title: Caspase-2 promotes obesity, the metabolic syndrome and nonalcoholic fatty liver disease.
abstract: 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.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.|Gastroenterology Department, Hospital de Santa Maria, Lisbon, Portugal.
authors.forename: M V
authors.initials: MV
authors.lastname: Machado
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Michelotti
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Jewell
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Pereira
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: G
authors.initials: G
authors.lastname: Xie
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: R T
authors.initials: RT
authors.lastname: Premont
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Diehl
mesh_terms: D000818:Animals; D053143:Caspase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D050356:Lipid Metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009765:Obesity / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
chemical_list: C090208:Casp2 protein, mouse; D053143:Caspase 2