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EET Analog Treatment Improves Insulin Signaling in a Genetic Mouse Model of Insulin Resistance
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posted on 2021-10-21, 16:48 authored by Kakali Ghoshal, Xiyue Li, Dungeng Peng, John R. Falck, Raghunath Reddy Anugu, Manuel Chiusa, John M. Stafford, David H. Wasserman, Roy Zent, James M. Luther, Ambra PozziWe previously showed
that global deletion of the cytochrome P450 epoxygenase Cyp2c44, a major
epoxyeicosatrienoic acid (EET) producing enzyme in mice, leads to impaired
hepatic insulin signaling resulting in insulin resistance. This finding led us
to investigate whether administration of a water soluble EET analog restores
insulin signaling in vivo in Cyp2c44(-/-) mice and investigated the underlying mechanisms
by which this effect is exerted. Cyp2c44(-/-) mice treated with the
analog EET-A for 4 weeks improved fasting glucose and glucose tolerance
compared to Cyp2c44(-/-) mice treated with vehicle alone. This
beneficial effect was accompanied by enhanced hepatic insulin signaling,
decreased expression of gluconeogenic genes and increased expression of
glycogenic genes. Mechanistically, we show that insulin-stimulated
phosphorylation of insulin receptor β (IRβ) is impaired in primary Cyp2c44(-/-) hepatocytes and this can be restored by cotreatment with EET-A and
insulin. Plasma membrane fractionations of livers indicated that EET-A enhances
the retention of IRβ in membrane rich fractions, thus potentiating its
activation. Altogether, EET analogs ameliorate insulin signaling in a genetic
model of hepatic insulin resistance by stabilizing membrane-associated IRβ and
potentiating insulin signaling.