The hepatic glucose fasting response is gaining traction as a therapeutic pathway to enhance hepatic and whole- host metabolism. However, the mechanisms underlying these metabolic effects remain unclear. Here, we demonstrate the lipoxygenase, ALOXE3, is a novel effector of the therapeutic fasting response. We show that ALOXE3 is activated during fasting, glucose withdrawal, or trehalose/trehalose analogue treatment. Hepatocyte- specific ALOXE3 expression reduced weight gain and hepatic steatosis in diet-induced and genetically obese (db/db) models. ALOXE3 expression moreover enhanced basal thermogenesis and abrogated insulin resistance in db/db diabetic mice. Targeted metabolomics demonstrated accumulation of the PPARg ligand, 12-KETE in hepatocytes overexpressing ALOXE3. Strikingly, PPARg inhibition reversed hepatic ALOXE3-mediated insulin sensitization, suppression of hepatocellular ATP production and oxygen consumption, and gene induction of PPARg coactivator-1a (PGC1a) expression. Moreover, hepatocyte-specific PPARg deletion reversed the therapeutic effect of hepatic ALOXE3 expression on diet-induced insulin intolerance. ALOXE3 is therefore a novel effector of the hepatocellular fasting response that leverages both PPARg-mediated and pleiotropic effects to augment hepatic and whole-host metabolism, and is thus a promising target to ameliorate metabolic disease.

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