GPAT1 Deficiency in Mice Modulates NASH Progression in a Model-Dependent Manner.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD), and its more severe form, nonalcoholic steatohepatitis (NASH), is the leading cause for liver failure and liver cancer. Although the etiology is likely multifactorial, genes involved in regulating lipid metabolism are enriched in human NAFLD genome-wide association studies (GWAS), pointing to dysregulated lipid metabolism as a major pathogenic factor. Glycerol-3-phosphate acyltransferase 1 (GPAT1), encoded by GPAM, converts acyl-CoAs and glycerol-3-phosphate into lysophosphatidic acid and has been shown to regulate lipid accumulation in the liver. However, its role in mediating the progression from NAFLD to NASH has not been explored. METHODS: GPAT1-deficient mice were generated and challenged with diets inducing hepatic steatosis and NASH. Effects of GPAT1 deficiency on lipid and systemic metabolic end points were evaluated. RESULTS: Ablating GPAT1 globally or specifically in mouse hepatocytes reduced hepatic steatosis in the context of diet-induced or genetic obesity. Interestingly, blunting of progression from NAFLD to NASH in global GPAT1 knockout (KO) mice was model dependent. GPAT1 KO mice were protected from choline deficient, amino acid defined high-fat diet-induced NASH development, but not from the high fat, high carbohydrate, and high cholesterol diet-induced NASH. CONCLUSIONS: Our preclinical data support the notion that lipid metabolism pathways regulated by GPAT1 in hepatocytes play an essential role in NASH progression, albeit in a model-dependent manner.

The TAS1R2 sweet taste receptor regulates skeletal muscle mass and fitness.

Muscle fitness and mass deteriorate under the conditions of obesity and aging for reasons yet to be fully elucidated. Herein, we describe a novel pathway linking peripheral nutrient sensing and skeletal muscle function through the sweet taste receptor TAS1R2 and the involvement of ERK2-PARP1-NAD signaling axis. Muscle-specific deletion of TAS1R2 (mKO) in mice produced elevated NAD levels due to suppressed PARP1 activity, improved mitochondrial function, increased muscle mass and strength, and prolonged running endurance. Deletion of TAS1R2 in obese or aged mice also ameliorated the decline in muscle mass and fitness arising from these conditions. Remarkably, partial loss-of-function of TAS1R2 (rs35874116) in older, obese humans recapitulated the healthier muscle phenotype displayed by mKO mice in response to exercise training. Our findings show that inhibition of the TAS1R2 signaling in skeletal muscle is a promising therapeutic approach to preserve muscle mass and function.

Saccharin Stimulates Insulin Secretion Dependent on Sweet Taste Receptor-Induced Activation of PLC Signaling Axis.

BACKGROUND: Saccharin is a common artificial sweetener and a bona fide ligand for sweet taste receptors (STR). STR can regulate insulin secretion in beta cells, so we investigated whether saccharin can stimulate insulin secretion dependent on STR and the activation of phospholipase C (PLC) signaling. METHODS: We performed in vivo and in vitro approaches in mice and cells with loss-of-function of STR signaling and specifically assessed the involvement of a PLC signaling cascade using real-time biosensors and calcium imaging. RESULTS: We found that the ingestion of a physiological amount of saccharin can potentiate insulin secretion dependent on STR. Similar to natural sweeteners, saccharin triggers the activation of the PLC signaling cascade, leading to calcium influx and the vesicular exocytosis of insulin. The effects of saccharin also partially require transient receptor potential cation channel M5 (TRPM5) activity. CONCLUSIONS: Saccharin ingestion may transiently potentiate insulin secretion through the activation of the canonical STR signaling pathway. These physiological effects provide a framework for understanding the potential health impact of saccharin use and the contribution of STR in peripheral tissues.

High-dose saccharin supplementation does not induce gut microbiota changes or glucose intolerance in healthy humans and mice.

