| Author: | Mansoori, Shama |
| Title: | Deletion of branched-chain amino ACID catabolic gene ppm1k induces adipose tissue dysfunction in mouse model |
| Advisors: | Cheng, K. Y. Kenneth (HTI) Wong, C. M. (HTI) |
| Degree: | Ph.D. |
| Year: | 2024 |
| Subject: | Branched chain amino acids -- Metabolism Adipose tissues Type 2 diabetes Obesity Phosphoprotein phosphatases Hong Kong Polytechnic University -- Dissertations |
| Department: | Department of Health Technology and Informatics |
| Pages: | 179 pages : color illustrations |
| Language: | English |
| Abstract: | Obesity and type 2 diabetes (T2D) are featured by dysfunctional adipose tissue and increased circulatory branched-chain amino acids (BCAAs). White and brown adipose tissues (WAT and BAT) play a crucial role in maintaining systemic BCAAs homeostasis. On the other hand, adipocytes utilise BCAAs for various metabolic functions such as lipogenesis and energy expenditure. Interestingly, an altered expression of BCAAs catabolic genes was reported in adipose tissue of db/db mice. However, the involvement of impaired BCAAs pathway in the development of adipose tissue dysfunction within the context of metabolic disorders remains elusive. Thus, we hypothesize that aberrant BCAAs metabolism contributes to adipose tissue dysfunctions, thereby inducing or exacerbating obesity/T2D. The current study is focused on delineating the role of Protein phosphatase 1K (PPM1K), a key regulatory enzyme that controls BCAAs catabolism, in the regulation of adipose tissue function. To investigate the hypothesis, two mouse models of global PPM1K knockout (KO) and adipocyte-specific PPM1K knockout (A-KO) were employed. As anticipated, the defective BCAAs catabolism is observed in global KO mice evidenced by higher circulatory/tissue levels of BCAAs and its downstream metabolites. PPM1K deletion had a modest impact on energy balance, glucose tolerance, and insulin sensitivity, while significantly increasing adipose tissue fibrosis and inflammation. Supporting this observation, a negative correlation between PPM1K and pro-fibrotic genes was found in datasets from Gene expression omnibus (GEO) database in obese human subjects. Subsequent analysis of WAT fractions revealed an upregulated fibrotic response in the stromal vascular fraction (SVF), while no changes were observed in the adipocyte fraction of PPM1K KO mice compared to wild-type controls. Fibrosis in WAT was accompanied by the induction of Hif-1α coinciding with pro-fibrotic and inflammatory gene markers. This observation suggests that activation of HIF-1α pathway may contribute to the induction of fibrosis, although it warrants further investigation. In the A-KO model, metabolic characterisation revealed significant impairments in glucose, lipid, and energy metabolism. Interestingly, deficiency of adipocyte PPM1K increased the circulatory BCKA levels. These defects were accompanied by fibrosis in different fat depots including WAT and BAT and increased M1 macrophage infiltration in WAT. Additionally, heightened cellular senescence was observed in adipose tissue of A-KO mice, highlighting the role of PPM1K in aging alongside its conventional involvement in BCAAs catabolism. Deletion of adipocyte PPM1K also led to impaired TCA cycle and mitochondrial respiration in eWAT, indicating cellular respiration defects. RNA sequencing data implicated the Rho GTPase pathway as a potential contributor to adipose tissue dysfunction, requiring further investigation for a detailed understanding of the mechanism. Furthermore, adipocyte PPM1K deletion altered the liver function leading to increased fibrosis, inflammation, and steatosis in addition to inducing adipose tissue dysfunction. Overall, this study investigated the unprecedented role of PPM1K in regulation of adipose tissue functions. |
| Rights: | All rights reserved |
| Access: | open access |
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