DAPK2 Downregulation Associates With Attenuated Adipocyte Autophagic Clearance in Human Obesity

Abstract

Adipose tissue dysfunction 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 tissue genes in human obesity, but the role of this kinase is unknown. We show that mature adipocytes rather than the stromal vascular cells in adipose tissue mainly expressed DAPK2 and that DAPK2 mRNA in obese patients gradually recovered after bariatric surgery–induced weight loss. DAPK2 mRNA is also downregulated in high-fat diet–induced obese mice. Adenoviral-mediated DAPK2 overexpression in 3T3-L1 adipocytes did not affect lipid droplet size or cell viability but did increase autophagic clearance in nutrient-rich conditions, dependent on 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 adipocytes freshly isolated from subcutaneous adipose tissue of obese patients. Severe reduction in autophagic flux was observed in obese adipocytes compared with control adipocytes, inversely correlated to fat cell lipids. After bariatric surgery, adipocyte autophagic clearance partially recovered proportional to the extent of fat cell size reduction. This study links adipocyte expression 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.

Lipids, lysosomes, and autophagy

“…In fact, autophagy was induced in adipose tissue from obese individuals, and inhibition of autophagy increased expression of the pro-inflammatory genes IL-1, IL-6 and IL-8 both in adipocytes and adipose tissue explants of obese individuals compared to non-obese controls (51). Consistent with these observations, in adipocytes isolated from obese patients recovering from bariatric surgery-induced weight loss, both DAPK2 expression and autophagic clearance were markedly increased and adipocyte size was proportionally reduced post-surgery compared to the adipocytes from same patients prior to surgery (52). Consistent with these observations, in adipocytes isolated from obese patients recovering from bariatric surgery-induced weight loss, both DAPK2 expression and autophagic clearance were markedly increased and adipocyte size was proportionally reduced post-surgery compared to the adipocytes from same patients prior to surgery (52).…”

Molecular mechanisms underlying metabolic syndrome: the expanding role of the adipocyte

“…The anatomic localization of adipocytes may determine a different response in autophagic flux in obesity conditions. Of note, Soussi et al (125) have recently shown an attenuation of autophagy in subcutaneous adipose tissue of patients with obesity in contrast with increased autophagy observed in dysfunctional visceral adipocytes.…”

DAPK2 (death-associated protein kinase 2)

“…DAPK2 regulates obesity-related attenuated autophagy in adipocytes -DAPK2 downregulation associates with attenuated adipocyte autophagic clearance in human obesity (Soussi H et al, 2015).…”