Treatment with constitutive androstane receptor ligand during pregnancy prevents insulin resistance in offspring from high-fat diet-induced obese pregnant mice

Abstract

The constitutive androstane receptor (CAR) has been reported to decrease insulin resistance even during pregnancy, while exposure to a high-fat diet (HFD) in utero in mice can induce a type 2 diabetes phenotype that can be transmitted to the progeny. Therefore, we examined whether treatment with a CAR ligand during pregnancy could prevent hypertension, insulin resistance, and hyperlipidemia in the offspring from HFD-induced obese pregnant mice (OH mice). We employed four groups of offspring from HFD-fed and control diet-fed pregnant mice with or without treatment with a CAR ligand. Treatment with a CAR ligand during pregnancy improved glucose tolerance and the levels of triglyceride and adipocytokine and restored the changes induced by HFD with amelioration of hypertension in the adult OH mice. This treatment also increased adiponectin mRNA expression, suppressed leptin expression in adipose tissues of OH mice, and abolished the effect of HFD on the epigenetic modifications of the genes encoding adiponectin and leptin in the offspring during immaturity and adulthood. Our data suggest that CAR might be a potential therapeutic target to prevent metabolic syndrome in adulthood of offspring exposed to an HFD in utero.

Role of Nuclear Receptors in Lipid Dysfunction and Obesity-Related Diseases

“…The metabolic benefits of CAR activation may have resulted from the combined effect of inhibition of lipogenesis, very low density cholesterol secretion and export of triglycerides, and gluconeogenesis; increases in brown adipose tissue energy expenditure and peripheral fat mobilization may have also played a role. Similar effects of CAR activation in relieving high-fat diet and ob/ob models of steatosis and type 2 diabetes (Dong et al, 2009) and gestational obesity and diabetes (Masuyama and Hiramatsu, 2012a;Masuyama and Hiramatsu, 2012b) have been independently reported. These results have revealed an important metabolic function of CAR and may establish this "xenobiotic receptor" as a novel therapeutic target for the prevention and treatment of obesity and type 2 diabetes.…”

Deciphering the roles of the constitutive androstane receptor in energy metabolism

“…The modes of action for such inhibitory effects may include the following: (1) competitive binding to cis-acting elements; (2) coactivator quenching; and (3) induction of suppressive genes, leading to direct inhibition of certain transcriptional factors, deactivation of pro-diabetic agonists or production of anti-diabetic substances, and changes in metabolite profiles. In addition, the metabolic benefits can also be transmitted to offspring due to permanent epigenetic switches [105,106] . In summary, CAR is a potential therapeutic target for the prevention and treatment of metabolic diseases.…”

Bile Acid Signaling in Metabolic Disease and Drug Therapy

“…It has long been known that phenobarbital reduces plasma fasting glucose and improves insulin sensitivity in diabetic patients (Lahtela et al, 1984). A few recent studies showed that activation of CAR by TCPOBOP improved hyperglycemia and insulin sensitivity in obese and diabetic ob/ob mice and high-fat diet-induced obese mice (Dong et al, 2009;Gao et al, 2009;Masuyama and Hiramatsu, 2012). It was reported that phenobarbital decreased the expression of PEPCK and G6Pase in both primary hepatocytes and mouse liver, suggesting that phenobarbital may inhibit hepatic gluconeogenesis (Kodama et al, 2004;Miao et al, 2006).…”

“…A few recent studies have reported antiobesity and lipid-lowering effects of CAR agonists in mice (Gao et al, 2009;Sberna et al, 2011;Masuyama and Hiramatsu, 2012). The mechanisms by which CAR activation decreases weight gain is not clear, but reduced body weight gain in mice likely contributes to reduced hepatic steatosis and hepatic VLDL production and promotes the antiatherogenic lipid profile in mice treated with CAR agonists.…”