PPARγ Acetylation Orchestrates Adipose Plasticity and Metabolic Rhythms

Systemic glucose metabolism and insulin activity oscillate in response to diurnal rhythms and nutrient availability with the necessary involvement of adipose tissue to maintain metabolic homeostasis. However, the adipose-intrinsic regulatory mechanism remains elusive. Here, the dynamics of PPAR gamma acetylation in adipose tissue are shown to orchestrate metabolic oscillation in daily rhythms. Acetylation of PPAR gamma displays a diurnal rhythm in young healthy mice, with the peak at zeitgeber time 0 (ZT0) and the trough at ZT18. This rhythmic pattern is deranged in pathological conditions such as obesity, aging, and circadian disruption. The adipocyte-specific acetylation-mimetic mutation of PPAR gamma K293Q (aKQ) restrains adipose plasticity during calorie restriction and diet-induced obesity, associated with proteolysis of a core circadian component BMAL1. Consistently, the rhythmicity in glucose tolerance and insulin sensitivity is altered in aKQ and the complementary PPAR gamma deacetylation-mimetic K268R/K293R (2KR) mouse models. Furthermore, the PPAR gamma acetylation-sensitive downstream target adipsin is revealed as a novel diurnal factor that destabilizes BMAL1 and mediates metabolic rhythms. These findings collectively signify that PPAR gamma acetylation is a hinge connecting adipose plasticity and metabolic rhythms, the two determinants of metabolic health.

Automated summary

This study reveals that the acetylation of PPAR gamma in adipose tissue orchestrates metabolic oscillation in daily rhythms. The findings suggest that PPAR gamma acetylation is a crucial link between adipose plasticity and metabolic rhythms, which are two determinants of metabolic health.