Assistant Professor The Brown Foundation Institute of Molecular Medicine, Center for Metabolic & Degenerative Diseases
Education & Training
- Postdoctoral Fellow
- The University of Texas Southwestern Medical Center at Dallas, 2011
- University of California, Riverside, 2005
- West China University of Medical Sciences, 1995
Areas of Interests
- Research Interest
- Targeting Adipose Tissue Remodeling for Treatment of Obesity and Type 2 Diabetes
Targeting Adipose Tissue Remodeling for Treatment of Obesity and Type 2 Diabetes
Research in my laboratory examines the essential contributions of adipocyte-derived factors to the dynamics of adipose tissue remodeling during obesity development and pinpoints them as critical factors with clinical significance in human obesity and insulin resistance.
In the past five years, I have published many paradigm-shifting findings about the tight connections between adipose tissue remodeling and obesity development. Specifically, we discovered that obese fat pads are frequently hypoxic and HIF1α induction is the initial step which ultimately leads to local fibrosis and inflammation in adipose tissue. More importantly, we further demonstrated that the effects of modulation of angiogenic activity in white adipose tissue by VEGF-A could be dichotomous and metabolic context dependent: at the early stage of obesity development, angiogenesis is metabolically beneficial by improving vascularization and inducing a “browning” phenotype in white adipocytes; In contrast, in pathologically expanded adipose tissue, antiangiogenic action leads to improvements in metabolism by ablating dysfunctional adipocytes. Our findings suggest that targeting HIF1α and VEGF-A in adipose tissue may offer the great opportunity for a novel therapeutic approach to prevent and treat the progression of obesity-related metabolic disorders.
We further explored the fine-tuned regulation of adipose tissue remodeling at other levels in obese and diabetic animal models. Indeed, we found fibrosis is the hallmark in the metabolically dysfunctional adipose tissue and MT1-MMP (MMP14) play a critical role in regulation of the levels of extracellular matrix (ECM). Of note, our recent research suggests that the regulation of ECM flexibility by MT1-MMP is also metabolic context dependent: On the one hand, at early stages of obesity, MT1-MMP cleaves collagenous proteins and stimulates angiogenesis in combination with VEGF-A and leptin, thus relieving the pathological conditions caused by hypoxia; On the other hand, in the context of pre-existing unhealthy adipose tissue, it digests collagen 6α3 and produces endotrophin which accelerates fibrosis and inflammation, ultimately leading a highly unfavorable microenvironment to sustain metabolic flexibility.
More recently, we use molecular tools and mouse models to study endotrophin. By using a doxycycline-inducible endotrophin overexpression model we demonstrate that endotrophin serves as a powerful co-stimulator of pathologically relevant pathways within the unhealthy adipose tissue milieu, triggering fibrosis and inflammation and ultimately leading to enhanced insulin resistance. We further demonstrate that blocking endotrophin with a neutralizing antibody ameliorates the adverse effects in adipose tissue and effectively reverses metabolic dysfunction induced by high-fat diet. All these exciting observations in our lab highlight endotrophin as an attractive target for obesity and type 2 diabetes.
- Zhao YS, Gu X, Zhang NY, Kolonin MK, An ZQ, Sun K. (2016). Divergent Functions of Endotrophin on Different Cell Populations in Adipose Tissue. AJP-Endo &Metab. 311(6):E952-E963.
- Sun K, Park J, Gupta O, Holland WL, Auerbach PL, Zhang N, Marangoni RG, Nicoloro SM, Czech MP, Varga J, Ploug T, An ZQ and Scherer PE.(2014). Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction. Nature Commun. 5:3485.
- Sun K, Tordjman J, Clément K, and Scherer PE . (2013). Fibrosis and adipose tissue dysfunction. Cell Metab. 18(4):470-7.
- He C, Wei Y*, Sun K*, Li B*, Zou Z, Liu Y, Kinch LN, Khan S, Xavier RJ, Grishin NV, Xiao G, Eskelinen EL, Scherer PE, Whistler JL, and Levine B. (2013). Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism. (* contributed equally). Cell. 154(5):1085-99.
- Sun K, Wernstedt Asterholm I, Kusminski CM, Bueno AC, Wang ZV, Pollard JW, Brekken RA, Scherer PE. (2012). Dichotomous effects of VEGF-A on adipose tissue dysfunction. Proc Natl Acad Sci U S A. 109(15):5874-9.
- He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, An Z, Loh J, Fisher J, Sun Q, Korsmeyer S, Packer M, May HI, Hill JA, Virgin HW, Gilpin C, Xiao G, Bassel-Duby R, Scherer PE, and Levine B. (2012). Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis.Nature. 481(7382):511-5.
- Sun K, Kusminski CM, Scherer PE. (2011). Adipose tissue remodeling and obesity. J Clin Invest. 121 (6): 2094-101.