (K293Q) and deacetylation-mimetic (K268R/K293R) PPARγ mutant mouse models.
• Assessment of adipose plasticity, BMAL1 stability, glucose tolerance, and insulin sensitivity in these models.
• Identification and characterization of PPARγ downstream targets, such as adipsin, involved in metabolic rhythm regulation.

Main Results:

• PPARγ acetylation exhibits a distinct diurnal rhythm in healthy mice, peaking at ZT0 and troughing at ZT18.
• This rhythmic acetylation pattern is disrupted in obesity, aging, and circadian-disrupted states.
• Acetylation-mimetic PPARγ mutation (aKQ) impairs adipose plasticity and leads to BMAL1 proteolysis.
• Both aKQ and deacetylation-mimetic (2KR) models show altered glucose tolerance and insulin sensitivity rhythmicity.
• Adipsin identified as a novel diurnal factor that destabilizes BMAL1, mediating metabolic rhythms.

Conclusions:

• PPARγ acetylation is a critical regulator of diurnal metabolic oscillations in adipose tissue.
• Dysregulation of PPARγ acetylation contributes to metabolic disturbances in pathological conditions.
• PPARγ acetylation acts as a molecular link between adipose tissue plasticity and metabolic rhythmicity, essential for metabolic health.