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.

Centre de Recherche du Centre Hospitalier de l'Université de Montréal Université de Montréal Quebec Canada; 1st Faculty of Medicine Charles University Prague Prague Czech Republic

Centre de Recherche du Centre Hospitalier de l'Université de Montréal Université de Montréal Quebec Canada; Department of Biochemistry and Molecular Medicine Université de Montréal Quebec Canada; Montreal Diabetes Research Center Quebec Canada

Centre de Recherche du Centre Hospitalier de l'Université de Montréal Université de Montréal Quebec Canada; Department of Kinesiology Université de Montréal Quebec Canada; Montreal Diabetes Research Center Quebec Canada

Centre de Recherche du Centre Hospitalier de l'Université de Montréal Université de Montréal Quebec Canada; Department of Physiology Université de Montréal Quebec Canada

Centre de Recherche du Centre Hospitalier de l'Université de Montréal Université de Montréal Quebec Canada; Department of Physiology Université de Montréal Quebec Canada; Montreal Diabetes Research Center Quebec Canada

Centre de Recherche du Centre Hospitalier de l'Université de Montréal Université de Montréal Quebec Canada; Montreal Diabetes Research Center Quebec Canada

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