Autophagy Ablation in Adipocytes Induces Insulin Resistance and Reveals Roles for Lipid Peroxide and Nrf2 Signaling in Adipose-Liver Crosstalk
Authors: Karla M Pires
Scott A Summers
Ashot Sargsyan
Maroua Ferhat
Jinjin Cai
Timothy E Graham
Rana Smalling
Donald L Atkinson
Bhagirath Chaurasia
Márcio A Buffolo
Sihem Boudina
Journal: Cell Reports (2018)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: adipocytes; adiponectin; adipose tissue; autophagy; inflammation
Affiliations: Division of Endocrinology Diabetes and Metabolism, University of Utah School of Medicine, Salt Lake City, UT 84112, USA., Department of Nutrition and Integrative Physiology, University of Utah College of Health and Program in Molecular Medicine, Salt Lake City, UT 84112, USA., Division of Endocrinology Diabetes and Metabolism, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Progenitor Life Sciences, Salt Lake City, UT 84108, USA. Electronic address: ., Department of Nutrition and Integrative Physiology, University of Utah College of Health and Program in Molecular Medicine, Salt Lake City, UT 84112, USA. Electronic address: .

Abstract:  Autophagy is a homeostatic cellular process involved in the degradation of long-lived or damaged cellular components. The role of autophagy in adipogenesis is well recognized, but its role in mature adipocyte function is largely unknown. We show that the autophagy proteins Atg3 and Atg16L1 are required for proper mitochondrial function in mature adipocytes. In contrast to previous studies, we found that post-developmental ablation of autophagy causes peripheral insulin resistance independently of diet or adiposity. Finally, lack of adipocyte autophagy reveals cross talk between fat and liver, mediated by lipid peroxide-induced Nrf2 signaling. Our data reveal a role for autophagy in preventing lipid peroxide formation and its transfer in insulin-sensitive peripheral tissues. 

Retracted: No

PubPeer comments:
 Authors developed and characterized adipose-specific Atg3 knockout mice. They show that the knockout animals are glucose intolerant and insulin resistant. Fig2A-D, The AUC plots for GTT and ITT show lot of variation in KOs. However, the line plots showing actual blood glucose values recorded during GTT and ITT show almost no error bars as only the animals with little variation are selectively shown here. Fig 2F, shows plasma insulin levels in fasted and 20min after glucose injection in control and Atg3 KO animals. Plasma insulin levels are higher than previously reported values and could be due to nonspecific signal due to insufficient washing during the ELISA. Fig 3. O-R shows Seahorse metabolic assay data performed adipose tissue explants obtained from control and adipose-Atg3 KO mice. They used 10mg well adipose explants in this assay to measure OCR and ECAR to measure rate of mitochondrial activity and glycolysis respectively. Since adipose is a heterogeneous tissue, it would be difficult to accurately assess the effect of Atg3 loss in fat cells on their energy metabolism using the adipose explants. The major issue here is that each piece of tissue will have different number of fat cells and the authors havenu2019t even normalized their data to protein, DNA or cell number, so Atg3u2019s role in fat cell mitochondrial metabolism canu2019t be accurately determined by this method. In Figure 1 A and B, authors show increased p62 in Atg3 knockout adipose tissue by immunoblotting. If this is a direct effect of Atg3 loss in fat cells, why p62 protein levels were unchanged in Atg3 knockout adipocytes generated by treating the Atg3fl fl preadipocytes with Cre-adenovirus? Authors claim that Nrf2 and Keap1 expression are upregulated in Atg3 KO fat cells. Keap1 is well-known negative regulator of Nrf2. Then how the concomitant induction of Keap1 and Nrf2 increased Nrf2 activity in Atg3 null fat cells. According to authors, p62 (which is also increased in Atg3 KO cells) might have sequestered Keap1 and that in turn increased the Nfr2 activity in Atg3 KO fat cells. But p62-Keap1 interaction requires p62 phosphorylation by mTOR whose activation requires Akt activity (Mol Cell. 2013; 51: 618u2013631), which they have shown to be downregulated in Atg3 KO fat cells. With all these discrepancies and if the protein bands they show are really Nrf2, p62 and Keap1, how their expression and functions are regulated in Atg3 KO fat cells? ,