A novel fatty acid analogue triggers CD36-GPR120 interaction and exerts anti-inflammatory action in endotoxemia.

Inflammation is a mediator of a number of chronic pathologies. We synthesized the diethyl (9Z,12Z)-octadeca-9,12-dien-1-ylphosphonate, called NKS3, which decreased lipopolysaccharide (LPS)-induced mRNA upregulation of proinflammatory cytokines (IL-1ß, IL-6 and TNF-α) not only in primary intraperitoneal and lung alveolar macrophages, but also in freshly isolated mice lung slices. The in-silico studies suggested that NKS3, being CD36 agonist, will bind to GPR120. Co-immunoprecipitation and proximity ligation assays demonstrated that NKS3 induced protein-protein interaction of CD36 with GPR120in RAW 264.7 macrophage cell line. Furthermore, NKS3, via GPR120, decreased LPS-induced activation of TAB1/TAK1/JNK pathway and the LPS-induced mRNA expression of inflammatory markers in RAW 264.7 cells. In the acute lung injury model, NKS3 decreased lung fibrosis and inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and nitric oxide (NO) production in broncho-alveolar lavage fluid. NKS3 exerted a protective effect on LPS-induced remodeling of kidney and liver, and reduced circulating IL-1ß, IL-6 and TNF-α concentrations. In a septic shock model, NKS3 gavage decreased significantly the LPS-induced mortality in mice. In the last, NKS3 decreased neuroinflammation in diet-induced obese mice. Altogether, these results suggest that NKS3 is a novel anti-inflammatory agent that could be used, in the future, for the treatment of inflammation-associated pathologies.

In Vitro Functional Characterization of Type-I Taste Bud Cells as Monocytes/Macrophages-like Which Secrete Proinflammatory Cytokines.

The sense of taste determines the choice of nutrients and food intake and, consequently, influences feeding behaviors. The taste papillae are primarily composed of three types of taste bud cells (TBC), i.e., type I, type II, and type III. The type I TBC, expressing GLAST (glutamate--aspartate transporter), have been termed as glial-like cells. We hypothesized that these cells could play a role in taste bud immunity as glial cells do in the brain. We purified type I TBC, expressing F4/80, a specific marker of macrophages, from mouse fungiform taste papillae. The purified cells also express CD11b, CD11c, and CD64, generally expressed by glial cells and macrophages. We further assessed whether mouse type I TBC can be polarized toward M1 or M2 macrophages in inflammatory states like lipopolysaccharide (LPS)-triggered inflammation or obesity, known to be associated with low-grade inflammation. Indeed, LPS-treatment and obesity state increased TNFα, IL-1ß, and IL-6 expression, both at mRNA and protein levels, in type I TBC. Conversely, purified type I TBC treated with IL-4 showed a significant increase in arginase 1 and IL-4. These findings provide evidence that type I gustatory cells share many features with macrophages and may be involved in oral inflammation.

Cellular and Molecular Mechanisms of Fat Taste Perception.

During the last couples of years, a number of studies have increasingly accumulated on the gustatory perception of dietary fatty acids in rodent models and human beings in health and disease. There is still a debate to coin a specific term for the gustatory perception of dietary fatty acids either as the sixth basic taste quality or as an alimentary taste. Indeed, the psycho-physical cues of orosensory detection of dietary lipids are not as distinctly perceived as other taste qualities like sweet or bitter. The cellular and molecular pharmacological mechanisms, triggered by the binding of dietary long-chain fatty acids (LCFAs) to tongue taste bud lipid receptors like CD36 and GPR120, involve Ca2+ signaling as other five basic taste qualities. We have not only elucidated the role of Ca2+ signaling but also identified different components of the second messenger cascade like STIM1 and MAP kinases, implicated in fat taste perception. We have also demonstrated the implication of Calhm1 voltage-gated channels and store-operated Ca2+ (SOC) channels like Orai1, Orai1/3, and TRPC3 in gustatory perception of dietary fatty acids. We have not only employed siRNA technology in vitro and ex vivo on tissues but also used animal models of genetic invalidation of STIM1, ERK1, Orai1, Calhm1 genes to explore their implications in fat taste signal transduction. Moreover, our laboratory has also demonstrated the importance of LCFAs detection dysfunction in obesity in animal models and human beings.

