ABSTRACT
OBJECTIVE: We previously demonstrated that the handle-region peptide, a prorenin/renin receptor [(P)RR] blocker, reduces body weight and fat mass and may improve insulin sensitivity in high-fat fed mice. We hypothesized that knocking out the adipose tissue (P)RR gene would prevent weight gain and insulin resistance. METHODS: An adipose tissue-specific (P)RR knockout (KO) mouse was created by Cre-loxP technology using AP2-Cre recombinase mice. Because the (P)RR gene is located on the X chromosome, hemizygous males were complete KO and had a more pronounced phenotype on a normal diet (ND) diet compared to heterozygous KO females. Therefore, we challenged the female mice with a high-fat diet (HFD) to uncover certain phenotypes. Mice were maintained on either diet for 9 weeks. RESULTS: KO mice had lower body weights compared to wild-types (WT). Only hemizygous male KO mice presented with lower total fat mass, higher total lean mass as well as smaller adipocytes compared to WT mice. Although food intake was similar between genotypes, locomotor activity during the active period was increased in both male and female KO mice. Interestingly, only male KO mice had increased O2 consumption and CO2 production during the entire 24-hour period, suggesting an increased basal metabolic rate. Although glycemia during a glucose tolerance test was similar, KO males as well as HFD-fed females had lower plasma insulin and C-peptide levels compared to WT mice, suggesting improved insulin sensitivity. Remarkably, all KO animals exhibited higher circulating adiponectin levels, suggesting that this phenotype can occur even in the absence of a significant reduction in adipose tissue weight, as observed in females and, thus, may be a specific effect related to the (P)RR. CONCLUSIONS: (P)RR may be an important therapeutic target for the treatment of obesity and its associated complications such as type 2 diabetes.
ABSTRACT
OBJECTIVE: Obesity is a worldwide epidemic and current treatments have limited success thus, novel therapies are warranted. Our objective was to determine whether the prorenin/renin receptor [(P)RR] is implicated in obesity. METHODS: Mice received a normal or high-fat/high-carbohydrate diet with the handle region peptide (HRP), a (P)RR blocker, or saline for 10 weeks. Post-menopausal non-diabetic obese women were enrolled in the Complication Associated with Obesity Study and were classified as insulin-resistant (IRO) or -sensitive (ISO) using a hyperinsulinemic-euglycemic clamp. RESULTS: In mice, obesity increased the (P)RR by twofold in adipose tissue. Likewise, renin increased by at least twofold. The HRP reduced weight gain in obese mice by 20% associated to a 19% decrease in visceral fat. This was accompanied by a 48% decrease in leptin mRNA in fat and 33% decrease in circulating leptin. Inflammatory markers were also decreased by the HRP treatment. HRP normalized triglyceridemia and reduced insulinemia by 34% in obese mice. Interestingly, we observed a 33% increase in (P)RR mRNA in the fat of IRO women compared to ISO. CONCLUSIONS: This is the first report of a potential implication in obesity of the (P)RR which may be a novel therapeutic target.
