20-HETE Interferes with Insulin Signaling and Contributes to Obesity-Driven Insulin Resistance
Envoyer une demande de publication

Demande de publication

Merci pour votre intérêt pour nos produits et votre demande concernant cette publication, qui vous sera envoyée si le chercheur et le journal l'autorisent. Notre équipe commerciale vous contactera rapidement.

A Gilani, K Agostinucci, S Hossain et al

Department of Pharmacology, New York Medical College School of Medicine, Valhalla, NY, United States

Prostaglandins & Other Lipid Mediators

20-HETE, a metabolite of arachidonic acid produced by Cytochrome P450 (CYP) 4A/4_F, has been implicated in the development of obesity-associated complications such as diabetes and insulin resistance. In this study, we examined whether the acute elevation of 20-HETE levels contributes to the development of diet-driven hyperglycemia and insulin resistance. We employed a conditional transgenic mouse model to overexpress Cyp4a12 (Cyp4a12tg), a murine 20-HETE synthase, together with high fat diet (HFD) feeding. Mice in which Cyp4a12 was induced by doxycycline (DOX) at the onset of HFD feeding gained weight at a greater rate and extent than corresponding DOX-untreated Cyp4a12 mice. Cyp4a12tg mice fed HFD_+_DOX displayed hyperglycemia and impaired glucose metabolism while corresponding HFD-fed Cyp4a12tg mice (no DOX) did not. Importantly, administration of a 20-HETE antagonist, 20-SOLA, to Cyp4a12tg mice fed HFD_+_DOX significantly attenuated weight gain and prevented the development of hyperglycemia and impaired glucose metabolism. Levels of insulin receptor (IR) phosphorylation at Tyrosine 972 and insulin receptor substrate-1 (IRS1) phosphorylation at serine 307 were markedly decreased and increased, respectively, in liver, skeletal muscle and adipose tissues from Cyp4a12tg mice fed HFD_+_DOX; 20-SOLA prevented the IR and IRS1 inactivation, suggesting that 20-HETE interferes with insulin signaling. Additional studies in 3T3-1 differentiated adipocytes confirmed that 20-HETE impairs insulin signaling and that its effect may require activation of its receptor GPR75. Taken together, these results provide strong evidence that 20-HETE interferes with insulin function and contributed to diet-driven insulin resistance

BIOSEB Instruments Used:
OXYLET, Indirect Calorimeter (OXYLET)

Partager ce contenu