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

Dev Cell. 2017 Oct 9;43(1):99-111.e5. doi: 10.1016/j.devcel.2017.09.001. Epub 2017 Sep 28.


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.

Keywords: Drosophila; HDAC6; Hsc70/dHsc4; PLIN2; acetylation; aging; autophagy; chaperone; fat metabolism; proteostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Animals
  • Autophagy / physiology
  • Cytosol / metabolism
  • Diet, High-Fat
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism*
  • Fats / metabolism*
  • Histone Deacetylase 6
  • Histone Deacetylases / metabolism*
  • Lipid Droplets / metabolism*
  • Longevity / physiology
  • Perilipin-2 / metabolism*


  • Drosophila Proteins
  • Fats
  • Perilipin-2
  • HDAC6 protein, Drosophila
  • Histone Deacetylase 6
  • Histone Deacetylases