Deregulated lipid sensing by intestinal CD36 in diet-induced hyperinsulinemic obese mouse model

The metabolic syndrome (MetS) greatly increases risk of cardiovascular disease and diabetes and is generally associated with abnormally elevated postprandial triglyceride levels. We evaluated intestinal synthesis of triglyceride-rich lipoproteins (TRL) in a mouse model of the MetS obtained by feeding a palm oil-rich high fat diet (HFD). By contrast to control mice, MetS mice secreted two populations of TRL. If the smaller size population represented 44% of total particles in the beginning of intestinal lipid absorption in MetS mice, it accounted for only 17% after 4 h due to the secretion of larger size TRL. The MetS mice displayed accentuated postprandial hypertriglyceridemia up to 3 h due to a defective TRL clearance. These alterations reflected a delay in lipid induction of genes for key proteins of TRL formation (MTP, L-FABP) and blood clearance (ApoC2). These abnormalities associated with blunted lipid sensing by CD36, which is normally required to optimize jejunal formation of large TRL. In MetS mice CD36 was not downregulated by lipid in contrast to control mice. Treatment of controls with the proteosomal inhibitor MG132, which prevented CD36 downregulation, resulted in blunted lipid-induction of MTP, L-FABP and ApoC2 gene expression, as in MetS mice. Absence of CD36 sensing was due to the hyperinsulinemia in MetS mice. Acute insulin treatment of controls before lipid administration abolished CD36 downregulation, lipid-induction of TRL genes and reduced postprandial triglycerides (TG), while streptozotocin-treatment of MetS mice restored lipid-induced CD36 degradation and TG secretion. In vitro, insulin treatment abolished CD36-mediated up-regulation of MTP in Caco-2 cells. In conclusion, HFD treatment impairs TRL formation in early stage of lipid absorption via insulin-mediated inhibition of CD36 lipid sensing. This impairment results in production of smaller TRL that are cleared slowly from the circulation, which might contribute to the reported association of CD36 variants with MetS risk

Link between Intestinal CD36 Ligand Binding and Satiety Induced by a High Protein Diet in Mice

CD36 is a ubiquitous membrane glycoprotein that binds long-chain fatty acids. The presence of a functional CD36 is required for the induction of satiety by a lipid load and its role as a lipid receptor driving cellular signal has recently been demonstrated. Our project aimed to further explore the role of intestinal CD36 in the regulation of food intake. Duodenal infusions of vehicle or sulfo-N-succinimidyl-oleate (SSO) was performed prior to acute infusions of saline or Intralipid (IL) in mice. Infusion of minute quantities of IL induced a decrease in food intake (FI) compared to saline. Infusion of SSO had the same effect but no additive inhibitory effect was observed in presence of IL. No IL- or SSO-mediated satiety occurred in CD36-null mice. To determine whether the CD36-mediated hypophagic effect of lipids was maintained in animals fed a satietogen diet, mice were subjected to a High-Protein diet (HPD). Concomitantly with the satiety effect, a rise in intestinal CD36 gene expression was observed. No satiety effect occurred in CD36-null mice. HPD-fed WT mice showed a diminished FI compared to control mice, after saline duodenal infusion. But there was no further decrease after lipid infusion. The lipid-induced decrease in FI observed on control mice was accompanied by a rise in jejunal oleylethanolamide (OEA). Its level was higher in HPD-fed mice than in controls after saline infusion and was not changed by lipids. Overall, we demonstrate that lipid binding to intestinal CD36 is sufficient to produce a satiety effect. Moreover, it could participate in the satiety effect induced by HPD. Intestine can modulate FI by several mechanisms including an increase in OEA production and CD36 gene expression. Furthermore, intestine of mice adapted to HPD have a diminished capacity to modulate their food intake in response to dietary lipids

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Regulation de l'oxydation mitochondriale des acides gras dans le foie du rat Zucker obese ou mince. Effets de regimes enrichis en acides gras en N-3. Mise en evidence d'un mecanisme regulateur impliquant le reticulum endoplasmique

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : T 79649 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Appetite control by the tongue-gut axis and evaluation of the role of CD36/SR-B2.

