Rebaudioside D decreases adiposity and hepatic lipid accumulation in a mouse model of obesity.

Overconsumption of added sugars has been pointed out as a major culprit in the increasing rates of obesity worldwide, contributing to the rising popularity of non-caloric sweeteners. In order to satisfy the growing demand, industrial efforts have been made to purify the sweet-tasting molecules found in the natural sweetener stevia, which are characterized by a sweet taste free of unpleasant aftertaste. Although the use of artificial sweeteners has raised many concerns regarding metabolic health, the impact of purified stevia components on the latter remains poorly studied. The objective of this project was to evaluate the impact of two purified sweet-tasting components of stevia, rebaudioside A and D (RebA and RebD), on the development of obesity, insulin resistance, hepatic health, bile acid profile, and gut microbiota in a mouse model of diet-induced obesity. Male C57BL/6 J mice were fed an obesogenic high-fat/high-sucrose (HFHS) diet and orally treated with 50 mg/kg of RebA, RebD or vehicle (water) for 12 weeks. An additional group of chow-fed mice treated with the vehicle was included as a healthy reference. At weeks 10 and 12, insulin and oral glucose tolerance tests were performed. Liver lipids content was analyzed. Whole-genome shotgun sequencing was performed to profile the gut microbiota. Bile acids were measured in the feces, plasma, and liver. Liver lipid content and gene expression were analyzed. As compared to the HFHS-vehicle treatment group, mice administered RebD showed a reduced weight gain, as evidenced by decreased visceral adipose tissue weight. Liver triglycerides and cholesterol from RebD-treated mice were lower and lipid peroxidation was decreased. Interestingly, administration of RebD was associated with a significant enrichment of Faecalibaculum rodentium in the gut microbiota and an increased secondary bile acid metabolism. Moreover, RebD decreased the level of lipopolysaccharide-binding protein (LBP). Neither RebA nor RebD treatments were found to impact glucose homeostasis. The daily consumption of two stevia components has no detrimental effects on metabolic health. In contrast, RebD treatment was found to reduce adiposity, alleviate hepatic steatosis and lipid peroxidation, and decrease LBP, a marker of metabolic endotoxemia in a mouse model of diet-induced obesity.

Obese-associated gut microbes and derived phenolic metabolite as mediators of excessive motivation for food reward.

BACKGROUND: Excessive hedonic consumption is one of the main drivers for weight gain. Identifying contributors of this dysregulation would help to tackle obesity. The gut microbiome is altered during obesity and regulates host metabolism including food intake. RESULTS: By using fecal material transplantation (FMT) from lean or obese mice into recipient mice, we demonstrated that gut microbes play a role in the regulation of food reward (i.e., wanting and learning processes associated with hedonic food intake) and could be responsible for excessive motivation to obtain sucrose pellets and alterations in dopaminergic and opioid markers in reward-related brain areas. Through untargeted metabolomic approach, we identified the 3-(3'-hydroxyphenyl)propanoic acid (33HPP) as highly positively correlated with the motivation. By administrating 33HPP in mice, we revealed its effects on food reward. CONCLUSIONS: Our data suggest that targeting the gut microbiota and its metabolites would be an interesting therapeutic strategy for compulsive eating, preventing inappropriate hedonic food intake. Video Abstract.

Inulin increases the beneficial effects of rhubarb supplementation on high-fat high-sugar diet-induced metabolic disorders in mice: impact on energy expenditure, brown adipose tissue activity, and microbiota.

Consumption of prebiotics and plant-based compounds have many beneficial health effects through modulation of gut microbiota composition and are considered as promising nutritional strategy for the treatment of metabolic diseases. In the present study, we assessed the separated and combined effects of inulin and rhubarb on diet-induced metabolic disease in mice. We showed that supplementation with both inulin and rhubarb abolished the total body and fat mass gain upon high-fat and high-sucrose diet (HFHS) as well as several obesity-associated metabolic disorders. These effects were associated with increased energy expenditure, lower whitening of the brown adipose tissue, higher mitochondria activity and increased expression of lipolytic markers in white adipose tissue. Despite modifications of intestinal gut microbiota and bile acid compositions by inulin or rhubarb alone, combination of both inulin and rhubarb had minor additional impact on these parameters. However, the combination of inulin and rhubarb increased the expression of several antimicrobial peptides and higher goblet cell numbers, thereby suggesting a reinforcement of the gut barrier. Together, these results suggest that the combination of inulin and rhubarb in mice potentiates beneficial effects of separated rhubarb and inulin on HFHS-related metabolic disease and could be considered as nutritional strategy for the prevention and treatment of obesity and related pathologies.

