title: 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.
authors.affiliation: Nutriomics 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.
authors.forename: Hedi
authors.initials: H
authors.lastname: Soussi
authors.affiliation: Nutriomics 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.
authors.forename: Sophie
authors.initials: S
authors.lastname: Reggio
authors.affiliation: Nutriomics 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.
authors.forename: Rohia
authors.initials: R
authors.lastname: Alili
authors.affiliation: Université Pierre et Marie Curie, Sorbonne Universités, UMR_S 1166, Paris, France.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Prado
authors.affiliation: Nutriomics 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.
authors.forename: Sonia
authors.initials: S
authors.lastname: Mutel
authors.affiliation: Nutriomics 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.
authors.forename: Maria
authors.initials: M
authors.lastname: Pini
authors.affiliation: Nutriomics 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.
authors.forename: Christine
authors.initials: C
authors.lastname: Rouault
authors.affiliation: Nutriomics 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.
authors.forename: Karine
authors.initials: K
authors.lastname: Clément
authors.affiliation: Nutriomics 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 isabelle.dugail@inserm.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dugail
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000328:Adult; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D064550:Death-Associated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004041:Dietary Fats; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008247:Lysosomes; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D012333:RNA, Messenger; C579104:DAPK2 protein, human; D064550:Death-Associated Protein Kinases; C579103:dapk2 protein, mouse