IF 3.112International audienceUnderstanding the mechanisms governing food intake is a public health issue given the dramatic rise of obesity over the world. The overconsumption of tasty energy-dense foods rich in lipids is considered to be one of the nutritional causes of this epidemic. Over the last decade, the identification of fatty acid receptors in strategic places in the body (i.e. oro-intestinal tract and brain) has provided a major progress in the deciphering of regulatory networks involved in the control of dietary intake. Among these lipid sensors, CD36/SR-B2 appears to play a significant role since this membrane protein, known to bind long-chain fatty acid with a high affinity, was specifically found both in enterocytes and in a subset of taste bud cells and entero-endocrine cells. After a short overview on CD36/SR-B2 structure, function and regulation, this mini-review proposes to analyze the key findings about the role of CD36/SR-B2 along of the tongue-gut axis in relation to appetite control. In addition, we discuss whether obesogenic diets might impair lipid sensing mediated by CD36/SR-B2 along this axis

Fatty acids and lipopolysaccharides from health to disease - Editorial

International audienceFatty acids (FAs) are “building blocks” of lipids (phospholipids triacylglycerol, ceramides/sphingolipids, lipopolysaccharides …). They also act individually as ligands for different receptors and as precursors of bioactive lipid mediators. Thus, FAs play diverse major roles in organisms ranging from energy source and fuel storage, constituents of membrane lipids, to cellular signaling and regulatory molecules. However, the fate, metabolism and function of FAs depend on their biochemical structures: acyl-chain length, number and location of double-bonds

Les acides linoléiques conjugués (CLA) permettent-ils de lutter contre l’obésité sans risque ?

International audienceAmong the conjugated linoleic acid (CLA) isomer 10t,12c-CLA is nutritionally and commercially attractive since it has anti-obesity effects. However, this fatty acid triggers in mice a drastic decrease in adipose tissue mass, which is associated with side effects such as insulin resistance, hepatic steatosis and cholelithiasis risk. The aim of this review is to understand mechanisms responsible for these effects observed in mice and consider their existence in humans.Parmi les acides linoléiques conjugués (CLA), l’isomère 10t,12c-CLA est nutritionnellement et commercialement attrayant puisqu’il a un effet anti-obésité. Cependant, cet acide gras en parallèle d’une fonte drastique du tissu adipeux, déclenche chez la souris des effets indésirables comme une insulinorésistance, une stéatose hépatique et une augmentation des risques de cholélithiase biliaire. L’objectif de cette revue est de comprendre les mécanismes à l’origine de ces effets à partir des données obtenues chez la souris et de vérifier leur existence chez l’Homme

La teneur en lipides du régime affecte les capacités d'absorption intestinale et la triglycéridémie post-prandiale (contribution du récepteur nucléaire PPARb ?)

L absorption intestinale des acides gras à longue chaines (AGLC) est très efficace. En revanche, on ignore si ce phénomène est inné ou adaptatif. C est pourquoi, des souris ont été soumises à un régime hyperlipidique (40% m/m) pendant 21 jours. Nous avons constaté une induction du captage des AGLC, de l activité proliférative et de la masse relative de la muqueuse, de l expression des gènes impliqués dans les différentes étapes du processus d absorption intestinale des AGLC. Ce phénomène est adaptatif puisque ces régulations retournent aux valeurs des témoins lorsque les souris sont renourries avec un régime normolipidique. Ces modifications s accompagnent d une augmentation de la clairance plasmatique des lipoprotéines riches en triglycérides. Le Peroxisome Proliferator-Activated ReceptorB (PPARB) pourrait être à l origine de cette adaptation intestinale. Les données obtenues ont montré que la sur-expression intestinale de PPARB engendre une adaptation moins efficace des capacités d absorption.It is well known that intestinal fat absorption is efficient. However, we don t if the high triglycerides bioavailability of gut is attributable to inborn properties or to acquired properties. To answer this question, mice were subjected to a high-fat diet (40%, w/w) during 21 days. We have shown that high-fat induces intestinal LCFA uptake, intestinal mitotic index which leads to an increase of intestinal relative mass, expression of genes involved in fatty uptake, trafficking and lipoprotein synthesis. These changes were lipid-mediated, in that they were fully abolished in mice refed the control diet. Moreover, these changes induces a higher efficiency of triglycerides clearance in blood. The molecular mechanism at the origin of this intestinal adaptation could be the nuclear receptor, Peroxisome Proliferator-Activated Receptor B PPARB). Our data have shown that the intestinal overexpression of PPARB led to a low fat-mediated adaptation.DIJON-BU Sciences Economie (212312102) / SudocSudocFranceF

Cellular and molecular aspects of fat metabolism in the small intestine.

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