HDAC6 Suppresses Age-Dependent Ectopic Fat Accumulation by Maintaining the Proteostasis of PLIN2 in Drosophila

Age-dependent ectopic fat accumulation (EFA) in animals contributes to the progression of tissue aging and diseases such as obesity, diabetes, and cancer. However, the primary causes of age-dependent EFA remain largely elusive. Here, we characterize the occurrence of age-dependent EFA in Drosophila and identify HDAC6, a cytosolic histone deacetylase, as a suppressor of EFA. Loss of HDAC6 leads to significant age-dependent EFA, lipid composition imbalance, and reduced animal longevity on a high-fat diet. The EFA and longevity phenotypes are ameliorated by a reduction of the lipid-droplet-resident protein PLIN2. We show that HDAC6 is associated physically with the chaperone protein dHsc4/Hsc70 to maintain the proteostasis of PLIN2. These findings indicate that proteostasis collapse serves as an intrinsic cue to cause age-dependent EFA. Our study suggests that manipulation of proteostasis could be an alternative approach to the treatment of age-related metabolic diseases such as obesity and diabetes. [Display omitted] •Age-dependent EFA (ectopic fat accumulation) occurs in Drosophila•dHDAC6, a proteostatic factor, suppresses age-dependent EFA•Proteostasis collapse of lipid droplet protein PLIN2 causes EFA and short lifespan•dHDAC6 maintains PLIN2 proteostasis through dHsc4 acetylation level Age-dependent ectopic fat accumulation (EFA) contributes to the effects of aging and metabolic diseases such as obesity. Yan et al. characterize age-dependent EFA in Drosophila and reveal that the maintenance of proteostasis of lipid droplet protein PLIN2 by proteostatic factors, dHDAC6 and dHsc4, is essential for suppressing age-dependent EFA.