Caspase-2 promotes obesity, the metabolic syndrome and nonalcoholic fatty liver disease

• Published in: Cell death & disease 2016-02, Vol.7 (2), p.e2096-e2096
• Main Authors: Machado, M V, Michelotti, G A, Jewell, M L, Pereira, T A, Xie, G, Premont, R T, Diehl, A M
• Format: Article
• Language: English
• Subjects: 13; 13/51; 38; 38/77; 38/90; 631/443/319/1642/2037; 631/45/607/1164; 631/80/82/23; 64; 64/110; 64/60; 692/699/1503/1607/2750; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Body fat; Caspase 2 - deficiency; Caspase 2 - genetics; Caspase 2 - metabolism; Cell Biology; Cell Culture; Disease Models, Animal; Immunology; Life Sciences; Lipid Metabolism; Liver diseases; Male; Metabolic disorders; Metabolic Syndrome - enzymology; Metabolic Syndrome - genetics; Metabolic Syndrome - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease - enzymology; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - pathology; Obesity; Obesity - enzymology; Obesity - genetics; Obesity - pathology; Original; original-article
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2016.19

Obesity and its resulting metabolic disturbances are major health threats. In response to energy surplus, overtaxed adipocytes release fatty acids and pro-inflammatory factors into the circulation, promoting organ fat accumulation (including nonalcoholic fatty liver disease), insulin resistance and the metabolic syndrome. Recently, caspase-2 was linked to lipoapoptosis, so we hypothesized that caspase-2 might be a critical determinant of metabolic syndrome pathogenesis. Caspase-2-deficient and wild-type mice were fed a Western diet (high-fat diet, enriched with saturated fatty acids and 0.2% cholesterol, supplemented with fructose and glucose in the drinking water) for 16 weeks. Metabolic and hepatic outcomes were evaluated. In vitro studies assessed the role of caspase-2 in adipose tissue proliferative properties and susceptibility for lipoapoptosis. Caspase-2-deficient mice fed a Western diet were protected from abdominal fat deposition, diabetes mellitus, dyslipidemia and hepatic steatosis. Adipose tissue in caspase-2-deficient mice was more proliferative, upregulated mitochondrial uncoupling proteins consistent with browning, and was resistant to cell hypertrophy and cell death. The liver was protected from steatohepatitis through a decrease in circulating fatty acids and more efficient hepatic fat metabolism, and from fibrosis as a consequence of reduced fibrogenic stimuli from fewer lipotoxic hepatocytes. Caspase-2 deficiency protected mice from diet-induced obesity, metabolic syndrome and nonalcoholic fatty liver disease. Further studies are necessary to assess caspase-2 as a therapeutic target for those conditions.