BACKGROUND: Non-caloric artificial sweeteners (NCAS) are widely used as a substitute for dietary sugars to control body weight or glycemia. Paradoxically, some interventional studies in humans and rodents have shown unfavorable changes in glucose homeostasis in response to NCAS consumption. The causative mechanisms are largely unknown, but adverse changes in gut microbiota have been proposed to mediate these effects. These findings have raised concerns about NCAS safety and called into question their broad use, but further physiological and dietary considerations must be first addressed before these results are generalized. We also reasoned that, since NCAS are bona fide ligands for sweet taste receptors (STRs) expressed in the intestine, some metabolic effects associated with NCAS use could be attributed to a common mechanism involving the host. RESULTS: We conducted a double-blind, placebo-controlled, parallel arm study exploring the effects of pure saccharin compound on gut microbiota and glucose tolerance in healthy men and women. Participants were randomized to placebo, saccharin, lactisole (STR inhibitor), or saccharin with lactisole administered in capsules twice daily to achieve the maximum acceptable daily intake for 2 weeks. In parallel, we performed a 10-week study administering pure saccharin at a high dose in the drinking water of chow-fed mice with genetic ablation of STRs (T1R2-KO) and wild-type (WT) littermate controls. In humans and mice, none of the interventions affected glucose or hormonal responses to an oral glucose tolerance test (OGTT) or glucose absorption in mice. Similarly, pure saccharin supplementation did not alter microbial diversity or composition at any taxonomic level in humans and mice alike. No treatment effects were also noted in readouts of microbial activity such as fecal metabolites or short-chain fatty acids (SCFA). However, compared to WT, T1R2-KO mice were protected from age-dependent increases in fecal SCFA and the development of glucose intolerance. CONCLUSIONS: Short-term saccharin consumption at maximum acceptable levels is not sufficient to alter gut microbiota or induce glucose intolerance in apparently healthy humans and mice. TRIAL REGISTRATION: Trial registration number NCT03032640 , registered on January 26, 2017. Video abstract.

A meta-analysis of nonsystematic responding in delay and probability reward discounting.

Delay discounting (DD) and probability discounting (PD) are behavioral measures of choice that index sensitivity to delayed and probabilistic outcomes, which are associated with a range of negative health-related outcomes. Patterns of discounting tend to be predictable, where preferences for immediate (vs. delayed) and certain (vs. probabilistic) rewards change as a function of delay and probability. However, some participants yield nonsystematic response patterns (NSR) that cannot be accounted for by theories of choice and could have implications for the validity of discounting-related experiments. Johnson and Bickel (2008) outline an algorithm for identifying NSR patterns in discounting, but the typical frequency of and methodological predictors of NSR patterns are not yet established in the extant literature. In this meta-analytic review, we identified papers for analysis by searching Web of Science, PubMed, and PsycInfo databases until November 8, 2015 for experiments identifying nonsystematic responders using Johnson and Bickel's algorithm. This yielded 114 experiments with nonsystematic data reported. The overall frequency of NSR across DD and PD studies was 18% and 19%, respectively. Nonmonetary outcomes (e.g., drugs, food, sex) yielded significantly more NSR patterns than did discounting for monetary outcomes. Participants recruited from a university setting had significantly more NSR patterns than did participants recruited from nonuniversity settings. Our review also indicates that researchers are inconsistent in whether or how they report NSR in discounting studies, which is relevant for a clearer understanding of the behavioral mechanisms that underlie impulsive choice. We make several recommendations regarding the assessment of NSR in discounting research. (PsycINFO Database Record

Inhibition of sweet chemosensory receptors alters insulin responses during glucose ingestion in healthy adults: a randomized crossover interventional study.

