Adipose tissue (fat) is a highly heterogeneous and dynamic organ that plays integral roles in metabolic and cardiovascular health. Too much fat (obesity), too little fat or fat in wrong anatomic location (lipodystrophy) all lead to the development of a cluster of cardio-metabolic diseases including diabetes, fatty liver, atherosclerosis and cancer cachexia. White adipose tissue (WAT) not only stores excessive energy but also secretes dozens of bioactive hormones (known as adipokines) for the regulation of cardio-metabolic homeostasis.
Fat depots in different anatomic locations exhibit differences in intrinsic cellular composition and physiological properties such as metabolism, adipokine production, progenitor capacity and insulin sensitivity. We have demonstrated that visceral WAT (vWAT) is deleterious to metabolic health and positively associated with cardiometabolic risks, whereas subcutaneous WAT (sWAT) is metabolically protective in both rodents and humans. In particular, our long-term prospective study “Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS)” clearly demonstrates that visceral obesity, characterized by accumulation of adipose tissue in visceral cavity, is an independent predictor for diabetes in Hong Kong Chinese. This coincides with the fact that a significant portion of obese individuals are metabolically healthy (MHO). Compared to those with central obesity, who have a higher risk of diabetes and/or cardiovascular diseases, MHO subjects are relatively having lower amount of vWAT and higher sWAT expansion capacity. The reason why these two fat depots exert opposite effects on cardiometabolic diseases remains unclear. vWAT is more susceptible to inflammation and secretes more inflammatory cytokines, while sWAT elicits metabolic protection by adipogenesis, increased glucose and lipid uptake, preserved insulin response, and inflammation resolution.
The major goal of the project is to elucidate the molecular basis underlying the differential functions and traits between vWAT and sWAT. An interdisciplinary study involving bioinformatics, molecular biology and assay development will be carried out, with a combinatorial usage of our unique biobanks and animal models. By RNA-sequencing analysis, we have identified 684 genes in vWAT and 753 genes in sWAT altered in dietary obesity. Among them, 385 genes and 454 genes are altered specifically in vWAT and sWAT, respectively. Further bioinformatics analysis for these differentially expressed genes will be performed to identify the possible molecular pathways attributing to the more detrimental effects of vWAT and the protective actions in sWAT. After that, the pathophysiological functions of the candidate genes will be examined by using adipose-selective knockout or transgenic animal models, followed by metabolic phenotyping to define their roles in determing adipose tissue remodeling and whole body metabolism. Furthermore, the clinical significance of these candidate genes will be interrogated using sWAT and vWAT biopsy samples from MHO and MUO subjects. Implementation of the project will identify key molecular switch controlling physiological signature, remodeling and functions of different fat depots, as well as the novel secretory protein which is differentially expressed in adipose of MHO and MUO subjects. They will be new targets for diagnosis and treatment of diabetes and metabolic diseases.
Professor Aimin Xu has been focusing on both basic and translational research on obesity/diabetes-related disorders. He is leading the State Key Laboratory of Pharmaceutical Biotechnology, which is at the forefront of innovation and discovery in the field of molecular metabolism, with a focus on hormones and biomarkers (www.sklpb.hku.hk). Professor Xu has made significant contributions to discovery and functional characterization of several adipokines and hormones including adiponectin, fibroblast growth factor 21 (FGF21), adipocyte-fatty acid binding protein (A-FABP) and lipocalin-2. For recent publications from his group, please visit https://scholar.google.com/citations?user=vyPfQmIAAAAJ&hl=en