CD44 Protein Deficiency Keeps Mice Lean, Despite a High-Fat Diet
Mice deficient in the protein CD44 were protected against diet-induced obesity in a new study.
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Surprising findings from a study in The American Journal of Pathology show that mice with a CD44 protein deficiency stay lean, despite being on a high-fat diet
Researchers investigating the role of the protein CD44 in obesity and metabolic health found that CD44-deficient mice stayed lean even on a high-fat diet, while the control mice developed obesity. A new study in The American Journal of Pathology, published by Elsevier, details the unexpected pivotal role of CD44, highlighting how it regulates fat cell formation and metabolic health.
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."
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Subscribe for FREERecent 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.”
Reference: Wu Y, Ma J, Chen J, et al. Ablation of CD44 attenuates adipogenesis in white adipocytes via the tryptophan 5-hydroxylase 2/5-hydroxytryptamine axis to protect mice from high-fat diet–induced obesity. Am J Pathol. 2025;195(2):247-264. doi: 10.1016/j.ajpath.2024.10.005
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