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In the context of elevated prevalence of obesity-associated metabolic diseases in the human population worldwide, interest in the autophagy degradation pathway is increasing, due to close links with energy metabolism, nutritional state, and inflammation. Here we highlight recent data focusing on adipose tissue which demonstrate alterations in fat cell autophagic flux in human obesity.

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., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

The effect of statins on heme oxygenase-1 (HO-1) was compared in 2 murine cell lines, RAW 264.7 and J774A.1 cell lines, and in primary peritoneal macrophages of BALB/c or C57BL/6 mice. The role of endogenous nitric oxide and the type of transcription factors involved were explored. Simvastatin and fluvastatin induced HO-1. Pretreatment of cells with l-NMMA or 1400 W, two different nitric oxide synthase inhibitors, partially blocked statin-dependent induction of HO-1 in RAW 264.7 and J774A.1 but not in primary peritoneal macrophages. Induction of HO-1 by statins was dependent on p-38 MAP kinase activation in all types of macrophages. In RAW 264.7 cells, both statins increased the activity of reporter genes linked to the proximal 1.3 kbp promoter of HO-1 (EC50 of 1.4±0.3 µM for simvastatin and 0.6±0.03 µM for fluvastatin). This effect was significantly blocked by 1400 W (80±5.2% inhibition, p<0.02) and mevalonate, the direct metabolite of HMGCoA reductase. Gel retardation experiments implicated C/EBPβ, AP-1 but not USF, for both RAW 264.7 and primary peritoneal macrophages of C57BL/6 mice. Collectively we showed a differential role of endogenous nitric oxide between macrophage cell lines and primary macrophages and an effect of statins in the protection against inflammation by increasing HO-1 expression.

During 1992 and 1993, outbreaks of an acute, highly fatal disease mainly affecting adult rabbits were observed in Tunisia. The clinical and pathological findings were consistent with rabbit haemorrhagic disease. A monoclonal antibody designated PG4G3 specific for surface determinants of the rabbit haemorrhagic disease virus was used to identify the aetiological agent by ELISA and by colloidal gold immunoelectron microscopy; a haemagglutination test and conventional immunoelectron microscopy were also used. The results confirmed the first recorded cases of the disease in Tunisia.