Intestinal fructose metabolism drives unsaturated fat absorption and synergizes with GLP-1 receptor agonism to promote weight loss.

High-fat, high-sucrose (HFHS) diets are established risk factors for obesity. In the intestine, sucrose is hydrolyzed into glucose and fructose, with fructose being taken up by epithelial cells and phosphorylated by ketohexokinase (KHK). We hypothesized that KHK is required for the obesogenic effects of HFHS diets and performed genetic and pharmacologic experiments in mice using diet-induced obesity (DIO) models. We show that genetic loss of KHK prevents HFHS-induced weight gain and intestinal villus elongation. Moreover, pharmacologic inhibition of KHK (KHKi) promotes weight and fat loss during continued HFHS feeding in DIO mice and enhances weight loss and weight maintenance during and after incretin-mimetic therapy. The anti-obesogenic effects of KHKi were associated with delayed intestinal lipid absorption, reprogramming of lipid metabolism in the distal intestinal epithelium, and reduced absorption of unsaturated dietary fats. Together, these findings identify fructose metabolism as a key regulator of intestinal lipid handling and suggest that fructose promotes obesity, in part, by enhancing intestinal lipid absorption and metabolism.