Adipocyte (Pro)Renin-Receptor Deficiency Induces Lipodystrophy, Liver Steatosis and Increases Blood Pressure in Male Mice

Abstract

Adipose tissue dysfunction related to obesity is overwhelmingly associated with increased risk of developing cardiovascular diseases. In the setting of obesity, (pro)renin receptor (PRR) is increased in adipose tissue of mice. We sought to determine the physiological consequences of adipocyte-PRR deficiency using adiponectin-Cre mice. We report a unique model of adipocyte-PRR-deficient mice (PRR(Adi/Y)) with almost no detectable white adipose tissues. As a consequence, the livers of PRR(Adi/Y) mice were enlarged and demonstrated a marked accumulation of lipids. Adipocyte-specific deficiency of PRR increased systolic blood pressure and the concentration of soluble PRR in plasma. To determine whether adipocyte-PRR was involved in the development of obesity-induced hypertension, mice were fed a low-fat or a high-fat diet for 16 weeks. Adipocyte-PRR-deficient mice were resistant to diet-induced obesity. Both high-fat- and low-fat-fed PRR(Adi/Y) mice had elevated insulin levels. Interestingly, adipocyte-PRR deficiency improved glucose tolerance in high-fat-fed PRR(Adi/Y) mice. In response to feeding either low-fat or high-fat diets, systolic blood pressure was greater in PRR(Adi/Y) mice than in control mice. High-fat feeding elevated soluble PRR concentration in control and PRR(Adi/Y) mice. In vitro knockdown of PRR by siRNA significantly decreased mRNA abundance of PPARγ (peroxisome proliferator-activated receptor gamma), suggesting an important role for PRR in adipogenesis. Our data indicate that adipocyte-PRR is involved in lipid homeostasis and glucose and insulin homeostasis, and that soluble PRR may be a predictor of metabolic disturbances and play a role in systolic blood pressure regulation.

Keywords: adipocytes; blood pressure; glucose; insulin; lipids; prorenin receptor.

© 2016 American Heart Association, Inc.

Figures

Figure 1

(A) Schematic representation of the loxP-flanked PRR allele before (a) and after recombination with Adiponectin-driven Cre expression (b). (B) mRNA PRR abundance of differentiated adipocyte from subcutaneous adipose tissue of PRRfl/Y and PRRAdi/Y mice. Data are mean±SEM of 3 to 6 mice. * P<0.05 compared with PRRfl/Y mice.

Figure 2

Adipocyte PRR deficiency reduced fat mass in mice fed a standard diet. (A) Body weight curves of PRRfl/Y and PRRAdi/Y mice. Data are mean±SEM of 4 to 6 mice. (B) Fat mass (% of body weight) for mice in each group. Data are mean±SEM of 4 to 6 mice. * P<0.05 compared with PRRfl/Y.

Figure 3

Adipocyte PRR deficiency increased systolic blood pressure (SBP; 24 h) in mice fed a standard diet. (A) SBP (24 h) for male PRRfl/Y and PRRAdi/Y mice. Data are mean±SEM of 4 mice. *P<0.05 compared with PRRfl/Y mice.

Figure 4

Adipocyte PRR deficiency increased plasma sPRR. (A) Plasma AGT concentrations in male PRRfl/Y and PRRAdi/Y mice. (B) Plasma renin activity (PRA; left y axis) and concentrations (PRC; right y axis) in male PRRfl/Y and PRRAdi/Y mice. (C) Plasma sPRR concentrations in male PRRfl/Y and PRRAdi/Y mice. Data are mean±SEM of 4 to 6 mice. * P<0.05 compared with PRRfl/Y mice.

Figure 5

Adipocyte PRR deficiency prevented the development of obesity and decreased fat mass. (A) Body weight curve of PRRfl/Y and PRRAdi/Y mice fed a low-fat (LF) or high-fat (HF) diet. Data are mean ± SEM from n = 5 to 8 mice/group. (B) Fat and lean mass (% of body weight) of PRRfl/Y and PRRAdi/Y mice fed a LF or HF diet. Data are mean±SEM of 3 to 8 mice.

Figure 6

Adipocyte PRR deficiency exaggerated diet-induced increase of blood pressure. SBP (24 h) of male PRRfl/Y and PRRAdi/Y mice fed a low-fat (LF) or high-fat (HF) diet. Data are mean±SEM from n = 5 to 8 mice. * P<0.05 compared with LF diet. ** P<0.05 compared with PRRfl/Y mice.

Figure 7

(A) Plasma AGT concentrations in male PRRfl/Y and PRRAdi/Y mice fed a LF- or HF-diet. (B) Plasma renin activity (PRA; left y axis) and concentration (PRC; right y axis). (C) Plasma sPRR concentration. Data are mean±SEM of 5 to 8 mice. * P<0.05 compared with LF diet. ** P<0.05 compared with PRRfl/Y mice.