Hormonal
Hepatic overexpression of the enzyme ALOXE3 enhances whole-body insulin sensitivity and reduces weight gain by generating the PPARγ ligand 12-KETE.
This research identifies ALOXE3 as a key enzyme induced by fasting that improves insulin sensitivity by activating PPARγ. While direct supplementation with ALOXE3 is not currently available, the findings suggest that strategies inducing this enzyme, such as fasting or specific glucose transporter blockers (like trehalose), may offer metabolic benefits. Current clinical application is limited as genetic therapy is not yet optimized for polygenic diseases like obesity.
Aloxe3 is, therefore, a potentially novel effector of the hepatocellular fasting response that leverages both PPARγ-mediated and pleiotropic effects to augment hepatic and whole-host metabolism, and it is, thus, a promising target to ameliorate metabolic disease.
Why this rating
Strong mechanistic evidence in mouse models (diet-induced and genetic obesity) with clear reversal by inhibitors and genetic deletion, but lacks human clinical trial data.
Source
Hepatocyte ALOXE3 is induced during adaptive fasting and enhances insulin sensitivity by activating hepatic PPARγ
Cassandra B. Higgins et al. · JCI Insight · 2018
DOI 10.1172/jci.insight.120794
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