LAUSR

ith the rise of the high-fat and sugar “Western Wdiet,” many countries face a growing epidemic of obesity and its related comorbidities. Outside of extreme dietary changes in society, identifying and targeting genetic pathways that can improve metabolic function in the context of Western diet could help to reduce comorbidities. Metabolic disease is complex, involving the interaction of multiple organ systems and the gut microbiome. As a result, it is often difficult to determine the mechanism by which genetic modulators of metabolic disease function, making treatments difficult to establish. In this issue of Cellular and Molecular Gastroenterology and Hepatology, Zhou et al describe the effects of a specific form of glycosylation, a1-2-fucosylation, on obesity and steatohepatitis in the context of Western diet. a1-2fucosylation occurs at high levels in the intestinal epithelium and requires a functional copy of Galactoside 2-alphaL-fucosyltransferase 2 (Fut2). The authors found that wildtype mice exposed to Western diet exhibited decreased a1-2-fucosylation of proteins and other substrates in the intestinal epithelium. In contrast, Fut2 mutants on a Western diet gained less weight and had elevated energy expenditure, along with improved triglyceride and cholesterol levels, insulin sensitivity, and hepatic steatosis. These findings suggest that downregulation of a1-2-fucosylation, in the context of Western diet, could be a protective mechanism against metabolic dysregulation. Strikingly, the protective effect of Fut2 loss is transmissible to cohoused wild-type mice, implicating the microbiome as a major driver of the observed metabolic effects. This finding is consistent with a known role of a1-2fucosylation in regulating the microbiome. Analysis of circulating metabolites and the microbiome uncovered altered bile acid metabolism as a potential protective mechanism. Prolonged exposure to Western diet increased the synthesis of primary bile acids from cholesterol in the liver, which is mediated by Cholesterol 7 alpha-hydroxylase (CYP7A1). Increased bile acids are postulated to contribute to diet-induced liver damage. In Fut2 mutants, the size of the bile acid pool was significantly reduced, likely caused by a combination of reduced production and increased excretion. Compared with wild-type mice, Western-diet-fed Fut2 mutants displayed reduced expression of Cyp7a1 in the liver and decreased primary bile acid levels in plasma. Additionally, the microbiome of Fut2 mutants contained higher levels of the gene encoding hsdh, which converts primary bile acids to secondary bile acids. The authors speculate that the induction of hsdh accounts for increased bile acid levels in the feces of Fut2 mutants. Importantly, the protective effect in Fut2 mutants was reversed with either antibiotic