The soluble form of the prorenin receptor disturbed glucose/insulin homeostasis and leptin secretion in obese male mice

Obesity is one of the major causes of the rise in prevalence of the metabolic syndrome and hypertension. We recently found that the circulating form of the prorenin receptor (sPRR) increased during the development of obesity. Interestingly, in high‐fat fed C57BL/6 male mice, the infusion of sPRR increased systolic blood pressure through an impairment of the baroreflex sensitivity and the increase in the sympathetic tone, potentially mediated by a leptin‐dependent mechanism. In the present study, we aim to address the contribution of sPRR to the development of the metabolic syndrome in obesity. We first investigated whether sPRR plays a role in glucose and insulin (G‐I) homeostasis. C57BL\6 male mice were fed a high fat (HF) diet for 16 weeks. On week 17 of HF feeding, mice were implanted with an osmotic pump infused for 4 weeks with saline (Veh, N=7) or sPRR (mouse recombinant sPRR‐HisTag, 30 μg/kg/day) (sPRR, N=7). After 12 days of infusion, fasting glucose were examined and intraperitoneal glucose and insulin tolerance tests were performed. Fasting glucose levels were significantly higher in HF‐fed mice infused with sPRR compared with HF‐fed mice infused with vehicle (Glucose: Veh: 180±8 mg/dl; sPRR: 205±5 mg/dl. P<0.05). In addition, HF‐fed mice infused with sPRR exhibited impaired glucose tolerance compared with HF‐fed mice infused with vehicle (area under the curve: Veh: 27143 ± 3210; sPRR: 34702±4191. P<0.05). Despite a higher glucose levels after insulin injection, HF‐fed mice infused with sPRR had a similar reduction in blood glucose in response to insulin compared with HF‐fed mice infused with vehicle. Interestingly, the phosphorylation levels of hepatic Akt decreased significantly in HF‐fed mice infused with sPRR compared with vehicle (p‐Akt/Akt ratio: Veh: 1.0±0.1, sPRR 0.4±0.1 AU, P<0.05) suggesting that sPRR might impair hepatic insulin sensitivity. Downstream glucose and lipid metabolic pathways are currently under investigation in liver and peripheral tissues. Since circulating leptin were elevated in HF‐fed mice infused with sPRR, we next aimed to determine the relative contribution of sPRR to leptin secretion. In vitro studies demonstrated that leptin secretion increased significantly in differentiated 3T3‐L1 cells treated with sPRR compared with cells treated with vehicle indicating that sPRR directly stimulated adipocyte release of leptin and could participate to leptin resistance in obesity. Together our data indicated that sPRR likely worsen the metabolic syndrome by affecting G‐I homeostasis and by stimulating leptin secretion. Support or Funding Information This work was supported by National Institutes of Health Grants [R01‐HL‐142969]; the American Heart Association [13SDG17230008]; the National Institute of General Medical Sciences [P30 GM127211]; and the University of Kentucky, Center for Clinical and Translational Sciences [UL1TR001998].