Missing protein keeps mice slim, even on a high-fat diet

Lead investigator Cheng Sun, PhD, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, China, says, "We previously reported that CD44 deficiency suppresses neuroinflammation. Given the critical role inflammation plays in the progression of obesity and its related complications, including hyperglycemia and insulin resistance, we hypothesized that CD44 might have a significant role in these processes. Therefore, we investigated the potential link between CD44 and metabolic disorders."

Co-investigator Lan Luo, MD, Department of Geriatrics, Affiliated Hospital of Nantong University, China, adds, "We were surprised to observe that mice genetically engineered to lack the CD44 protein maintained a lean phenotype despite having been put on a high-fat diet, while the control mice developed obesity. This unexpected finding highlights CD44's pivotal role in regulating fat cell formation and metabolic health."

Recent studies have shown that CD44, a transmembrane protein that plays an essential role in transducing extracellular stimuli into intracellular signaling cascades, contributes to metabolic regulation. In the current study, the effect protecting against obesity was attributed to suppressed adipogenesis (fat cell formation) in white adipose tissue, the most common type of body fat.

Unlike GLP-1 receptor agonists, which primarily regulate appetite and glucose metabolism, CD44 inhibition addresses obesity through a distinct mechanism by directly impairing adipogenesis.

Dr. Sun concludes: "Mechanistically, we found that CD44 deficiency downregulates tryptophan hydroxylase 2 expression in white adipose tissue, leading to reduced serotonin (5-HT) levels, which subsequently impair adipogenesis. These findings reveal a novel mechanism linking CD44 to metabolic regulation, thereby offering a novel therapeutic target for obesity and its related metabolic disorders. This unique mode of action suggests that CD44 inhibitors could serve as a complementary or synergistic treatment alongside GLP-1s, potentially enhancing the overall efficacy of obesity management strategies."