Increased Fat Taste Preference in Progranulin-Deficient Mice

Progranulin deficiency in mice is associated with deregulations of the scavenger receptor signaling of CD36/SCARB3 in immune disease models, and CD36 is a dominant receptor in taste bud cells in the tongue and contributes to the sensation of dietary fats. Progranulin-deficient mice (Grn−/−) are moderately overweight during middle age. We therefore asked if there was a connection between progranulin/CD36 in the tongue and fat taste preferences. By using unbiased behavioral analyses in IntelliCages and Phenomaster cages we showed that progranulin-deficient mice (Grn−/−) developed a strong preference of fat taste in the form of 2% milk as opposed to 0.3% milk, and for diluted MCTs versus tap water. The fat preference in the 7d-IntelliCage observation period caused an increase of 10% in the body weight of Grn−/− mice, which did not occur in the wildtype controls. CD36 expression in taste buds was reduced in Grn−/− mice at RNA and histology levels. There were no differences in the plasma or tongue lipids of various classes including sphingolipids, ceramides and endocannabinoids. The data suggest that progranulin deficiency leads to a lower expression of CD36 in the tongue resulting in a stronger urge for fatty taste and fatty nutrition.

Anorexia and fat aversion induced by vertical sleeve gastrectomy is attenuated in neurotensin receptor 1 deficient mice

Neurotensin (NT) is an anorexic gut hormone and neuropeptide that increases in circulation following bariatric surgery in humans and rodents. We sought to determine the contribution of NT to the metabolic efficacy of vertical sleeve gastrectomy (VSG). To explore a potential mechanistic role of NT in VSG, we performed sham or VSG surgeries in diet-induced obese neurotensin receptor 1 (NTSR1) wildtype (wt) and knockout (ko) mice and compared their weight and fat mass loss, glucose tolerance, food intake, and food preference after surgery. NTSR1 ko mice had reduced initial anorexia and body fat loss. Additionally, NTSR1 ko mice had an attenuated reduction in fat preference following VSG. Results from this study suggest that NTSR1 signaling contributes to the potent effect of VSG to initially reduce food intake following VSG surgeries and potentially also on the effects on macronutrient selection induced by VSG. However, maintenance of long-term weight loss after VSG requires signals in addition to NT.

Sweet/Fat Preference Taste in Subjects Who are Lean, Obese and Very Obese

Purpose This study assessed the perception of sweetness, creaminess, and pleasantness from a sweet/fat preference test in subjects who are lean (BMI: 19–25), obese (BMI: 30–33) or very obese (BMI: 34–40) using categorical modeling. Methods Subjects tasted 16 dairy solutions consisting of 0%, 3.5%, 11.3% and 37.5% fat and each containing 0%, 5%, 10%, or 20% sugar and rated them for sweetness, creaminess and pleasantness. Results A proportional odds model described the perception of sweetness using an Emax for the effect of sugar and a linear effect for fat. Perception of creaminess was dependent on the fat and sugar content and was described with proportional odds model with linear effects of sugar and fat. Perception of pleasantness increased with sugar and fat but decreased in solutions containing 37.5% fat. A differential odds model using an Emax model for fat and sugar with a negative interaction between them allowed the sugar content to be less than proportional and the fat content to be greater than proportional for pleasantness. Conclusions Application of modeling provided understanding of these complex interactions of sugar and fat on the perception of sweetness, creaminess, and pleasantness and provides a tool to investigate obesity and pharmacological intervention.

Novel GPR120 agonist TUG891 modulates fat taste perception and preference and activates tongue-brain-gut axis in mice

GPR120 is implicated as a lipid receptor in the oro-sensory detection of dietary fatty acids. However, the effects of GPR120 activation on dietary fat intake or obesity are not clearly understood. We investigated to determine whether the binding of TUG891, a novel GPR120 agonist, to lingual GPR120 modulates fat preference in mice. We explored the effects of TUG891 on obesity-related hormones and conducted behavioral choice tests on mice to better understand the physiologic relevance of the action of TUG891. In cultured mouse and human taste bud cells (TBCs), TUG891 induced a rapid increase in Ca2+ by acting on GPR120. A long-chain dietary fatty acid, linoleic acid (LA), also recruited Ca2+ via GPR120 in human and mouse TBCs. Both TUG891 and LA induced ERK1/2 phosphorylation and enhanced in vitro release of glucagon-like peptide-1 from cultured human and mouse TBCs. In situ application of TUG891 onto the tongue of anesthetized mice triggered the secretion of pancreatobiliary juice, probably via the tongue-brain-gut axis. Furthermore, lingual application of TUG891 altered circulating concentrations of cholecystokinin and adipokines, associated with decreased circulating LDL, in conscious mice. In behavioral tests, mice exhibited a spontaneous preference for solutions containing either TUG891 or LA instead of a control. However, addition of TUG891 to a solution containing LA significantly curtailed fatty acid preference. Our study demonstrates that TUG891 binds to lingual GPR120 receptors, activates the tongue-brain-gut axis, and modulates fat preference. These findings may support the development of new fat taste analogs that can change the approach to obesity prevention and treatment.