Proanthocyanidin-Rich Cranberry Extract Lowers Glycemia in Established Obesity by Delaying Glucose Absorption

Dietary polyphenols, including proanthocyanidins, have emerged as potential modulators of metabolic health. Evidence supports benefits on glucose and hepatic metabolism in diet-induced obesity. However, reported effects vary widely across polyphenol sources and experimental design, and the key physiological mediators of benefit in established obesity remain incompletely defined. Moreover, ambient temperature, a key determinant of metabolic phenotype that may influence therapeutic responses, is rarely considered. Here we aim to determine the metabolic effects and mechanisms of action of a proanthocyanidin-rich cranberry extract (PRCE) in established diet-induced obesity under cold (10°C) and thermoneutral (30°C) housing conditions. Male mice with established obesity were supplemented with PRCE or vehicle while housed at 10°C or 30°C. Metabolic phenotyping included body composition, glucose homeostasis, intestinal carbohydrate digestion and glucose absorption, circadian profiling of peripheral and central clocks, and gut microbiota analysis. PRCE supplementation significantly improved glycemia and glucose tolerance independently of temperature, without altering body weight, adiposity, thermogenic gene expression, or circadian expression of clock genes centrally and peripherally. Mechanistically, PRCE inhibited α-amylase activity and delayed early intestinal glucose absorption. These effects were accompanied by selective remodeling of the gut microbiota, including increased abundance of Akkermansia muciniphila. We conclude that PRCE improves glucose homeostasis in established obesity through intestinal mechanisms involving reduced carbohydrate digestion, delayed glucose absorption, and selective remodeling of the gut microbiota.