Glucose and Lipid Dysregulation Following Loss of Hepatic Aryl Hydrocarbon Receptor in Mice.
Carter, Dwayne E
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The aryl hydrocarbon receptor (AhR) is a cytosolic, ligand activated transcription factor commonly known for its role in environmental toxicant metabolism. However, the generation of AhR knockout (AhR-KO) mice has shown physiological roles for the AhR in normal liver growth and development, insulin homeostasis, glucose homeostasis, and lipid metabolism. The liver is a major regulator of energy and glucose homeostasis and recent data have also shown that reduced AhR activity results in increased energy expenditure and susceptibility to weight gain and hepatic steatosis on an obesogenic diet. To date, no one has conclusively shown how AhR activity in the liver affects overall mouse lipid energy and glucose metabolism. To investigate how AhR activity in the mouse liver affects glucose and lipid metabolism, we utilized liver specific, AhR conditional knockout (AhR-CKO) mice. We discovered a novel phenotype wherein, AhR-CKO mice exhibited reduced body weight with age, reduced adiposity and increased expression of thermogenic gene, uncoupling protein 1 (UCP1) or the browning of the white adipose tissue (WAT) vs. controls. Next generation RNA sequencing of AhR-CKO vs. control mice liver transcriptomes revealed significantly increased expression of fibroblast growth factor (FGF) 21, a known hepatokine and activator of thermogenesis in mice WAT. We hypothesized that hepatic AhR activity alters the thermogenic gene program in white adipocytes by driving beige adipocyte recruitment through direct regulation of the metabolic hormone, FGF21. Using ChIP analyses and a luciferase reporter system we demonstrated that AhR directly regulates FGF21 at the gene level. The generation and utilization of AhR/FGF21 double conditional knockout mice demonstrated that FGF21 is responsible for the browning of white fat seen after hepatic loss of AhR as evident by no increased UCP1 expressions in the white fat taken from mice after hepatic loss of AhR and FGF21.