Sex‐specific difference in adipose tissue and blood pressure control in a new mouse model expressing human soluble prorenin receptor in adipocytes
Authors: Nichols Kellea , Poupeau Audrey , Gatineau Eva , Arthur Gertrude , Gong Ming , Lindner Volkhard , Yiannikouris Frederique 
Published: April 2020

Sex difference exists in the prevalence of obesity associated with hypertension, however, underlying mechanisms responsible are not completely understood. Previous studies from our laboratory demonstrated that the prorenin receptor (PRR) and its soluble form (sPRR) contribute to adipogenesis and blood pressure control. The present study aimed to determine whether adipose‐sPRR stimulated obesity is associated with hypertension and whether it is sex‐dependent.

Transgenic mice on the C57BL/6J background were generated expressing the human form of the soluble prorenin receptor (HsPRR) in a Cre‐inducible manner. Male mice expressing Cre recombinase under the control of the adiponectin promotor were bred to heterozygote HsPRR/+ female mice to generate mice over‐secreting sPRR (adi‐HsPRR) and control littermate mice (CTL). To validate this new mouse model, primary pre‐adipocytes from adi‐HsPRR and CTL mice were collagenase‐digested and differentiated into adipocytes. After 2 days, the secretion of sPRR in the media doubled in adipocytes of adi‐HsPRR mice compared to control mice (sPRR. CTL: 3729±805 pg/ml; adi‐HsPRR: 6170±1237 pg/ml, p<0.05) and is sustained throughout differentiation. Male and female mice were fed a low‐fat (LF) diet or a high‐fat diet (HF) for 20 weeks. Body weight was assessed weekly and EchoMRI was examined monthly. A glucose tolerance test was performed after 12 weeks of diet and blood pressure was measured by radiotelemetry after 15 weeks.

Results showed that adi‐HsPRR male mice fed a LF diet gained significantly more weight than CTL male mice fed a LF diet (CTL=4; adi‐HsPRR=8), whereas no significant differences in body weights were observed in female mice (CTL=10; adi‐HsPRR=10). After 20 weeks of LF feeding, the body weights of adi‐HsPRR male mice were significantly higher than CTL male mice (CTL: 25.1±0.8g; adi‐HsPRR: 29.0±0.8g p<0.05). In contrast, female mice exhibited similar body weights (CTL: 20.6±0.3g; adi‐HsPRR: 20.4±0.4g). The body composition revealed a significant increase of fat mass, specifically in the epidydimal fat (CTL: 0.35±0.04g; adi‐HsPRR: 0.61±0.07g, p<0.05), and lean mass of HsPRR male mice compared to CTL male mice. In contrast, there was no differences of fat mass or lean mass between CTL and adi‐HsPRR female mice. Although adi‐HsPRR male mice tend to have higher fasting glucose on a LF diet, adi‐HsPRR male and female mice exhibited similar glucose tolerance compared with CTL male and female mice, respectively. The sex‐specific mechanism of sPRR on adipogenesis and blood pressure with LF and HF diet is currently under investigation.

Overall, our data demonstrated for the first time that sPRR stimulated body weight gain and fat mass expansion in male mice but not in female mice suggesting that female mice are protected from sPRR induced‐hypertrophic effect.

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].