Date of Award
5-1-2023
Degree Name
Doctor of Philosophy
Department
Pharmacology
First Advisor
Tischkau, Shelley
Abstract
Calorie imbalance due to high energy intake vs. expenditure is considered a major cause of obesity. Molecular mechanisms underlying diet-induced obesity remain unclear due to the complexity of disease progression. The impact of environmental factors contributing to obesity also remains poorly understood. Activation of the xenobiotic sensor, aryl hydrocarbon receptor (AhR), by obesogens may contribute to diet-induced obesity. AhR has the potential to influence lipid metabolism, insulin resistance, and the development of diabetes. Activation of AhR increases the risk of metabolic dysfunction by impairing adipose tissue function. Thus, the hypothesis was that conditional AhR depletion specifically from mature adipose tissue (CadKO) would improve high fat diet (HFD) induced metabolic dysfunction.Our study suggests CadKO protects mice from HFD (60% calories from fat) induced weight gain. However, the effects were more profound in females compared to males. CadKO female intake significantly less food/calorie and increase energy expenditure (EE) on HFD. No changes in calorie intake and EE were observed among the genotypes in males. Morphology of adipocytes by H&E reveals CadKO improves adipose tissue biology such that females can maintain a lean adipocyte phenotype. This assists in resisting HFD-induced serum leptin rise, as well as promotes maintaining leptin receptor (LepR) expression in the energy regulatory regions of the hypothalamus, suggesting an increased sensitivity to leptin in CadKO female. Furthermore, estrogen receptor α (ERα), which has anti-obesity effects, was higher in CadKO female adipose tissue and energy regulatory regions hinting that the sex differences observed may be mediated by differences in estrogen signaling. Concurrently, exploration of other metabolic functions, such as lipid spillover, beiging of adipose tissue, adipogenesis, lipolysis, and glucose metabolism also demonstrated sexual asymmetry. Depletion of AhR from adipocytes provides female mice with beneficial metabolic parameters mediated by the PPAR-family, HSL, and Fgf21 pathways. Furthermore, the study also demonstrated improved adipose biology in CadKO females as also advantageous for systemic glucose homeostasis. Fasting glucose and glucose tolerance were significantly better in CadKO females under HFD compared to WT. However, contrary to our previous study on global AhR knockout (AhRKO), CadKO male were not protected from HFD-induced changes in systemic glucose tolerance and insulin sensitivity. Although, we did find that CadKO male mice were delayed in disease progression for both obesity and insulin resistance. In males, CadKO ameliorated proinflammatory adipocytokine secretion (such as TNFα, IL1β, IL6) that facilitates less inflammatory macrophage infiltration into adipose depots.Altogether, these results indicate AhR deficiency from adipocytes improves overall weight control and systemic glucose homeostasis when faced with HFD challenges in both sexes, but more profoundly in females. Exploration of metabolic functions of tissues demonstrates definite sexual dimorphism. Adipose-specific depletion facilitates the maintenance of a lean phenotype in females that is mediated by healthy adipose-hypothalamic crosstalk. Whereas in males, adipose-specific AhR depletion delays the development of obesity and insulin resistance, due to the maintenance of healthy crosstalk between adipose tissue and the peripheral immune cells.
Access
This dissertation is Open Access and may be downloaded by anyone.