Background: Glucose is a natural ligand for sweet taste receptors (STRs) that are expressed on the tongue and in the gastrointestinal tract. Whether STRs directly contribute to the regulation of glucose homeostasis in response to glucose ingestion is unclear.Objective: We sought to determine the metabolic effects of the pharmacologic inhibition of STRs in response to an oral glucose load in healthy lean participants.Design: Ten healthy lean participants with a body mass index (in kg/m2) of 22.4 ± 0.8 were subjected to an oral-glucose-tolerance test (OGTT) on 4 separate days with the use of a randomized crossover design. Ten minutes before the 75-g OGTT, participants consumed a preload solution of either 300 parts per million (ppm) saccharin or water with or without the addition of 500 ppm lactisole, a human-specific inhibitor of STRs. When present, lactisole was included in both the preload and OGTT solutions. We assessed plasma responses of glucose, insulin, C-peptide, glucagon, glucagon-like peptides 1 and 2, gastric inhibitory peptide, acetaminophen, and 3-O-methylglucose. With the use of mathematical modeling, we estimated gastric emptying, glucose absorption, ß-cell function, insulin sensitivity and clearance, and the portal insulin:glucagon ratio.Results: The addition of lactisole to the OGTT caused increases in the plasma responses of insulin (P = 0.012), C-peptide (P = 0.004), and the insulin secretory rate (P = 0.020) compared with the control OGTT. The addition of lactisole also caused a slight reduction in the insulin sensitivity index independent of prior saccharin consumption (P < 0.025). The ingestion of saccharin before the OGTT did not alter any of the measured variables but eliminated the effects of lactisole on the OGTT.Conclusion: The pharmacologic inhibition of STRs in the gastrointestinal tract alters insulin responses during an oral glucose challenge in lean healthy participants. This trial was registered at clinicaltrials.gov as NCT02835859.

Geographic divergence and colour change in response to visual backgrounds and illumination intensity in bearded dragons.

Animals may improve camouflage by both dynamic colour change and local evolutionary adaptation of colour but we have little understanding of their relative importance in colour-changing species. We tested for differences in colour change in response to background colour and light intensity in two populations of central bearded dragon lizards (Pogona vitticeps) representing the extremes in body coloration and geographical range. We found that bearded dragons change colour in response to various backgrounds and that colour change is affected by illumination intensity. Within-individual colour change was similar in magnitude in the two populations but varied between backgrounds. However, at the endpoints of colour change, each population showed greater similarity to backgrounds that were representative of the local habitat compared with the other population, indicating local adaptation to visual backgrounds. Our results suggest that even in species that change colour, both phenotypic plasticity and geographic divergence of coloration may contribute to improved camouflage.

Color Change for Thermoregulation versus Camouflage in Free-Ranging Lizards.

Animal coloration has multiple functions including thermoregulation, camouflage, and social signaling, and the requirements of each function may sometimes conflict. Many terrestrial ectotherms accommodate the multiple functions of color through color change. However, the relative importance of these functions and how color-changing species accommodate them when they do conflict are poorly understood because we lack data on color change in the wild. Here, we show that the color of individual radio-tracked bearded dragon lizards, Pogona vitticeps, correlates strongly with background color and less strongly, but significantly, with temperature. We found no evidence that individuals simultaneously optimize camouflage and thermoregulation by choosing light backgrounds when hot or dark backgrounds when cold. In laboratory experiments, lizards showed both UV-visible (300-700 nm) and near-infrared (700-2,100 nm) reflectance changes in response to different background and temperature treatments, consistent with camouflage and thermoregulatory functions, respectively, but with no interaction between the two. Overall, our results suggest that wild bearded dragons change color to improve both thermoregulation and camouflage but predominantly adjust for camouflage, suggesting that compromising camouflage may entail a greater potential immediate survival cost.

Effects of an after-school care-administered physical activity and nutrition protocol on body mass index, fitness levels, and targeted psychological factors in 5- to 8-year-olds.

