Short Term Palmitate Supply Impairs Intestinal Insulin Signaling via Ceramide Production

Thi Thu Trang Tran,Bárbara Graziela Postal,Sylvie Demignot,Agnès Ribeiro,Céline Osinski,Jean-Paul Pais De Barros,Agnieszka Blachnio-Zabielska,Armelle Leturque,Monique Rousset,Pascal Ferré,Eric Hajduch,Véronique Carrière

doi:10.1074/jbc.m115.709626

Abstract

The worldwide prevalence of metabolic diseases is increasing, and there are global recommendations to limit consumption of certain nutrients, especially saturated lipids. Insulin resistance, a common trait occurring in obesity and type 2 diabetes, is associated with intestinal lipoprotein overproduction. However, the mechanisms by which the intestine develops insulin resistance in response to lipid overload remain unknown. Here, we show that insulin inhibits triglyceride secretion and intestinal microsomal triglyceride transfer protein expression in vivo in healthy mice force-fed monounsaturated fatty acid-rich olive oil but not in mice force-fed saturated fatty acid-rich palm oil. Moreover, when mouse intestine and human Caco-2/TC7 enterocytes were treated with the saturated fatty acid, palmitic acid, the insulin-signaling pathway was impaired. We show that palmitic acid or palm oil increases ceramide production in intestinal cells and that treatment with a ceramide analogue partially reproduces the effects of palmitic acid on insulin signaling. In Caco-2/TC7 enterocytes, ceramide effects on insulin-dependent AKT phosphorylation are mediated by protein kinase C but not by protein phosphatase 2A. Finally, inhibiting de novo ceramide synthesis improves the response of palmitic acid-treated Caco-2/TC7 enterocytes to insulin. These results demonstrate that a palmitic acid-ceramide pathway accounts for impaired intestinal insulin sensitivity, which occurs within several hours following initial lipid exposure.

Highlights

The worldwide obesity epidemic has stimulated numerous research efforts to identify factors that affect energy balance
In Mouse Intestine, a Single Oral Gavage with Palm Oil Impairs Insulin Effects on Lipid Absorption—Following a single administration of those oils that are enriched in monounsaturated fatty acids or saturated fatty acids (Table 1), the effects of insulin on lipid absorption were analyzed in mice
It has been established that enterocytes express all of the receptors and mediators involved in the insulin-signaling pathway [35]

Summary

Introduction

The worldwide obesity epidemic has stimulated numerous research efforts to identify factors that affect energy balance. The intestine could contribute to the development of metabolic disease, especially through its role in postprandial lipemia. The increased amplitude and duration of the postprandial peak of circulating triglyceride-rich lipoproteins (TRL) are known risk factors for atherosclerosis and cardiovascular diseases [1, 2]. Microsomal triglyceride transfer protein (MTP) transports neutral lipids [6] and plays a central role in the efficiency of lipid absorption by modulating chylomicron size. Alterations in MTP protein expression can impact intestinal fat transport and lipoprotein metabolism [7]. In metabolic syndrome, which encompasses dyslipidemia, hypertension, and insulin resistance, the mechanisms underlying perturbed chylomicron assembly and secretion remain poorly explored. The other TRL-secreting organ, insulin inhibits the production of very low density lipoproteins via the inhibition of MTP expression and apoB secretion (8 –10). The mechanisms involved in the inhibitory effect of insulin on chylomicron production remain unclear

Objectives

Results

Conclusion