Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling.
Yadav Hariom,Quijano Celia,Kamaraju Anil K,Gavrilova Oksana,Malek Rana,Chen Weiping,Zerfas Patricia,Zhigang Duan,Wright Elizabeth C,Stuelten Christina,Sun Peter,Lonning Scott,Skarulis Monica,Sumner Anne E,Finkel Toren,Rane Sushil G
Cell metabolism
Imbalances in glucose and energy homeostasis are at the core of the worldwide epidemic of obesity and diabetes. Here, we illustrate an important role of the TGF-β/Smad3 signaling pathway in regulating glucose and energy homeostasis. Smad3-deficient mice are protected from diet-induced obesity and diabetes. Interestingly, the metabolic protection is accompanied by Smad3(-)(/-) white adipose tissue acquiring the bioenergetic and gene expression profile of brown fat/skeletal muscle. Smad3(-/-) adipocytes demonstrate a marked increase in mitochondrial biogenesis, with a corresponding increase in basal respiration, and Smad3 acts as a repressor of PGC-1α expression. We observe significant correlation between TGF-β1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-β signaling protects mice from obesity, diabetes, and hepatic steatosis. Together, these results demonstrate that TGF-β signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-β activity might be an effective treatment strategy for obesity and diabetes.
10.1016/j.cmet.2011.04.013
High expression of CD52 in adipocytes: a potential therapeutic target for obesity with type 2 diabetes.
Mao Rui,Yang Fan,Zhang Yu,Liu Hongtao,Guo Pengsen,Liu Yanjun,Zhang Tongtong
Aging
The aim of the present study was to evaluate the involvement of CD52 in adipocytes as well as to explore its effect on type 2 diabetes mellitus (T2DM), and to improve our understanding of the potential molecular events of obesity with type 2 diabetes. Global changes in the CD52 expression patterns were detected in adipocytes and preadipocytes derived from obese and lean individuals. In particular, CD52 was identified as significantly differentially upregulated and was analyzed, both and , using various approaches. experiments, CD52 was a significantly up-regulated mRNA in mature adipocytes and preadipocytes. In addition, CD52 gradually increased with the differentiation of preadipocytes. experiments, the expression of CD52 in high-fat diet (HFD) -fed mice tended to be higher than that in regular diet (RD) -fed mice. Further analysis showed that CD52 expression was positively correlated with Smad3 and TGF-β in mice, and the downregulation of CD52 was accompanied by increased glucose tolerance and insulin sensitivity. Moreover, a comparison of CD4+CD52 T cells and CD4+CD52 T cells showed that many T2DM-related genes were aberrantly expressed. Overall, CD52 may functioned as an important potential target for obesity with T2DM via TGF-β/Smad3 axis.
10.18632/aging.202714
Unbiased gene expression analysis of the delayed fracture healing observed in Zucker diabetic fatty rats.
Bone & joint research
Aims:Impaired fracture repair in patients with type 2 diabetes mellitus (T2DM) is not fully understood. In this study, we aimed to characterize the local changes in gene expression (GE) associated with diabetic fracture. We used an unbiased approach to compare GE in the fracture callus of Zucker diabetic fatty (ZDF) rats relative to wild-type (WT) littermates at three weeks following femoral osteotomy. Methods:Zucker rats, WT and homozygous for leptin receptor mutation (ZDF), were fed a moderately high-fat diet to induce T2DM only in the ZDF animals. At ten weeks of age, open femoral fractures were simulated using a unilateral osteotomy stabilized with an external fixator. At three weeks post-surgery, the fractured femur from each animal was retrieved for analysis. Callus formation and the extent of healing were assessed by radiograph and histology. Bone tissue was processed for total RNA extraction and messenger RNA (mRNA) sequencing (mRNA-Seq). Results:Radiographs and histology demonstrated impaired fracture healing in ZDF rats with incomplete bony bridge formation and an influx of intramedullary inflammatory tissue. In comparison, near-complete bridging between cortices was observed in Sham WT animals. Of 13,160 genes, mRNA-Seq analysis identified 13 that were differentially expressed in ZDF rat callus, using a false discovery rate (FDR) threshold of 10%. Seven genes were upregulated with high confidence (FDR = 0.05) in ZDF fracture callus, most with known roles in inflammation. Conclusion:These findings suggest that elevated or prolonged inflammation contributes to delayed fracture healing in T2DM. The identified genes may be used as biomarkers to monitor and treat delayed fracture healing in diabetic patients.
10.1302/2046-3758.1210.BJR-2023-0062.R1