Effect of a p38 MAPK inhibitor on FFA-induced hepatic insulin resistance in vivo.

W Q Yu,J Moore,Y Mori,E Tsiani,A Giacca,S Pereira

doi:10.1038/nutd.2016.11

Abstract

The mechanisms whereby prolonged plasma free fatty acids elevation, as found in obesity, causes hepatic insulin resistance are not fully clarified. We herein investigated whether inhibition of p38 mitogen-activated protein kinase (MAPK) prevented hepatic insulin resistance following prolonged lipid infusion. Chronically cannulated rats were subdivided into one of four intravenous (i.v.) treatments that lasted 48 h: Saline (5.5 μl min−1), Intralipid plus heparin (IH, 20% Intralipid+20 U ml−1 heparin; 5.5 μl min−1), IH+p38 MAPK inhibitor (SB239063) and SB239063 alone. During the last 2 h of treatment, a hyperinsulinemic (5 mU kg−1 min−1) euglycemic clamp together with [3-3H] glucose methodology was carried out to distinguish hepatic from peripheral insulin sensitivity. We found that SB239063 prevented IH-induced hepatic insulin resistance, but not peripheral insulin resistance. SB239063 also prevented IH-induced phosphorylation of activating transcription factor 2 (ATF2), a marker of p38 MAPK activity, in the liver. Moreover, in another lipid infusion model in mice, SB239063 prevented hepatic but not peripheral insulin resistance caused by 48 h combined ethyloleate plus ethylpalmitate infusion. Our results suggest that inhibition of p38 MAPK may be a useful strategy in alleviating hepatic insulin resistance in obesity-associated disorders.

Highlights

Elevated plasma free fatty acids (FFAs), as found in obesity, induce hepatic insulin resistance.[1,2,3] Prolonged exposure of hepatocytes to FFAs activates p38 mitogen-activated protein kinase (MAPK), which decreases the ability of insulin to reduce gluconeogenesis.[4]
We have found that protein kinase C (PKC)-δ is activated in the liver after prolonged lipid infusion,[3] and studies in hepatocytes have shown that PKC-δ activates p38 MAPK.[6]
We found that the p38 MAPK inhibitor SB239063 prevented hepatic insulin resistance caused by prolonged plasma FFA elevation in rats

Summary

INTRODUCTION

Elevated plasma free fatty acids (FFAs), as found in obesity, induce hepatic insulin resistance.[1,2,3] Prolonged exposure of hepatocytes to FFAs activates p38 mitogen-activated protein kinase (MAPK), which decreases the ability of insulin to reduce gluconeogenesis.[4] In murine models of obesity, hepatic p38 MAPK is activated and when p38 MAPK is overexpressed in the liver, impairment of insulin signalling ensues.[5] the role of p38 MAPK in FFA-induced hepatic insulin resistance in vivo has not been assessed. We have found that protein kinase C (PKC)-δ is activated in the liver after prolonged lipid infusion,[3] and studies in hepatocytes have shown that PKC-δ activates p38 MAPK.[6] in the current study we used a p38 MAPK inhibitor to determine whether it prevented hepatic insulin resistance caused by prolonged plasma FFA elevation

Experiments

RESULTS

DISCUSSION