Author ORCID Identifier

https://orcid.org/0009-0006-7411-1469

Date Available

8-6-2025

Year of Publication

2025

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Pharmacology and Nutritional Sciences

Faculty

Analia S. Loria

Faculty

Olivier Thibault

Abstract

Obesity is a burgeoning health epidemic caused by chronic overnutrition and exacerbated by genetic, environmental and developmental factors. The adipocyte mineralocorticoid receptor (MR), a transcriptionally active nuclear receptor, is speculated to contribute to metabolic dysfunction in the obese state. MR expression is increased in obese adipose tissue, and MR modulates the expression of fat-derived hormones such as leptin and adiponectin. In women, obesity can be exacerbated by early life stress, such as adverse childhood experiences (ACEs). Studies show that women display a positive association between cumulative ACE exposures and increased body mass index. Previously, we demonstrated that maternal separation and early weaning (MSEW) is a mouse model that recapitulates sex-specific effects of early life stress, and that chronic MR antagonism reduces exacerbated adiposity in female mice.

Therefore, we hypothesized that adipocyte MR deletion reduces fat expansion and improves glucose homeostasis, particularly in obese female MSEW mice. To test this hypothesis, we developed an inducible adipocyte-specific MR knockout mouse model. Control and MSEW mice were generated and randomized by genotype, wherein tamoxifen treatment resulted in mice with intact MR (AdipoMRfl) or deleted MR (AdipoMRKO). Five-week-old male and female mice were placed on an obesogenic high-fat diet (HFD), then body weight and composition were followed into adulthood. At 14 weeks of age, deletion of the adipocyte MR was induced, and body composition, glucose tolerance and metabolic profile were assessed after 4 weeks.

In control male mice fed HFD, deletion of the adipocyte MR improved glucose tolerance, reduced insulin resistance, and upregulated glucose handling genes in adipose tissue. Additionally, AdipoMRKO male mice showed increases in the metabolically-sensitizing hepatokine FGF-21, and upregulation of FGF-21 co-receptor β-klotho. MSEW blunted these insulin sensitizing effects. As expected in female mice, MSEW increased obesogenic response to HFD compared with controls prior to MR deletion. However, tamoxifen treatment reduced fat mass and improved glucose homeostasis only in MSEW AdipoMRfl mice, suggesting a beneficial role of an MR-dependent estrogen receptor modulation. Altogether, these studies provide insight into the multi-factorial roles of the adipocyte MR under obese conditions, which can be modified in a sex-specific manner by early life stress exposure.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2025.354

Funding Information

This study was supported by the National Heart Lung and Blood Institute R01HL135158 in 2017, and by pilot grant awarded by the National Institute of General Medical Sciences P30GM127211 through the Center of Biomedical Research Excellence to the University of Kentucky in 2023.

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