The reduced intake of protein is what triggers many of the beneficial changes in cell behavior that result from calorie restriction. One of the many outcomes of calorie restriction is that some white fat tissue transitions to become beige fat via an increase the number of brown fat cells present in the tissue. Brown fat cells are involved in thermogenesis and, on balance, a greater proportion of brown fat in the body leads to incrementally better metabolic health and modestly slowed aging. Interestingly, activity in specific microbial species of the gut microbiome is necessary for the browning of white fat to take place in response to reduced protein intake, suggesting possible paths to the production of novel therapies that induce fat browning.
Interactions between diet and the gut microbiota are fundamental to metabolic health, shaping energy balance and disease susceptibility. However, the underlying mechanisms by which dietary and microbial factors converge to regulate host physiology remain unclear. Here we show that protein availability profoundly modulates the functional landscape of the gut microbiota and promotes remodelling of white adipose tissue (WAT). Specifically, low-protein diets (LPDs) robustly induce signature genes of browning in WAT to a similar extent to that seen in response to classical stimuli, such as cold exposure or β-adrenergic receptor activation.
LPD-mediated browning was markedly diminished in germ-free mice, and this defect was rescued by colonization with defined bacterial consortia made up of strains that were isolated and down-selected from the faeces of either LPD-fed mice or healthy human volunteers with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)-confirmed brown- or beige-fat activity. Microbiota-induced browning was mediated both by bile acids driving the activation of the farnesoid X receptor (FXR) in adipose progenitor cells, and by nrfA-encoding commensal-derived ammonia driving the expression of fibroblast growth factor 21 (FGF21) in hepatocytes. The bile acid-FXR and ammonia-FGF21 axes both have non-redundant, essential roles in promoting WAT browning.
These findings highlight a mechanistic link between diet, gut microbial metabolism and adipose tissue remodelling, uncovering microbiota-dependent pathways by which the host responds to dietary cues.
