Philippe Besnard

Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human

Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.

CD36- and GPR120-Mediated Ca2+ Signaling in Human Taste Bud Cells Mediates Differential Responses to Fatty Acids and Is Altered in Obese Mice

BACKGROUND & AIMSnIt is important to increase our understanding of gustatory detection of dietary fat and its contribution to fat preference. We studied the roles of the fat taste receptors CD36 and GPR120 and their interactions via Ca(2+) signaling in fungiform taste bud cells (TBC).nnnMETHODSnWe measured Ca(2+) signaling in human TBC, transfected with small interfering RNAs against messenger RNAs encoding CD36 and GPR120 (or control small interfering RNAs). We also studied Ca(2+) signaling in TBC from CD36(-/-) mice and from wild-type lean and obese mice. Additional studies were conducted with mouse enteroendocrine cell line STC-1 that express GPR120 and stably transfected with human CD36. We measured release of serotonin and glucagon-like peptide-1 from human and mice TBC in response to CD36 and GPR120 activation.nnnRESULTSnHigh concentrations of linoleic acid induced Ca(2+) signaling via CD36 and GPR120 in human and mice TBC, as well as in STC-1 cells, and low concentrations induced Ca(2+) signaling via only CD36. Incubation of human and mice fungiform TBC with lineoleic acid down-regulated CD36 and up-regulated GPR120 in membrane lipid rafts. Obese mice had decreased spontaneous preference for fat. Fungiform TBC from obese mice had reduced Ca(2+) and serotonin responses, but increased release of glucagon-like peptide-1, along with reduced levels of CD36 and increased levels of GPR120 in lipid rafts.nnnCONCLUSIONSnCD36 and GPR120 have nonoverlapping roles in TBC signaling during orogustatory perception of dietary lipids; these are differentially regulated by obesity.

Lipids and obesity: Also a matter of taste?

Obesity is undoubtedly one of the major public health challenges worldwide because of its rapid progression and deleterious effects of associated diseases. The easier access to tasty and energy-dense foods is thought to greatly contribute to this epidemic. Studies also report that obese subjects and animals (rats and mice) preferentially consume foods rich in fat when they can choose. The origin of this eating behavior remains elusive. Over the last decade, the existence of a taste of fat, besides textural and olfactory cues, was supported by a growing number of studies. The existence of a sixth taste modality devoted to the detection/perception of dietary lipids might offer additive information on the quality of food. While the sense of taste is recognized to be a driving-force guiding food choice, interest in the putative relationships between lipids, gustation and obesity is only now emerging. This mini-review will attempt to summarize our current knowledge on this new field of research.

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

Understanding 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.

Obese Subjects With Specific Gustatory Papillae Microbiota and Salivary Cues Display an Impairment to Sense Lipids

Some obese subjects overeat lipid-rich foods. The origin of this eating behavior is unknown. We have here tested the hypothesis that these subjects could be characterized by an impaired fatty taste sensitivity linked to a change in the gustatory papillae microbial and salivary environment. The composition of microbiota and saliva surrounding the circumvallate papillae was analyzed in combination with the orosensory lipid detection threshold in normal weight (NW) and obese (O) adults. Microbial architecture was similar to what was known in feces, but with an increased frequency of Proteobacteria. No difference in the orosensory sensitivity to lipids and composition of oral microbiota and saliva was observed between NW and O subjects. By contrast, specific bacterial and salivary signatures were found in lipid non-tasters, irrespectively of BMI. A multivariate approach highlighted that the salivary flow, lysozyme activity, total antioxidant capacity and TM7 bacterial family discriminated between tasters and non-tasters. Subgroup analysis of obese tasters (OT) versus obese non-tasters (ONT) identified specific bacterial metabolic pathways (i.e. phosphotransferase and simple sugar transport systems) as being higher in ONT. Altogether with the identification of a set of significant salivary variables, our study suggests that an “obese tongue” phenotype is associated with decreased orosensory sensitivity to lipids in some obese subjects.

Author Correction: Obese Subjects With Specific Gustatory Papillae Microbiota and Salivary Cues Display an Impairment to Sense Lipids

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

A chronic LPS-induced low-grade inflammation fails to reproduce in lean mice the impairment of preference for oily solution found in diet-induced obese mice

Diet-induced obesity (DIO) is associated with a decreased oral fat detection in rodents. This alteration has been explained by an impairment of the lipid-mediated signaling in taste bud cells (TBC). However, factors responsible for this defect remain elusive. Diet rich in saturated fatty acids is known to elicit a metabolic inflammation by promoting intestinal permeation to lipopolysaccharides (LPS), Gram-negative bacteria-derived endotoxins. To determine whether a local inflammation of the gustatory tissue might explain the obese-induced impairment of the oro-sensory detection of lipids, mice were subjected to a DIO protocol. Using a combination of behavioral tests, transcriptomic analyses of gustatory papillae and biochemical assays, we have found that i) DIO elicits a pro-inflammatory genic profile in the circumvallate papillae (CVP), known to house the highest density of lingual taste buds, ii) NFkB, a key player of inflammatory process, might play a role in this transcriptomic pattern, iii) plasma LPS levels are negatively correlated with the preference for oily solution, and iv) a chronic infusion of LPS at a level similar to that found in DIO mice is not sufficient to alter the spontaneous preference for fat in lean mice. Taken together these data bring the demonstration that a saturated high fat diet elicits an inflammatory response at the level of peripheral gustatory pathway and a LPS-induced low-grade endotoxemia alone does not explain the change in the preference for dietary lipids observed in DIO mice.

P168 Augmentation par les lipopolysaccharides de la sécrétion d’insuline stimulée par le glucose : Implication de la voie du Glucagon Like Peptide-1 (GLP-1)

Introduction L’obesite est devenue la premiere maladie non infectieuse de l’histoire. Elle peut etre associee a d’autres pathologies constituant le syndrome metabolique. L’obesite est associee a une situation inflammatoire chronique a bas bruit dont l’origine est inconnue. Recemment, les lipopolysaccharides (LPS), des molecules presentes a la surface de la membrane externe des bacteries gram (-) et entrainant la secretion de cytokines pro inflammatoires ont ete impliquees dans l’etiologie des maladies metaboliques. L’objectif de cette etude a ete d’etudier l’effet d’une injection aigue ou continue (a l’aide de pompes alzet) de LPS lors d’une hyperglycemie induite experimentalement Materiels et methodes Du LPS a ete administre a des souris de type C57bl6J soit via une injection aigue intraperitoneale soit via une infusion continue intraperitoneale utiilsant des mini pompes osmotiques. Suite a une hyperglycemie induite experimentalement, les reponses glycemiques et insulinemiques ont ete mesurees. Resultats Quel que soit le mode d’administration ainsi que la dose de LPS utilisee, nos resultats montrent une augmentation de la secretion d’insuline stimulee par le glucose (GSIS). De facon originale, nous montrons que cette augmentation de GSIS induite par les LPS est due a une augmentation des taux circulants de Glucagon Like Peptide-1 (GLP-1). Suite a une approche pharmacologique, visant a augmenter les taux de GLP-1 ou a antagoniser son action, l’effet des LPS sur le metabolisme glucidique est modifie. Enfin, des etudes complementaires realisees chez des souris sauvages et deficientes en recepteur GLP-1 (souris GLP-1R-KO) montrent que la voie du GLP-1/GLP-1R est impliquee dans la reponse du metabolisme glucidique aux LPS. Conclusion Ainsi, nos resultats montrent que l’augmentation des taux de GLP-1 est associe au developpement de l’hyper insulinemie induite par le glucose lors d’une endotoxemie.