A mutation in the peroxisome proliferator-activated receptor γ-binding site in the gene for the cytosolic form of phosphoenolpyruvate carboxykinase reduces adipose tissue size and fat content in mice

Abstract

Regulation of the turnover of triglycerides in adipose tissue requires the continuous provision of 3-glycerophosphate, which may be supplied by the metabolism of glucose or by glyceroneogenesis, the de novo synthesis of 3-glycerophosphate from sources other than hexoses or glycerol. The importance of glyceroneogenesis in adipose tissue was assessed in mice by specifically eliminating the expression of the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C), an enzyme that plays a pivotal role in the pathway. To accomplish this, we mutated the binding site for the peroxisome proliferator-activated receptor ␥ (PPAR␥) called the peroxisome proliferator-activated receptor element (PPARE), in the 5 flanking region of the PEPCK-C gene in the mouse by homologous recombination. The mutation abolished expression of the gene in white adipose tissue and considerably reduced its expression in brown adipose tissue, whereas the level of PEPCK-C mRNA in liver and kidney remained normal. Epididymal white adipose tissue from these mice had a reduced triglyceride deposition, with 25% of the animals displaying lipodystrophy. There was also a greatly reduced level of lipid accumulation in brown adipose tissue. A strong correlation between the hepatic content of triglycerides and the size of the epididymal fat pad in PPARE ؊/؊ mice suggests that hepatic triglyceride synthesis predominantly utilizes free fatty acids derived from the adipose tissue. Unlike other models, PPARE ؊/؊ mice with lipodystrophy did not exhibit the lipodystrophy-associated features of diabetes and displayed only moderate hyperglycemia. These studies establish the importance of the PPARE site for PEPCK-C gene expression in adipose tissue and the role of PEPCK-C in the regulation of glyceroneogenesis, a pathway critical for maintaining the deposition of triglycerides in adipose tissue.

ATF-2 Regulates Fat Metabolism inDrosophila

“…However, adipose tissue-specific PEPCK knockdown mice exhibited lower triglyceride levels not only under fasted condition but also under fed condition (Olswang et al, 2002). This observation is consistent with our results using dATF-2 knockdown flies.…”

“…The important role of PEPCK in glyceroneogenesis was demonstrated using the mice in which PEPCK was down-or up-regulated in WAT. Mice in which the PPAR␥-binding site in the PEPCK-C gene promoter exhibited reduced adipose tissue size and fat content (Olswang et al, 2002). Conversely, transgenic mice expressing PEPCK in adipose tissue increased adipocyte size and fat mass (Franckhauser et al, 2002).…”

Chronically increased glucose uptake by adipose tissue leads to lactate production and improved insulin sensitivity rather than obesity in the mouse

“…This is associated with higher susceptibility to diet-induced insulin resistance and obesity [5]. In contrast, the ablation of PEPCK in adipose tissue leads to reduced triacylglycerol deposition and lipodystrophy [6]. In addition, although there are few studies of the relative contribution of pyruvate, via glyceroneogenesis, vs glucose, via glycolysis, to glyceride-glycerol synthesis, it has been demonstrated that glyceroneogenesis is quantitatively the predominant source of glycerol in triacylglycerol [7,8].…”

Fat poetry: a kingdom for PPARγ

“…It also promotes the esterification of FFA into TG and their storage by regulating the expression of enzymes such as phosphoenol pyruvate carboxykinase, glycerol phosphate dehydrogenase, and diacylglycerol O acyltransferase. Expression of perilipin, which is the predominant protein associated with adipocyte lipid droplets and has a key function in regulating adipocyte lipid storage and body fat accumulation, is stimulated, too [167,[169][170][171][172][173][174]. Finally, PPARg participates in the de novo FFA synthesis by regulating directly or indirectly the expression of enzymes such as fatty acid synthase, acetyl CoA synthetase, and stearoyl CoA desaturase 1 ( Figure 5) [163,166,167,175].…”