Sex-specific subcutaneous adipose renin-angiotensin system receptor expression patterns associate with differential metabolic outcomes in obesity

Obesity is a global epidemic that exacerbates the risk of metabolic complications. Consistent with clinical observations, female rodents are partially protected against high-fat diet (HFD)-induced metabolic dysfunction, exhibiting milder hyperinsulinemia and insulin resistance compared to males. Previous data suggest these sex differences are mediated, at least in part, by alterations in the renin-angiotensin system (RAS), with males favoring metabolically deleterious angiotensin (Ang) II pathways and females favoring protective Ang-(1-7) pathways. However, data on sex-specific expression of RAS components in metabolic tissues of obese rodents, and their relevance to metabolic outcomes, remain limited. In particular, subcutaneous adipose tissue (SAT) is a key regulator of metabolic function and is linked to improved insulin sensitivity and glycemic control. Contrary to males, obese females tend to favor SAT over metabolically unfavorable visceral depots, suggesting SAT may contribute to sex differences in metabolic outcomes in obesity, although specific mechanisms remain under investigation. In this study, we hypothesized that HFD-induced obesity would upregulate deleterious RAS receptors in males and protective RAS receptors in females in SAT, and these sex-specific patterns would correlate with differences in metabolic function. Male and female C57BL/6J mice were placed on a 60% HFD or matched-control diet for 12 weeks (n=9-12 per group). At the end of the diet period, mice underwent metabolic testing, and SAT was collected to quantify differential gene expression via RT-qPCR for deleterious Ang II type 1a receptor (AT1Ra) and protective Ang II type 2 receptor (AT2R), Ang-(1-7) mas receptor (MasR), and mas-related G protein-coupled receptor (MrgD) RAS receptors. HFD increased body weight and adiposity and induced hyperglycemia, hyperinsulinemia, and glucose intolerance in both sexes. Compared to males, obese females were resistant to HFD-induced insulin resistance and displayed milder elevations in fasting glucose and insulin. HFD increased expression of AT1Ra in SAT of males (1.03±0.07 vs. 1.72±0.15, p=0.002), which positively correlated with fasting insulin (r2=0.343, p=0.004) and worsened insulin resistance (r2=0.364, p=0.003). There was no impact of HFD on the expression of protective RAS receptors in the SAT of males. While HFD did not impact AT1Ra or MasR expression in females, it increased expression of the other protective RAS receptors, AT2R (1.08±0.16 vs. 3.87±0.77, p=0.008) and MrgD (1.10±0.28 vs. 2.90±0.61, p=0.020), although these were not correlated with metabolic outcomes. These findings provide evidence for sex-specific regulation of RAS components in SAT during obesity, which may correspond to differences in metabolic outcomes, particularly in males. Complementary studies are ongoing to investigate RAS expression in additional metabolic tissues and to dissect specific mechanisms by which distinct RAS components mediate metabolic protection in obese females. This study was supported by NIH grants R01 HL156986 and TL1 TR002016. This abstract was presented at the American Physiology Summit 2026 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.