Taste perception and its effects on oral nutritional supplements in younger life phases.

PURPOSE OF REVIEW: The current review summarizes the importance of taste perception with regard to acceptance of oral nutritional supplements (ONS) in young children. We also shed light on how basic tastes may influence the orosensory detection of ONS in the light of genetic variations, encoding for different taste modalities, particularly for sweet and bitter (and fat), in children. RECENT FINDINGS: Single nucleotide polymorphism (SNP) of bitter and sweet taste receptor genes, that is, respectively, TAS2R38 and T1R2/T1R3, may influence orosensory perception of 'bitter-made-sweet' ONS. The SNP of fat taste receptor gene, that is, CD36, might communicate with bitter taste perception. The emerging new sixth fat taste may interfere with obesity in children. SUMMARY: Sweet and bitter taste modalities are innate cues, expressed by children from birth to adolescence, either by a strong preference or by food aversion. Sweet and bitter tastes also communicate with each other as sweeteners can mask bitter phenotype. The fat preference, encoded by specific lingual taste receptors, is also modulated, via its interaction with phenotype and genotype, by bitter taste. Sodium salts might interact with bitter taste. Finally, the taste modalities will impact on the intake of ONS in children as the taste phenotype changes in this population, irrespective to genotype.

Novel Fat Taste Receptor Agonists Curtail Progressive Weight Gain in Obese Male Mice.

BACKGROUND & AIMS: The spontaneous preference for dietary lipids is principally regulated by 2 lingual fat taste receptors, CD36 and GPR120. Obese animals and most of human subjects exhibit low orosensory perception of dietary fat because of malfunctioning of these taste receptors. Our aim was to target the 2 fat taste receptors by newly synthesized high affinity fatty acid agonists to decrease fat-rich food intake and obesity. METHODS: We synthesized 2 fat taste receptor agonists (FTA), NKS-3 (CD36 agonist) and NKS-5 (CD36 and GPR120 agonist). We determined their molecular dynamic interactions with fat taste receptors and the effect on Ca2+ signaling in mouse and human taste bud cells (TBC). In C57Bl/6 male mice, we assessed their gustatory perception and effects of their lingual application on activation of tongue-gut loop. We elucidated their effects on obesity and its related parameters in male mice fed a high-fat diet. RESULTS: The two FTA, NKS-3 and NKS-5, triggered higher Ca2+ signaling than a dietary long-chain fatty acid in human and mouse TBC. Mice exhibited a gustatory attraction for these compounds. In conscious mice, the application of FTA onto the tongue papillae induced activation of tongue-gut loop, marked by the release of pancreato-bile juice into collecting duct and cholecystokinin and peptide YY into blood stream. Daily intake of NKS-3 or NKS-5 via feeding bottles decreased food intake and progressive weight gain in obese mice but not in control mice. CONCLUSIONS: Our results show that targeting fat sensors in the tongue by novel chemical fat taste agonists might represent a new strategy to reduce obesity.

Tongue Leptin Decreases Oro-Sensory Perception of Dietary Fatty Acids.

Leptin, an anorectic hormone, regulates food intake, energy expenditure and body weight. We assessed the implication of tongue leptin in the modulation of oro-sensory detection of dietary fatty acids in mice. The RT-PCR analysis showed that mRNA encoding leptin and leptin receptor (Ob-Rb) was expressed in mice taste bud cells (TBC). Confocal microscopic studies showed that the lipid sensor CD36 was co-expressed with leptin in mice TBC. Silencing of leptin or Ob-Rb mRNA in tongue papillae upregulated preference for a long-chain fatty acid (LCFA), i.e., linoleic acid (LA), in a two-bottle paradigm in mice. Furthermore, tongue leptin application decreased the preference for the LCFA. These results suggest that tongue leptin exerts an inhibitory action on fatty acid preference. In isolated mice TBC, leptin decreased LCFA-induced increases in free intracellular calcium concentrations, [Ca2+]i. Leptin and LCFA induced the phosphorylation of ERK1/2 and STAT-3 and there were no additive or opposite effects of the two agents on the degree of phosphorylation. However, leptin, but not the LCFA, induced phosphoinositide-3-kinase (PI-3-K)-dependent Akt phosphorylation in TBC. Furthermore, leptin induced hyperpolarization, whereas LCFA induced depolarization in TBC. Our study demonstrates that tongue leptin exerts an inhibitory action on oro-sensory detection of a dietary fatty acid by interfering with Ca2+ signaling and membrane potential in mice TBC.

