Overfeeding and overweight rapidly reprogram inflammatory signaling

Epidemiologic studies have shown a continuous increase in mortality risk associated with overweight, thus highlighting the health risks beginning before the onset of obesity. However, early changes in inflammatory signaling induced by an obesogenic diet remain largely unknown since studies of obesity typically utilize models induced by months of continuous exposure to a high-fat diet. Here, we investigated how short-term overfeeding remodels inflammatory signaling. We developed and characterized a mouse model of overweight induced by seven days of the Western diet enriched in saturated fats and sucrose, compared to the standard, low-fat laboratory diet or a long-term Western diet for 22 weeks. The short-term Western diet caused a median weight gain of 6 %, while the long-term Western diet increased weight by 92 %. Circulating levels of cholesterol, triglycerides, insulin, and leptin were increased by both diets, but only the long-term Western diet caused transaminitis and significant hepatic steatosis. Both models reduced the alpha and beta diversity of the microbiome. Tryptophan metabolism was perturbed by both models; the long-term Western diet also affected histidine and vitamin B6 metabolism. The short-term and long-term Western diets increased expression of TLR4 on peritoneal immune cells and TLR4-driven plasma levels of proinflammatory cytokines comparably, showing one week of the Western diet was sufficient for inducing inflammation typical of chronic obesity. These findings highlight the importance of diet not only in preclinical studies, but also in the clinical care of individuals with inflammatory disorders.