Missing Protein Keeps Mice Slim, Even 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 studyopens in new tab/window in The American Journal of Pathologyopens in new tab/window, 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."

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.”

Notes for editors

The article is “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,” by Yuting Wu, Jinyu Ma, Jing Chen, Xiaoyu Liu, Zhe Wang, Lan Luo, and Cheng Sun (https://doi.org/10.1016/j.ajpath.2024.10.005opens in new tab/window). It appears in The American Journal of Pathology, volume 195, issue 2 (February 2025), published by Elsevier.

The article is openly available at https://ajp.amjpathol.org/article/S0002-9440(24)00397-3/fulltextopens in new tab/window.

Full text of the article is also available to credentialed journalists upon request. Contact Eileen Leahy at +1 732 406 1313 or [email protected]opens in new tab/window to request a PDF of the article or more information. To reach the study’s authors contact Cheng Sun at [email protected].

The study was supported by the National Natural Science Foundation of China number 32271193, the Jiangsu Provincial Research Hospital number YJXYY202204-XKA03, the scientific research project from Jiangsu Health Commission number Ym2023113, the medical project from Jiangsu Commission of Health number M2020033, and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

About The American Journal of Pathology

The American Journal of Pathologyopens in new tab/window, official journal of the American Society for Investigative Pathologyopens in new tab/window, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. https://ajp.amjpathol.orgopens in new tab/window

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