DAPK2 Downregulation Associates With Attenuated Adipocyte Autophagic Clearance in Human Obesity

Adipose tissuedysfunction in obesity has been linked to low-grade inflammation causing insulin resistance. Transcriptomic studies have identified death-associated protein kinase 2 (DAPK2) among the most strongly downregulated adipose tissuegenes in human obesity, but the role of this kinase is unknown. We show that mature adipocytesrather than the stromal vascular cells in adipose tissuemainly expressed DAPK2 and that DAPK2 mRNA in obese patients gradually recovered after bariatricsurgery–induced weight loss. DAPK2 mRNA is also downregulated in high-fat diet–induced obesemice. Adenoviral-mediated DAPK2 overexpression in 3T3-L1 adipocytesdid not affect lipid dropletsize or cell viability but did increase autophagic clearance in nutrient-rich conditions, dependenton protein kinase activity. Conversely, DAPK2 inhibition in human preadipocytes by small interfering RNA decreased LC3-II accumulation rates with lysosome inhibitors. This led us to assess autophagic clearance in adipocytesfreshly isolated from subcutaneous adipose tissueof obese patients. Severe reduction in autophagic flux was observed in obese adipocytescompared with control adipocytes, inversely correlated to fat cell lipids. After bariatricsurgery, adipocyteautophagic clearance partially recovered proportional to the extent of fat cell size reduction. This study links adipocyteexpression of an autophagy-regulating kinase, lysosome-mediated clearance and fat cell lipid accumulation; it demonstrates obesity-related attenuated autophagy in adipocytes, and identifies DAPK2 dependence in this regulation.