Gender-dependent effect of Gpbar1 genetic deletion on the metabolic profiles of diet-induced obese mice

Abstract

G-protein-coupled bile acid receptor 1 (GPBAR1/TGR5/ M-Bar/GPR131) is a cell surface receptor involved in the regulation of bile acid metabolism. We have previously shown that Gpbar1-null mice are resistant to cholesterol gallstone disease when fed a lithogenic diet. Other published studies have suggested that Gpbar1 is involved in both energy homeostasis and glucose homeostasis. Here, we examine the functional role of Gpbar1 in diet-induced obese mice. We found that body weight, food intake, and fasted blood glucose levels were similar between Gpbar1-null mice and their wild-type (WT) littermates when fed a chow or high-fat diet (HFD) for 2 months. However, insulin tolerance tests revealed improved insulin sensitivity in male Gpbar1 K/K mice fed chow, but impaired insulin sensitivity when fed a HFD. In contrast, female Gpbar1 K/K mice exhibited improved insulin sensitivity when fed a HFD compared with their WT littermates. Female Gpbar1 K/K mice had significantly lower plasma cholesterol and triglyceride levels than their WT littermates on both diets. Male Gpbar1 K/K mice on HFD displayed increased hepatic steatosis when compared with Gpbar1 C/C males and Gpbar1 K/K females on HFD. These results suggest a gender-dependent regulation of Gpbar1 function in metabolic disease.

Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease

“…Female TGR5-defi cient mice present an increase in hepatic fat content, especially when fed a high-fat diet ( 92 ). In line, TGR5 activation with INT-777 improves liver function by decreasing steatosis and preventing fi brosis ( 98 ).…”

“…Whereas TGR5-defi cient mice have normal weight and fat mass ( 92 ), when fed a high-fat diet, females display increased weight gain resulting from increased fat accumulation ( 91 ). Conversely, TGR5 activation by supplementing CA to the diet prevents the high-fat-induced changes in adipose tissue mass and morphology ( 96 ).…”

Bile Acid Signaling in Metabolic Disease and Drug Therapy

“…The high-fat diet feeding effect on insulin sensitivity showed sex-specific differences, with male tgr5 2/2 mice showing impaired, but female tgr5 2/2 mice showing improved, insulin sensitivity (Vassileva et al, 2010). Thus, it is possible that TGR5 is not highly activated by the physiologic concentration of circulating bile acids outside of the enterohepatic system, which may explain why loss of TGR5 did not have a major impact on weight gain and glucose metabolism.…”

“…Bile Acid in Metabolic Diseases a high-fat diet feeding condition did tgr5 2/2 mice show higher body weight than wild-type controls (Vassileva et al, 2010). The high-fat diet feeding effect on insulin sensitivity showed sex-specific differences, with male tgr5 2/2 mice showing impaired, but female tgr5 2/2 mice showing improved, insulin sensitivity (Vassileva et al, 2010).…”

Membrane Bile Acid Receptor Tgr5 - A New Target in the Study of Metabolic, Inflammatory and Neoplastic Diseases

“…Также примечательными являются данные о гендер-ных различиях, связанных с регуляцией метаболиче-ских процессов через TGR5. Так отмечается значи-тельное повышение массы тела при высокожировой диете у женских особей, TGR5-негативных [6,12]. …”