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.

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.

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.

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 in 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 weeks. The impact of the different diets on obesity, glucose metabolism, inflammation, and oxidative and ER stress were 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. Additionally, 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. 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.