M. Chevrot

The Lipid-Sensor Candidates CD36 and GPR120 Are Differentially Regulated by Dietary Lipids in Mouse Taste Buds: Impact on Spontaneous Fat Preference

Background Recent studies in rodents and humans suggest that the chemoreception of long-chain fatty acids (LCFA) in oral cavity is involved in the spontaneous preference for fatty foods and might contribute to the obesity risk. CD36 and GPR120 are LCFA receptors identified in rodent taste bud cells. The fact that CD36 or GPR120 gene inactivation leads to a decrease in the preference for lipids raises the question of the respective role(s) played by these gustatory lipid-sensor candidates. Methodology/Principal Findings Using a combination of biochemical, nutritional and behavioural studies in wild-type, CD36+/−and CD36−/− mice, it was found that: 1°) CD36 and GPR120 display different diurnal rhythms in the gustatory circumvallate papillae, CD36 mRNA levels being down-regulated during the dark period in contrast to GPR120, 2°) this change is due to food intake and strictly dependent of the presence of lipids in the diet, 3°) CD36 protein levels are also rapidly but transiently decreased by the food intake, a two-fold drop in CD36 protein levels being found 1 h after refeeding, followed by a progressive return to the pre-prandial values, 4°) this down-regulation, which has a post-transcriptional origin, seems sufficient to alter the spontaneous fat preference, independently to change in the GPR120 gene expression. Conclusions/Significance In contrast to GPR120, CD36 appears to be a food-sensitive lipid sensor in the gustatory circumvallate papillae. Lipid-mediated change in lingual CD36 expression might modulate the motivation for fat during a meal, initially high and then gradually decreasing secondary to the food intake. This short-term lipid-mediated effect is reminiscent of sensory-specific satiety. These findings, which highlight the role played by CD36 in the oro-sensory perception of dietary lipids, raise the possibility of novel pharmacological strategies to modify attraction for fatty foods and decrease obesity risks.

CD36 as a lipid sensor

CD36 is a multifunctional protein homologous to the class B scavenger receptor SR-B1 mainly found in tissues with a sustained lipid metabolism and in several hematopoieic cells. CD36 is thought to be involved in various physiological and pathological processes like angiogenesis, thrombosis, atherogenesis, Alzheimers disease or malaria. An additive emerging function for CD36 is a role as a lipid sensor. Location of CD36 and orthologue molecules in plasma membrane of cells in contact with the external environment (e.g. gustatory, intestinal or olfactory epithelia) allows the binding of exogenous-derived ligands including dietary lipids, diglycerides from bacterial wall in mammals and even a lipid-like pheromone in insects. Similar function might also exist in the brain in which a CD36-dependent sensing of fatty acids has been reported in ventromedial hypothalamic neurons in rodents. Specific recognition of lipid-related molecules by a receptor-like protein highly conserved throughout the evolution strongly suggests that lipid-sensing by CD36 is responsible for basic physiological functions in relation with behavior, energy balance and innate immunity.

Lipid-mediated release of GLP-1 by mouse taste buds from circumvallate papillae: putative involvement of GPR120 and impact on taste sensitivity

Glucagon-like peptide-1 (GLP-1) signaling modulates sweet-taste sensitivity in the mouse. Because circumvallate papillae (CVPs) express both GLP-1 and its receptor, a local regulation has been suggested. However, whether dietary lipids are involved in this regulation, as shown in the gut, is unknown. By using a combination of biochemical, immunohistochemical, and behavioral approaches, the present data i) confirm the role of GLP-1 signaling in the attraction for sucrose, ii) demonstrate that minute quantities of long-chain FAs (LCFAs) reinforce the attraction for sucrose in a GLP-1 receptor-dependent manner, iii) suggest an involvement of the LCFA receptor GPR120 expressed in taste buds in this system, and iv) support the existence of a regulation by GLP-1 of the lipid sensing mediated by lingual CD36. Therefore, oro-sensory detection of LCFAs may affect sweet and fatty taste responsiveness by controlling the secretion of lingual GLP-1. This regulatory loop, probably triggered by the LCFA-GPR120 interaction, might contribute to the high palatability of foods rich both in fat and sugar.