DHA induces Jurkat T-cell arrest in G2/M phase of cell cycle and modulates the plasma membrane expression of TRPC3/6 channels.

We investigated whether docosahexaenoic acid (DHA), a dietary n-3 fatty acid, modulates calcium (Ca2+) signaling and cell cycle progression in human Jurkat T-cells. Our study demonstrates that DHA inhibited Jurkat T-cell cycle progression by blocking their passage from S phase to G2/M phase. In addition, DHA decreased the plasma membrane expression of TRPC3 and TRPC6 calcium channels during T-cell proliferation. Interestingly, this fatty acid increased plasma membrane expression of TRPC6 after 24 h of mitogenic stimulation by phorbol-13-myristate-12-acetate (PMA) and ionomycin. These variations in the membrane expression of TRPC3 and TRPC6 channels were not directly correlated with the mRNA expression, indicating that it was a post-translational phenomenon. DHA increased free intracellular calcium concentrations, [Ca2+]i, via opening TRPC3 and TRPC6 channels. We conclude that the anti-proliferative effect of DHA might involve the modulation of TRPC3 and TRPC6 channels in human T-cells.

Obesity and COVID-19: Oro-Naso-Sensory Perception.

Through a recent upsurge of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, the clinical assessment of most of the coronavirus disease 19 (COVID-19) patients clearly presents a health condition with the loss of oro-naso-sensory (ONS) perception, responsible for the detection of flavor and savor. These changes include anosmia and dysgeusia. In some cases, these clinical manifestations appear even before the general flu-like symptoms, e.g., sore throat, thoracic oppression and fever. There is no direct report available on the loss of these chemical senses in obese COVID-19 patients. Interestingly, obesity has been shown to be associated with low ONS cues. These alterations in obese subjects are due to obesity-induced altered expression of olfacto-taste receptors. Besides, obesity may further aggravate the SARS-CoV-2 infection, as this pathology is associated with a high degree of inflammation/immunosuppression and reduced protection against viral infections. Hence, obesity represents a great risk factor for SARS-CoV-2 infection, as it may hide the viral-associated altered ONS symptoms, thus leading to a high mortality rate in these subjects.

Bile acid receptor TGR5 is critically involved in preference for dietary lipids and obesity.

We investigated the implication of Takeda G protein-coupled receptor 5 (TGR5) in fat preference and fat sensing in taste bud cells (TBC) in C57BL/6 wild-type (WT) and TGR5 knock out (TGR5-/-) male mice maintained for 20 weeks on a high-fat diet (HFD). We also assessed the implication of TGR5 single nucleotide polymorphism (SNP) in young obese humans. The high-fat diet (HFD)-fed TGR5-/- mice were more obese, marked with higher liver weight, lipidemia and steatosis than WT obese mice. The TGR5-/- obese mice exhibited high daily food/energy intake, fat mass and inflammatory status. WT obese mice lost the preference for dietary fat, but the TGR5-/- obese mice exhibited no loss towards the attraction for lipids. In lingual TBC, the fatty acid-triggered Ca2+ signaling was decreased in WT obese mice; however, it was increased in TBC from TGR5-/- obese mice. Fatty acid-induced in vitro release of GLP-1 was higher, but PYY concentrations were lower, in TBC from TGR5-/- obese mice than those in WT obese mice. We noticed an association between obesity and variations in TGR5 rs11554825 SNP. Finally, we can state that TGR5 modulates fat eating behavior and obesity.

Fatty Acid Lingual Application Activates Gustatory and Reward Brain Circuits in the Mouse.

