Abstract Body: The mineralocorticoid receptor (MR) is broadly implicated in obesity and metabolic dysfunction, and is upregulated in visceral fat of obese rodents and humans, and expressed in adipocytes and non-adipocytes cells including pericytes, mesothelial cells, macrophages, and other immune cells. Women show increased body mass that correlates with the number of early life stressors experienced. A rodent model of the developmental effects of Maternal Separation and Early Weaning (MSEW) recapitulates an exacerbated obesogenic response to overnutrition observed in adult women. Previously, we have shown that MR antagonist with spironolactone reduce fat mass in obese female MSEW mice. Therefore, we hypothesized that the adipocyte MR modulates the effects of an obesogenic diet on fat expansion and metabolic dysfunction in female MSEW mice. Thus, we developed an inducible adipocyte-specific MR knockout model. Mice were exposed to postnatal MSEW protocol or reared normally. Male and female mice were then placed on high fat diet (60% kcal/fat) and followed until adulthood. Mice were randomized by genotype, Adipo^MRfl mice served as genetic controls for Adipo^MRKO mice. At 14 weeks of age, we induced the deletion of the adipocyte MR using tamoxifen (40mg/kg, 5 days i.p.), and allowed mice to recover for four weeks prior to oral glucose tolerance testing (2mg/kg glucose).
After tamoxifen, expression of MR was reduced specifically in adipose tissue compared to liver by approximately 75% in male Adipo^MRKO compared to Adipo^MRfl (1.07±0.19 vs. 0.25±0.23 ddCT2, p=0.03; 1.17±0.36 vs. 0.80±0.27 ddCT2, p=0.44) and approximately 90% in females (1.05±0.16 vs. 0.11±0.03 ddCT2, p=0.001; 1.26±0.37 vs. 1.14±0.41 ddCT2, p=0.83). We found that male Adipo^MRKO mice showed improved glucose tolerance (AUC, 62687.5 vs. 47520, p=0.01) and HOMA-IR index (12.06±1.6 vs. 5.47±1.36, p=0.01), as well as increased expression of glucose handling genes Glut4 , Irs1 , InsR and β-klotho in adipose tissue . Additionally, FGF-21 was increased in plasma (2.68±0.69 vs. 6.89±1.08 ng/mL, p=0.004), a hepatokine that acts on the tissue-specific β-klotho receptor in the adipocyte to improve insulin sensitivity. These effects were not observed in control female Adipo^MRKO mice. Additionally, female MSEW Adipo^MRKO mice did not show reductions in adiposity compared with genetic controls, excluding the adipocyte MR as the principle target mediating the obesogenic effects of MSEW.