Glycosaminoglycans are complex carbohydrates used as nutraceuticals for diverse applications. We studied the potential of the glycosaminoglycan dermatan sulfate (DS) to counteract the development of diet-induced obesity (DIO) using obesity-prone mice fed a high-fat diet (HFD) as a model. Oral DS supplementation protected the animals against HFD-induced increases in whole-body adiposity, visceral fat mass, adipocyte size, blood glucose levels, insulin resistance, and pro-inflammatory lipids levels in brown adipose tissue (BAT) and the liver, where it largely counteracted the HFD-induced changes in the nonpolar metabolome. Protection against DIO in the DS-supplemented mice occurred despite higher energy intake and appeared to be associated with increased energy expenditure, higher uncoupling protein 1 expression in BAT, decreased BAT “whitening,” and an enhanced channeling of fuel substrates toward skeletal muscle. This work is the first preclinical study to examine the anti-obesity activity of DS tested individually in vivo. The results support possible uses of DS as an active component in functional foods/supplements to manage obesity and associated metabolic diseases. © 2023 The Authors. BioFactors published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.

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