Fat and not sugar as the determining factor for gut microbiota changes, obesity, and related metabolic disorders in mice.

Diet-induced obesity contributes to the development of type 2 diabetes, insulin resistance, metabolic inflammation, oxidative and endoplasmic reticulum (ER) stress. Overall, obesity is associated with deviations in the composition and functionality of the gut microbiota. There are many divergent findings regarding the link between the excessive intake of certain dietary components (i.e., fat and sugar) and obesity development. We therefore investigated the effect of specific diets, with a different content of sugar and fat, in promoting obesity and related comorbidities as well as their impact on microbial load and gut microbiota composition/diversity. C57BL/6J mice were fed either a low-sugar, low-fat control diet (CT), a high-sugar diet (HS), a high-fat, high-sugar diet (HF/HS), or a high-fat diet (HF) for 8 wk. The impact of the different diets on obesity, glucose metabolism, inflammation, and oxidative and ER stress was determined. Diet-induced changes in the gut microbiota composition and density were also analyzed. HF diet-fed mice showed the highest body weight and fat mass gains and displayed the most impaired glucose and insulin profiles. HS, HF/HS, and HF diets differently affected hepatic cholesterol content and mRNA expression of several markers associated with immune cells, inflammation, oxidative and ER stress in several organs/tissues. In addition, HF diet feeding resulted in a decreased microbial load at the end of the experiment. When analyzing the gut microbiota composition, we found that HS, HF/HS, and HF diets induced specific changes in the abundance of certain bacterial taxa. This was not associated with a specific change in systemic inflammatory markers, but HS mice exhibited higher FGF21 plasma levels compared with HF diet-fed mice. Taken together, our results highlight that dietary intake of different macronutrients distinctively impacts the development of an obese/diabetic state and the regulation of metabolic inflammation in specific organs. We propose that these differences are not only obesity-driven but that changes in the gut microbiota composition may play a key role in this context.NEW & NOTEWORTHY To our knowledge, this study is the first to demonstrate that dietary macronutrients (i.e., sugar and fat) have an impact on fecal bacterial cell counting and quantitative microbiome profiling in mice. Yet, we demonstrate that dietary fat is the determining factor to promote obesity and diabetes progression, and local inflammation in different body sites. These observations can help to disentangle the conundrum of the detrimental effects of fat and sugar in our dietary habits.

Gut microbes and food reward: From the gut to the brain.

Inappropriate food intake behavior is one of the main drivers for fat mass development leading to obesity. Importantly the gut microbiota-mediated signals have emerged as key actors regulating food intake acting mainly on the hypothalamus, and thereby controlling hunger or satiety/satiation feelings. However, food intake is also controlled by the hedonic and reward systems leading to food intake based on pleasure (i.e., non-homeostatic control of food intake). This review focus on both the homeostatic and the non-homeostatic controls of food intake and the implication of the gut microbiota on the control of these systems. The gut-brain axis is involved in the communications between the gut microbes and the brain to modulate host food intake behaviors through systemic and nervous pathways. Therefore, here we describe several mediators of the gut-brain axis including gastrointestinal hormones, neurotransmitters, bioactive lipids as well as bacterial metabolites and compounds. The modulation of gut-brain axis by gut microbes is deeply addressed in the context of host food intake with a specific focus on hedonic feeding. Finally, we also discuss possible gut microbiota-based therapeutic approaches that could lead to potential clinical applications to restore food reward alterations. Therapeutic applications to tackle these dysregulations is of utmost importance since most of the available solutions to treat obesity present low success rate.

Food Reward Alterations during Obesity Are Associated with Inflammation in the Striatum in Mice: Beneficial Effects of Akkermansia muciniphila.

