Role of the soluble (pro)renin receptor in diet induced obesity

Background: Cleavage of the extra-cellular domain of the (pro)renin receptor (PRR) yields a soluble fragment (sPRR). Recent studies have reported elevated plasma sPRR levels in lipodystrophy as well as a therapeutic role for recombinant sPRR in diet induced obesity. In this study, we examined whether absence of sPRR might attenuate the effects of diet induced obesity using a novel mouse model with mutation in the cleavage site of the PRR using CRISPR/Cas9, such that sPRR is not generated. Methods: Male mutant sPRR mice and littermate controls aged 4-6 months were fed a high fat diet (60% fat) for 16 weeks. Body composition was analyzed using Minispec NMR and indirect colorimetry was performed using comprehensive laboratory animal monitoring system metabolic chambers. Glucose and insulin tolerance tests were performed before sacrifice. Results: Compared to controls, male mutant sPRR mice had markedly lower plasma sPRR levels (control: 21.5 ± 2.5 vs mutant 0.2 ± 0.03 ng/ml) and lower body weight at baseline (control: 37.8 ± 1.4 vs mutant 28.4 ± 1.3 g). Mutant sPRR mice had parallel increases in body weight with high fat diet although body weight remained lower than controls at the end of the study (Table 1). Body composition analyses and indirect colorimetry did not demonstrate any differences between the two groups (Table 1). However, liver weight/body weight ratio was lower and epididymal fat weight/body weight was higher in mutant sPRR mice compared to controls. Mutant sPRR mice tended to have higher blood glucose levels at 60 (control: 344 ± 30 vs mutant 402 ± 15 mg/dl) and 90 minutes (control: 229 ± 34 vs mutant 296 ± 22 mg/dl) following a glucose load and improved insulin sensitivity (control: 135 ± 9 vs mutant 85 ± 18 mg/dl at 60 minutes following insulin administration, p =0.01). Conclusion: Loss of sPRR alters fat distribution and glucose tolerance in diet induced obesity. Further studies are ongoing to determine the mechanisms by which sPRR might mediate these metabolic effects. [Table: see text] NIH/NIDDK This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.