Date of Award

2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Paul M. Titchenell

Abstract

The hepatic transcription factor forkhead box O1 (FOXO1) is a critical regulator of hepatic and systemic insulin sensitivity. Previous studies demonstrate that genetic inhibition of liver FOXO1 improves insulin sensitivity in both genetic and dietary mouse models of metabolic disease. Mechanistically, this is due in part to cell non-autonomous control of adipose tissue insulin sensitivity. However, the mechanisms mediating this liver-adipose tissue crosstalk remain ill-defined. This thesis work comprises of two studies that sought to determine the role of hepatic insulin signaling via FOXO1 regulation over adipose tissue biology. The brown adipose tissue’s (BAT) ability to increase energy expenditure has made it a potential target for combating obesity, diabetes, and associated diseases. However, significant gaps remain in our understanding of how metabolic organs, such as the liver, coordinate the supply of hepatokines and energy substrates that can activate and fuel BAT thermogenesis. In the first study, we identify a role for hepatic insulin signaling via AKT-FOXO1 in the adaptive response to acute cold stress. Mechanistically, inhibition of FOXO1 by AKT controls BAT thermogenesis by enhancing catecholamine-induced lipolysis in the white adipose tissue and increasing circulating fibroblast growth factor 21 (FGF21). These studies provide relevant and missing fundamental knowledge to the liver’s response to acute cold exposure, in addition to providing an understanding of the inter-organ communication system that mobilizes energy for heat production. In the second study, we investigated how the FOXO1-dependent hepatokine FGF21 regulates glucose homeostasis, insulin tolerance and adipocyte lipolysis. The pharmacological effect of FGF21 on metabolism has been fairly well-studied, however how hepatic insulin signaling contributes to the regulation of endogenous hepatic FGF21 expression and its physiological role as a FOXO1-dependent hepatokine in the regulation of metabolism is not completely understood. We demonstrated that acute deletion of FGF21 did not alter glucose tolerance, insulin tolerance, or adipocyte lipolysis suggesting a permissive role for endogenous FGF21 and that liver FOXO1 controls glucose homeostasis independently of liver-derived FGF21. Taken together, these two studies have developed a deeper understanding on the cell-autonomous and cell-nonautonomous regulation of liver hepatic insulin signaling via FOXO1.

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