Leptin signaling in vagal afferent neurons supports the absorption and storage of nutrients from high-fat diet.

OBJECTIVE: Activation of vagal afferent neurons (VAN) by postprandial gastrointestinal signals terminates feeding and facilitates nutrient digestion and absorption. Leptin modulates responsiveness of VAN to meal-related gastrointestinal signals. Rodents with high-fat diet (HF) feeding develop leptin resistance that impairs responsiveness of VAN. We hypothesized that lack of leptin signaling in VAN reduces responses to meal-related signals, which in turn decreases absorption of nutrients and energy storage from high-fat, calorically dense food. METHODS: Mice with conditional deletion of the leptin receptor from VAN (Nav1.8-Cre/LepRfl/fl; KO) were used in this study. Six-week-old male mice were fed a 45% HF for 4 weeks; metabolic phenotype, food intake, and energy expenditure were measured. Absorption and storage of nutrients were investigated in the refed state. RESULTS: After 4 weeks of HF feeding, KO mice gained less body weight and fat mass that WT controls, but this was not due to differences in food intake or energy expenditure. KO mice had reduced expression of carbohydrate transporters and absorption of carbohydrate in the jejunum. KO mice had fewer hepatic lipid droplets and decreased expression of de novo lipogenesis-associated enzymes and lipoproteins for endogenous lipoprotein pathway in liver, suggesting decreased long-term storage of carbohydrate in KO mice. CONCLUSIONS: Impairment of leptin signaling in VAN reduces responsiveness to gastrointestinal signals, which reduces intestinal absorption of carbohydrates and de novo lipogenesis resulting in reduced long-term energy storage. This study reveals a novel role of vagal afferents to support digestion and energy storage that may contribute to the effectiveness of vagal blockade to induce weight loss.

Human milk oligosaccharide 2'-fucosyllactose supplementation improves gut barrier function and signaling in the vagal afferent pathway in mice.

2'-Fucosyllactose (2'-FL) is one of the predominant oligosaccharides found in human milk and has several well-established beneficial effects in the host. It has previously been shown that 2'-FL can improve the metabolic phenotype in high-fat (HF)-fed mice. Here we investigated whether dietary supplementation with 2'-FL was associated with improved intestinal barrier integrity, signaling in the vagal afferent pathway and cognitive function. Mice were fed either a low-fat (LF, 10% fat per kcal) or HF (45% fat per kcal) diet with or without supplementation of 2'-FL (10% w/w) in the diet for 8 weeks. Body weight, energy intake, fat and lean mass, intestinal permeability (ex vivo in Ussing chambers), lipid profiles, gut microbiome and microbial metabolites, and cognitive functions were measured. Vagal afferent activity was measured via immunohistochemical detection of c-Fos protein in the brainstem in response to peripheral administration of cholecystokinin (CCK). 2'-FL significantly attenuated the HF-induced increase in fat mass and energy intake. 2'-FL significantly reduced intestinal permeability and significantly increased expression of interleukin (IL)-22, a cytokine known for its protective role in the intestine. Additionally, 2'-FL led to changes in the gut microbiota composition and in the associated microbial metabolites. Signaling in the vagal afferent pathway was improved but there was no effect on cognitive function. In conclusion, 2'-FL supplementation improved the metabolic profiles, gut barrier integrity, lipid metabolism and signaling in the vagal afferent pathway. These findings support the utility of 2'-FL in the control of gut barrier function and metabolic homeostasis under a metabolic challenge.

2'-fucosyllactose Supplementation Improves Gut-Brain Signaling and Diet-Induced Obese Phenotype and Changes the Gut Microbiota in High Fat-Fed Mice.

Obesity is characterized by fat accumulation, chronic inflammation and impaired satiety signaling, which may be due in part to gut microbial dysbiosis. Manipulations of the gut microbiota and its metabolites are attractive targets for obesity treatment. The predominant oligosaccharide found in human milk, acts as a prebiotic with beneficial effects on the host. However, little is known about the beneficial effects of 2'-FL in obesity. The aim of this study was to determine the beneficial effects of 2'-FL supplementation on the microbiota-gut-brain axis and the diet-induced obese phenotype in high fat (HF)-fed mice. Male C57/BL6 mice (n = 6/group; six weeks old) were counter-balanced into six weight-matched groups and fed either a low-fat (LF; 10% kcal as fat), HF (45% kcal as fat) or HF diet with 2'-FL (HF_2'-FL) at 1, 2, 5 and 10% (w/v) in drinking water for six weeks. General phenotypes (body weight, energy intake, fat and lean mass), cecal microbiome and metabolites, gut-brain signaling, intestinal permeability and inflammatory and lipid profiles were assessed. Only 10% 2'-FL, but not 1, 2 or 5%, decreased HF diet-induced increases in energy intake, fat mass and body weight gain. A supplementation of 10% 2'-FL changed the composition of cecal microbiota and metabolites compared to LF- and HF-fed mice with an increase in Parabacteroides abundance and lactate and pyruvate, respectively, whose metabolic effects corresponded to our study findings. In particular, 10% 2'-FL significantly reversed the HF diet-induced impairment of cholecystokinin-induced inhibition of food intake. Gene expressions of interleukin (IL)-1ß, IL-6, and macrophage chemoattractant protein-1 in the cecum were significantly downregulated by 10% 2'-FL compared to the HF group. Furthermore, 10% 2'-FL suppressed HF diet-induced upregulation of hepatic peroxisome proliferator-activated receptor gamma, a transcription factor for adipogenesis, at the gene level. In conclusion, 10% 2'-FL led to compositional changes in gut microbiota and metabolites associated with improvements in metabolic profiles and gut-brain signaling in HF-fed mice. These findings support the use of 2'-FL for modulating the hyperphagic response to HF diets and improving the microbiota-gut-brain axis.