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.
Yuting Wu, Jinyu Ma, Jing Chen, Xiaoyu Liu, Zhe Wang, Lan Luo, Cheng Sun
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引用次数: 0
Abstract
CD44 is a transmembrane protein that plays an essential role in transducing extracellular stimuli into intracellular signaling cascades, especially in cancer cells. Recent studies have shown that CD44 contributes to metabolic regulation. However, the effect of CD44 on adipogenesis in white adipose tissue (WAT) remains unclear. Here, the results showed that the expression of CD44 was largely increased in the inguinal and epididymal WAT of obese mice. Ablation or neutralization of CD44 inhibits adipogenesis in cultured adipocytes. CD44-deficient mice are resistant to high-fat diet-induced obesity and metabolic dysfunction. RNA-sequencing, together with functional studies, revealed that reduced expression of tryptophan 5-hydroxylase 2 (Tph2) in WAT is responsible for the repressed adipogenesis in the absence of CD44. The application of 5-hydroxytryptamine, a product of TPH2, rescues the repressed adipogenesis induced by CD44 neutralization. Moreover, the inhibition of TPH2 by p-chlorophenylalanine recapitulates the beneficial phenotypes observed in CD44-deficient mice. Taken together, these data indicate that CD44 plays a pivotal role in adipogenesis in WAT. In this regard, CD44 and its downstream target TPH2 may hold great therapeutic potential for treating excessive adiposity-related metabolic disorders, such as obesity, insulin resistance, and type 2 diabetes.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., 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. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.