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DAPK2 Downregulation Associates With Attenuated Adipocyte Autophagic Clearance in Human Obesity
Hedi Soussi1, Sophie Reggio1, Rohia Alili1
1Nutriomics Team, INSERM, UMR_S U1166, Paris, France Université Pierre et Marie Curie, Sorbonne Universités, UMR_S 1166, Paris, France Institute of Cardiometabolism and Nutrition, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France.
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.
Insights
Death-associated protein kinase 2 (DAPK2) is downregulated in obesity, impairing autophagy in fat cells. Restoring DAPK2 may improve autophagic clearance and reduce lipid accumulation in obesity.
Area of Science:
- Metabolic research
- Cell biology
- Obesity research
Background:
- Adipose tissue dysfunction in obesity is linked to inflammation and insulin resistance.
- Death-associated protein kinase 2 (DAPK2) is downregulated in human obesity adipose tissue.
- The role of DAPK2 in adipocytes and obesity remains unclear.
Purpose of the Study:
- To investigate the role of DAPK2 in adipocyte function and autophagy.
- To determine the impact of DAPK2 on autophagic clearance in obesity.
- To assess DAPK2 expression and autophagic flux in obese patients and after weight loss.
Main Methods:
- DAPK2 expression analysis in human adipose tissue and mice.
- Adenoviral-mediated DAPK2 overexpression in 3T3-L1 adipocytes.
- Small interfering RNA (siRNA) mediated DAPK2 inhibition in human preadipocytes.
- Assessment of autophagic flux using LC3-II accumulation.
- Analysis of adipocyte autophagic clearance in obese patients before and after bariatric surgery.
Main Results:
- DAPK2 is primarily expressed in mature adipocytes and downregulated in obesity.
- DAPK2 overexpression enhances autophagic clearance in adipocytes.
- DAPK2 inhibition impairs autophagic flux.
- Obese adipocytes exhibit reduced autophagic flux, inversely correlated with fat cell lipid content.
- Bariatric surgery-induced weight loss partially restores adipocyte autophagic clearance.
Conclusions:
- Adipocyte DAPK2 expression regulates lysosome-mediated clearance and lipid accumulation.
- Obesity is associated with attenuated autophagy in adipocytes.
- DAPK2 plays a crucial role in regulating adipocyte autophagy, suggesting it as a potential therapeutic target for obesity-related metabolic dysfunction.
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