Over one third of U.S. youth are overweight or obese. Treatments typically have had unreliable effects, inconsistently incorporating behavior-change theory. After-school care might be a viable setting for health behavior-change programs. We evaluated effects of two consecutive 12-week segments of a revised self-efficacy/social cognitive theory-based physical activity and nutrition treatment on fitness levels, body mass index (BMI), and targeted psychosocial factors in after-school care participants, ages 5-8 years. Changes in physiological measures, exercise self-efficacy (ESE), and physical self-concept over 9 months were contrasted in experimental (n = 72) vs. typical-care (n = 42) groups. Mediation of the group-BMI change relationship by the psychosocial factors was also assessed. Improvements in physiological measures and ESE were significantly greater in the experimental group. ESE change completely mediated the association of treatment type with BMI change. The experimental group demonstrated significantly greater improvements in the physiological measures, with its treatment's theoretical basis and application within after-school care supported.

Disruption of the sugar-sensing receptor T1R2 attenuates metabolic derangements associated with diet-induced obesity.

Sweet taste receptors (STRs) on the tongue mediate gustatory sweet sensing, but their expression in the gut, pancreas, and adipose tissue suggests a physiological contribution to whole body nutrient sensing and metabolism. However, little is known about the function and contribution of these sugar sensors during metabolic stress induced by overnutrition and subsequent obesity. Here, we investigated the effects of high-fat/low-carbohydrate (HF/LC) diet on glucose homeostasis and energy balance in mice with global disruption of the sweet taste receptor protein T1R2. We assessed body composition, energy balance, glucose homeostasis, and tissue-specific nutrient metabolism in T1R2 knockout (T1R2-KO) mice fed a HF/LC diet for 12 wk. HF/LC diet-fed T1R2-KO mice gained a similar amount of body mass as did WT mice, but had reduced fat mass and increased lean mass relative to WT mice. T1R2-KO mice were also hyperphagic and hyperactive. Ablation of the T1R2 sugar sensor protected mice from HF/LC diet-induced hyperinsulinemia and altered substrate utilization, including increased rates of glucose oxidation and decreased liver triglyceride (TG) accumulation, despite normal intestinal fat absorption. Finally, STRs (T1r2/T1r3) were upregulated in the adipose tissue of WT mice in response to HF/LC diet, and their expression positively correlated with fat mass and glucose intolerance. The chemosensory receptor T1R2, plays an important role in glucose homeostasis during diet-induced obesity through the regulation of yet to be identified molecular mechanisms that alter energy disposal and utilization in peripheral tissues.

Sweet taste receptors regulate basal insulin secretion and contribute to compensatory insulin hypersecretion during the development of diabetes in male mice.

ß-Cells rapidly secrete insulin in response to acute increases in plasma glucose but, upon further continuous exposure to glucose, insulin secretion progressively decreases. Although the mechanisms are unclear, this mode of regulation suggests the presence of a time-dependent glucosensory system that temporarily attenuates insulin secretion. Interestingly, early-stage ß-cell dysfunction is often characterized by basal (ie, fasting) insulin hypersecretion, suggesting a disruption of these related mechanisms. Because sweet taste receptors (STRs) on ß-cells are implicated in the regulation of insulin secretion and glucose is a bona fide STR ligand, we tested whether STRs mediate this sensory mechanism and participate in the regulation of basal insulin secretion. We used mice lacking STR signaling (T1R2(-/-) knockout) and pharmacologic inhibition of STRs in human islets. Mouse and human islets deprived of STR signaling hypersecrete insulin at short-term fasting glucose concentrations. Accordingly, 5-hour fasted T1R2(-/-) mice have increased plasma insulin and lower glucose. Exposure of isolated wild-type islets to elevated glucose levels reduced STR expression, whereas islets from diabetic (db/db) or diet-induced obese mouse models show similar down-regulation. This transcriptional reprogramming in response to hyperglycemia correlates with reduced STR function in these mouse models, leading to insulin hypersecretion. These findings reveal a novel mechanism by which insulin secretion is physiologically regulated by STRs and also suggest that, during the development of diabetes, STR function is compromised by hyperglycemia leading to hyperinsulinemia. These observations further suggest that STRs might be a promising therapeutic target to prevent and treat type 2 diabetes.