1. Defective Adipose Lipolysis and Altered Global Energy Metabolism in Mice with Adipose Overexpression of the Lipolytic Inhibitor G0/G1 Switch Gene 2 (G0S2)
- Author
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Xitao Xie, Xiaodong Zhang, Xingyuan Yang, Alicia M. Saarinen, Jun Liu, Bradlee L. Heckmann, and Xin Lu
- Subjects
Male ,medicine.medical_specialty ,Lipolysis ,Adipose tissue ,Cell Cycle Proteins ,Mice, Transgenic ,White adipose tissue ,Biology ,Biochemistry ,Mice ,chemistry.chemical_compound ,Insulin resistance ,Internal medicine ,Ketogenesis ,medicine ,Animals ,Molecular Biology ,Triglycerides ,Adiposity ,Fatty acid metabolism ,Triglyceride ,Fatty Acids ,Fasting ,Cell Biology ,medicine.disease ,Adaptation, Physiological ,Cold Temperature ,Adipocytes, Brown ,Glucose ,Metabolism ,Endocrinology ,Adipose Tissue ,Gene Expression Regulation ,chemistry ,Adipose triglyceride lipase ,Carbohydrate Metabolism ,Female ,Insulin Resistance ,Energy Metabolism - Abstract
Biochemical and cell-based studies have identified the G0S2 (G0/G1 switch gene 2) as a selective inhibitor of the key intracellular triacylglycerol hydrolase, adipose triglyceride lipase. To better understand the physiological role of G0S2, we constructed an adipose tissue-specific G0S2 transgenic mouse model. In comparison with wild type animals, the transgenic mice exhibited a significant increase in overall fat mass and a decrease in peripheral triglyceride accumulation. Basal and adrenergically stimulated lipolysis was attenuated in adipose explants isolated from the transgenic mice. Following fasting or injection of a β3-adrenergic agonist, in vivo lipolysis and ketogenesis were decreased in G0S2 transgenic mice when compared with wild type animals. Consequently, adipose overexpression of G0S2 prevented the "switch" of energy substrate from carbohydrates to fatty acids during fasting. Moreover, G0S2 overexpression promoted accumulation of more and larger lipid droplets in brown adipocytes without impacting either mitochondrial morphology or expression of oxidative genes. This phenotypic change was accompanied by defective cold adaptation. Furthermore, feeding with a high fat diet caused a greater gain of both body weight and adiposity in the transgenic mice. The transgenic mice also displayed a decrease in fasting plasma levels of free fatty acid, triglyceride, and insulin as well as improved glucose and insulin tolerance. Cumulatively, these results indicate that fat-specific G0S2 overexpression uncouples adiposity from insulin sensitivity and overall metabolic health through inhibiting adipose lipolysis and decreasing circulating fatty acids.
- Published
- 2014