title: CARD3 deficiency exacerbates diet-induced obesity, hepatosteatosis, and insulin resistance in male mice.
abstract: Caspase activation and recruitment domain 3 (CARD3) is a 61-kDa protein kinase with an N-terminal serine/threonine kinase domain and a C-terminal CARD. Previous research on the function of CARD3 has focused on its role in the immune response and inflammatory diseases. Obesity is now a worldwide health problem and is generally recognized as an inflammatory disease. Unexpectedly, we found that CARD3 expression was lower during obesity. In this study, we explored the biological and genetic bases of obesity using CARD3-knockout (KO) and wild-type (WT) mice fed a high-fat diet (HFD) for 24 weeks. We demonstrate that KO mice were more obese than their WT littermates, and KO mice exhibited obvious visceral fat accumulation and liver weight gains after 24 weeks of HFD feeding. We also observed more severe hepatosteatosis in KO mice compared with the WT controls. Hepatic steatosis in the HFD-fed KO mice was linked to a significant increase in the expression of key lipogenic and cholesterol synthesis enzymes, whereas the expression of the enzymes involves in β-oxidation was dramatically reduced. Furthermore, we confirmed the repression of AMP-activated protein kinase signaling and activation of the endoplasmic reticulum stress response. Fatty liver impaired the global glucose and lipid metabolism, which further exacerbated the insulin resistance associated with the repression of Akt signaling and up-regulated systemic inflammation through the M1/M2 (pro- and anti-inflammation) type switch and the activation of the nuclear factor-κB pathway. Our studies demonstrate the crucial role of CARD3 in metabolism and indicate that CARD3 deficiency promotes the diet-induced phenotype of type 2 diabetes.
authors: Department of Cardiology, Renmin Hospital of Wuhan University, and Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors: Xin-An
authors: XA
authors: Wang
authors: Shan
authors: S
authors: Deng
authors: Dingsheng
authors: D
authors: Jiang
authors: Ran
authors: R
authors: Zhang
authors: Shumin
authors: S
authors: Zhang
authors: Jinfeng
authors: J
authors: Zhong
authors: Li
authors: L
authors: Yang
authors: Tao
authors: T
authors: Wang
authors: Shufen
authors: S
authors: Hong
authors: Sen
authors: S
authors: Guo
authors: Zhigang
authors: Z
authors: She
authors: Xiao-Dong
authors: XD
authors: Zhang
authors: Hongliang
authors: H
authors: Li
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000378:metabolism; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000209:etiology / Q000503:physiopathology*; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications / Q000503:physiopathology*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*
chemical_list: D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse; D055372:AMP-Activated Protein Kinases; D005947:Glucose