The reward system involved in hedonic food intake presents neuronal and behavioral dysregulations during obesity. Moreover, gut microbiota dysbiosis during obesity promotes low-grade inflammation in peripheral organs and in the brain contributing to metabolic alterations. The mechanisms underlying reward dysregulations during obesity remain unclear. We investigated if inflammation affects the striatum during obesity using a cohort of control-fed or diet-induced obese (DIO) male mice. We tested the potential effects of specific gut bacteria on the reward system during obesity by administrating Akkermansia muciniphila daily or a placebo to DIO male mice. We showed that dysregulations of the food reward are associated with inflammation and alterations in the blood-brain barrier in the striatum of obese mice. We identified Akkermansia muciniphila as a novel actor able to improve the dysregulated reward behaviors associated with obesity, potentially through a decreased activation of inflammatory pathways and lipid-sensing ability in the striatum. These results open a new field of research and suggest that gut microbes can be considered as an innovative therapeutic approach to attenuate reward alterations in obesity. This study provides substance for further investigations of Akkermansia muciniphila-mediated behavioral improvements in other inflammatory neuropsychiatric disorders.

Gut microbes participate in food preference alterations during obesity.

Hypothalamic regulations of food intake are altered during obesity. The dopaminergic mesocorticolimbic system, responsible for the hedonic response to food intake, is also affected. Gut microbes are other key players involved in obesity. Therefore, we investigated whether the gut microbiota plays a causal role in hedonic food intake alterations contributing to obesity. We transferred fecal material from lean or diet-induced obese mice into recipient mice and evaluated the hedonic food intake using a food preference test comparing the intake of control and palatable diets (HFHS, High-Fat High-Sucrose) in donor and recipient mice. Obese mice ate 58% less HFHS during the food preference test (p < 0.0001) than the lean donors, suggesting a dysregulation of the hedonic food intake during obesity. Strikingly, the reduction of the pleasure induced by eating during obesity was transferable through gut microbiota transplantation since obese gut microbiota recipient mice exhibited similar reduction in HFHS intake during the food preference test (40% reduction as compared to lean gut microbiota recipient mice, p < 0.01). This effect was associated with a consistent trend in modifications of dopaminergic markers expression in the striatum. We also pinpointed a highly positive correlation between HFHS intake and Parabacteroides (p < 0.0001), which could represent a potential actor involved in hedonic feeding probably through the gut-to-brain axis. We further demonstrated the key roles played by gut microbes in this paradigm since depletion of gut microbiota using broad-spectrum antibiotics also altered HFHS intake during food preference test in lean mice. In conclusion, we discovered that gut microbes regulate hedonic aspects of food intake. Our data demonstrate that gut microbiota modifications associated with obesity participate in dysregulations of the reward and hedonic components of the food intake. These data provide evidence that gut microbes could be an interesting therapeutic target to tackle hedonic disorders related to obesity.

Intestinal epithelial N-acylphosphatidylethanolamine phospholipase D links dietary fat to metabolic adaptations in obesity and steatosis.

Variations in N-acylethanolamines (NAE) levels are associated with obesity and metabolic comorbidities. Their role in the gut remains unclear. Therefore, we generated a mouse model of inducible intestinal epithelial cell (IEC)-specific deletion of N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD), a key enzyme involved in NAE biosynthesis (Napepld∆IEC). We discovered that Napepld∆IEC mice are hyperphagic upon first high-fat diet (HFD) exposure, and develop exacerbated obesity and steatosis. These mice display hypothalamic Pomc neurons dysfunctions and alterations in intestinal and plasma NAE and 2-acylglycerols. After long-term HFD, Napepld∆IEC mice present reduced energy expenditure. The increased steatosis is associated with higher gut and liver lipid absorption. Napepld∆IEC mice display altered gut microbiota. Akkermansia muciniphila administration partly counteracts the IEC NAPE-PLD deletion effects. In conclusion, intestinal NAPE-PLD is a key sensor in nutritional adaptation to fat intake, gut-to-brain axis and energy homeostasis and thereby constitutes a novel target to tackle obesity and related disorders.