The origin of spontaneous preference for dietary lipids in humans and rodents is debated, though recent compelling evidence has shown the existence of fat taste that might be considered a sixth taste quality. We investigated the implication of gustatory and reward brain circuits, triggered by linoleic acid (LA), a long-chain fatty acid. The LA was applied onto the circumvallate papillae for 30 min in conscious C57BL/6J mice, and neuronal activation was assessed using c-Fos immunohistochemistry. By using real-time reverse transcription polymerase chain reaction (RT-qPCR), we also studied the expression of mRNA encoding brain-derived neurotrophic factor (BDNF), Zif-268, and Glut-1 in some brain areas of these animals. LA induced a significant increase in c-Fos expression in the nucleus of solitary tract (NST), parabrachial nucleus (PBN), and ventroposterior medialis parvocellularis (VPMPC) of the thalamus, which are the regions known to be activated by gustatory signals. LA also triggered c-Fos expression in the central amygdala and ventral tegmental area (VTA), involved in food reward, in conjunction with emotional traits. Interestingly, we noticed a high expression of BDNF, Zif-268, and Glut-1 mRNA in the arcuate nucleus (Arc) and hippocampus (Hipp), where neuronal activation leads to memory formation. Our study demonstrates that oral lipid taste perception might trigger the activation of canonical gustatory and reward pathways.

Orosensory detection of bitter in fat-taster healthy and obese participants: Genetic polymorphism of CD36 and TAS2R38.

BACKGROUND & AIMS: We assessed orosensory detection of a long-chain fatty acid, linoleic acid (LA), and a bitter taste marker, 6-n-propylthiouracil (PROP), and correlated lipid-taster subjects with PROP detection and polymorphism in genes encoding bitter and lipid taste receptors, respectively, TAS2R38 and CD36, in normal weight and obese subjects. DESIGN: The normal weight (n = 52, age = 35.3 ± 4.10 years, BMI = 23.22 ± 1.44 kg/m2) and obese (n = 52, age = 35.0 ± 5.43 years, BMI = 34.29 ± 5.31 kg/m2) participants were recruited to determine fat and bitter detection thresholds. The genomic DNA was used to determine single nucleotide polymorphism (SNP) of CD36 (rs1761667) and TAS2R38 (rs1726866 and rs10246939). RESULTS: The study included the participants who could detect LA, i.e., lipid-tasters. There was a positive correlation between BMI and detection thresholds for fat and bitter taste in normal weight and obese subjects. Obese participants showed a positive correlation between LA and PROP detection thresholds. PROP detection thresholds were higher for CD36 SNP (rs1761667) and TAS2R38 SNPs (rs1726866 and rs10246939) in obese participants compared to normal weight subjects. LA detection thresholds were not high for CD36 SNP (rs1761667) or TAS2R38 SNP (rs1726866 and rs10246939) in obese participants. CONCLUSIONS: Orosensory detection thresholds for fat and bitter taste are associated with BMI, and CD36 and TAS2R38 genotypes are not always associated with taste phenotypes.

ERK1 and ERK2 activation modulates diet-induced obesity in mice.

Obesity is a worldwide problem, and dietary lipids play an important role in its pathogenesis. Recently, Erk1 knock-out (ERK1-/-) mice have been shown to exhibit low preference for dietary fatty acids. Hence, we maintained Erk1-/- mice on a high-fat diet (HFD) to assess the implication of this mitogen-activated protein (MAP) kinase in obesity. The Erk1-/- mice, fed the HFD, were more obese than wild-type (WT) animals, fed the same diet. Erk1-/- obese mice gained more fat and liver mass than WT obese animals. No difference was observed in daily food and energy intake in HFD-fed both group of animals. However, feed efficiency was higher in Erk1-/- than WT animals. Blood cholesterol, triglyceride and insulin concentrations were higher in Erk1-/- obese mice compared to WT obese animals. Accordingly, homeostatic model assessment of insulin resistance (HOMA-IR) value was higher in Erk1-/- obese mice compared to WT obese animals. Interestingly, only Erk1-/- obese mice, but not WT-obese animals, exhibited high degree of phosphorylation of liver MEK, the upstream regulator of ERK1/2. This phenomenon was associated with high liver ERK2 phosphorylation in Erk1-/- obese mice which also had high liver acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) mRNA expression, suggesting high lipogenesis in these animals. The Erk1-/- obese mice also had low PPAR-α and CPT1ß mRNA, indicating low fatty acid oxidation. Our observations suggest that ERK1 and ERK2 might play key roles in the regulation of obesity.