Obesity alters the gustatory perception of lipids in the mouse: plausible involvement of lingual CD36

A relationship between orosensory detection of dietary lipids, regulation of fat intake, and body mass index was recently suggested. However, involved mechanisms are poorly understood. Moreover, whether obesity can directly modulate preference for fatty foods remains unknown. To address this question, exploration of the oral lipid sensing system was undertaken in diet-induced obese (DIO) mice. By using a combination of biochemical, physiological, and behavioral approaches, we found that i) the attraction for lipids is decreased in obese mice, ii) this behavioral change has an orosensory origin, iii) it is reversed in calorie-restricted DIO mice, revealing an inverse correlation between fat preference and adipose tissue size, iv) obesity suppresses the lipid-mediated downregulation of the lipid-sensor CD36 in circumvallate papillae, usually found during the refeeding of lean mice, and v) the CD36-dependent signaling cascade controlling the intracellular calcium levels ([Ca2+]i) in taste bud cells is decreased in obese mice. Therefore, obesity alters the lipid-sensing system responsible for the oral perception of dietary lipids. This phenomenon seems to take place through a CD36-mediated mechanism, leading to changes in eating behavior.

Obesity interferes with the orosensory detection of long-chain fatty acids in humans

BACKGROUND The association between the orosensory detection of lipids, preference for fatty foods, and body mass index (BMI; in kg/m(2)) is controversial in humans. OBJECTIVE We explored the oral lipid-sensing system and the orosensory-induced autonomic reflex system in lean and obese subjects. DESIGN Lean (BMI: 19 to <25; n = 30) and obese (BMI >30; n = 29) age-matched men were enrolled. Their oral threshold sensitivity to linoleic acid (LA) was determined by using a 3-alternative forced-choice ascending procedure, and their eating habits were established by the analysis of 4 consecutive 24-h food-consumption diaries. The effect of brief oral lipid stimulations on plasma triglyceride [(TG)pl] concentrations was analyzed in overnight-fasted lean and obese individuals subjected to a whole-mouth stimulation (sip-and-spit procedure) with a control or 1% LA emulsions for 5 min according to a within-subject randomized design. RESULTS A large distribution of LA detection was shown in both groups. Mean detection thresholds were 0.053% (wt:wt) and 0.071% (wt:wt) in lean and obese subjects, respectively. No relation between the LA detection threshold and BMI was observed. The 5 subjects who detected only the higher concentration of LA (5% wt:wt) or were unable to distinguish properly between control and LA emulsions were obese. An analysis of dietary habits showed that these obese LA nontasters consumed more lipids and energy than did all other subjects. Brief whole-mouth stimulations (sip-and-spit procedure) with a control or 1% LA emulsion revealed an LA-mediated rise in (TG)pl concentrations in overnight-fasted, lean subjects. The origin of this change seemed to be hepatic. This (TG)pl upregulation was not shown in obese subjects, which suggested that obesity led to disturbances in the oral-brainstem-periphery loop. CONCLUSION Altogether, these data strongly suggest that obesity may interfere with the orosensory system responsible for the detection of free long-chain fatty acids in humans. This trial was registered at clinicaltrials.gov as NCT02028975.

Is the taste of fat regulated

Over the last decade, converging data have been accumulated both in rodents and humans, supporting the existence of a sixth taste modality devoted to the perception of dietary lipids. It is well known that the sense of taste is determinant for the food choice and that the overconsumption of highly palatable energy-dense foods contributes to the current obesity epidemic. Thus, an important issue in terms of Public Health is to understand the mechanisms by which the oro-sensory perception of fat is regulated. An overview of our current knowledge in this field of investigations is proposed in this mini-review.

Different effects of pioglitazone and rosiglitazone on lipid metabolism in mouse cultured liver explants

Pioglitazone (PIO) and rosiglitazone (ROSI) are widely used as oral antidiabetic agents for treatment of type 2 diabetes. Although these medications exert similar effects on blood glucose, recent clinical studies indicated that PIO has a more pronounced beneficial effect on lipid parameters than ROSI. In order to get further insight into the lipid effects of both drugs, we tested whether PIO, compared to ROSI, could exert direct effects on lipid liver metabolism in relation with plasma lipids.

Role of CD36 in Oral and Postoral Sensing of Lipids

Obesity and associated plethora of diseases constitute a major public health challenge worldwide. The conjunction of profound changes in our lifestyle and a thrifty genetic that evolved in an environment of food scarcity largely explains this epidemic situation. Food abundance promotes our specific appetite for the more palatable food generally rich in lipids. It is noteworthy that this attraction for fatty food is not specific to humans. Rats and mice also spontaneously prefer lipid-rich food in a free-choice situation. Detection of lipids in food requires the presence of specific sensors located in strategic places (e.g., oral cavity, small intestine, brain) whose activation results in a modulation of the eating behavior. Recent data strongly suggest that the glycoprotein CD36 plays a significant role in this sensing system.