Author ORCID Identifier

https://orcid.org/0000-0002-0890-398x

Date Available

5-15-2023

Year of Publication

2022

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Pharmacology and Nutritional Sciences

First Advisor

Dr. Analia S. Loria

Second Advisor

Dr. Hollie Swanson

Abstract

Adverse childhood experiences (ACEs) are an independent risk factor for chronic disease, including obesity and metabolic syndrome. We have previously shown that a mouse model of early life stress, maternal separation and early weaning (MSEW), exacerbates high-fat diet (HF)-induced obesity only in adult female mice. In agreement, the analysis of several cohorts of participants exposed to ACEs have shown that women are more susceptible to develop obesity than men. Therefore, the aim of this study was to investigate the link between early life stress and obesity in pre-clinical and clinical settings. Male and female MSEW mice fed 1 week a HF displayed increased fat mass compared with controls. However, only MSEW female mice showed elevated leptin mRNA expression in gonadal white adipose tissue. After 12 wk of HF, fat mass remained increased only in female MSEW mice compared with control counterparts. Moreover, plasma leptin and both leptin mRNA and protein expression in gWAT were augmented in female MSEW mice compered to controls, but not in male MSEW mice. This association was not present in subcutaneous WAT. Furthermore, among 16 CpG sites in the leptin promoter, we identified three hypomethylated sites in tissue from HF-fed female MSEW mice compared with controls. These hypomethylated sites have been shown to bind adipogenic factors such as PPARγ. Further investigation into gWAT function in female MSEW mice fed a HF for 16 weeks beginning at weaning showed increased adiposity and whitening markers, despite a similar number of preadipocytes and energy expenditure. Single-cell RNA sequencing in isolated pre- and mature adipocytes showed a ~9-fold downregulation of aquaglycerolporin 3 (Aqp3), a channel responsible for glycerol efflux in adipocytes. Obese MSEW mice showed high levels of circulating and adrenal-derived aldosterone, while increased gWAT-derived corticosterone. Further, spironolactone treatment (Spiro, 100 mg/kg/day, 2 weeks) normalized the elevated intracellular glycerol levels, the greater in vitro lipolysis response, and the number of large size adipocytes in MSEW mice compared to the controls. Our data suggests that MR plays a role promoting adipocyte hypertrophy in female MSEW mice by preventing lipolysis via glycerol release in favor of triglyceride formation and storage. Finally, the analysis of ACE and metabolic data from the Southern Community Cohort Study (SCCS) was conducted in 38,353 non-Hispanic Black and White men and women with the goal of determining whether race and sex influenced the effect of ACE on BMI and metabolic biomarkers. Cumulative ACE score was associated with a steady increase in BMI among Black women, while BMI sharply increased with 1 ACE event, and steadily increased thereafter in White women. In White men, BMI increased with 3 ACE events but remained relatively stable among individuals with >4 ACEs. In Black men, BMI decreased with cumulative ACEs; however, this group showed an inverse increase in waist circumference, a measure of central adiposity development, which suggests a possible worsened metabolic risk. Overall, Women showed the strongest association between ACE and BMI. These effects of ACE on BMI also correlated with different types of ACEs, whereas emotional and sexual abuse were highly prevalent factor among Black Women. In addition, regression analysis revealed an association between total ACE score and waist circumference, total cholesterol, the ratio of leptin to adiponectin, HbA1c, and insulin in all groups. However, the extent of these effects differed based on sex and race. Overall, this body of work supports the role of ACE on adiposity development in females with potential implications for the mineralocorticoid receptor on adipocyte function. Future pre-clinical studies are needed to investigate the mechanisms underlying a sex-specific link between ACEs and obesity risk. In addition, race may determine a greater effect on this association. Therefore, including cohorts of different backgrounds is critical to determine how ACEs affect health disparities.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2022.151

Funding Information

This study was supported by funds from the National Institutes of Health (NIH)-National Heart, Lung, and Blood Institute R01 HL135158 to ASL, R01 HL135158-S1 to JRL, the University of Kentucky Center of Research in Obesity and Cardiovascular Disease COBRE P20 GM103527, and the NIH-National Institute of Diabetes and Digestive and Kidney Diseases grant 1R01DK121797-01A1 to TDHJ and MU, and the National Cancer Institute of the National Institutes of Health under Award Number U01CA202979. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. SCCS data collection was performed by the Survey and Biospecimen Shared Resource which is supported in part by the Vanderbilt‐Ingram Cancer Center (P30 CA68485).

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