Inflammation in hypertrophic adipose tissue is a critical inducer of adipose tissue dysfunction, which ultimately leads to systemic insulin resistance and type 2 diabetes. Elevation of lipopolysaccharide (LPS) induced by high fat diet has been recently proposed to be one of the potential mechanisms contributing to the development of inflammation and metabolic dysfunction of adipose tissue in obesity. Therefore, it is of interest to expand our understanding of LPS effect on adipocyte metabolism and to identify the molecular mechanism by which LPS deteriorates adipose tissue metabolism. In the first study, we investigated the effect of LPS on the adipogenic capacity and cellular senescence of adipocyte progenitors by using stromal-vascular (SV) cells isolated from inguinal adipose tissue of C57BL/6 mice. We found that LPS treatment for 24-hour prior to the induction of differentiation led to the inhibition of adipogenesis. In addition, LPS induced features of premature senescence of SV cells. Further studies showed that LPS treatment caused a reduction in Zfp423 and PPARγ expression in SV cells, suggesting that LPS impairs pre-adipocyte differentiation. In the second study, we explored the role of endosomal/lysosomal protein NPC2 (Niemann-Pick disease, Type C2) in regulating lysosomal activity and in mediating LPS effect on adipocyte inflammation and function. NPC2 knockdown reduced lysosomal protease cathepsin B levels and impaired autophagy-lysosomal activity in 3T3-L1 adipocytes. Interestingly, NPC2 knockdown diminished LPS effect on inflammatory response and blunted LPS-induced glucose uptake in adipocytes. In the third study, we determined the effect of eicosapentaenoic acid (EPA) on promoting metabolic health of adipocytes, specifically the browning of subcutaneous white adipocytes. When added to SV cell cultures during 8-day adipocyte differentiation, EPA significantly increased the expression of thermogenic genes as well as mitochondrial DNA content. These results indicate that EPA enhances energy expenditure capacity by recruiting beige adipocytes. In summary, we have demonstrated a new mechanism by which LPS disrupts adipogenesis and adipocyte metabolism. We have also characterized the role of NPC2 as an important molecular mediator of LPS-induced adipocyte inflammation and the effect of EPA on promoting the browning of subcutaneous adipocytes.
University of Minnesota Ph.D. dissertation. August 2015. Major: Nutrition. Advisor: Xiaoli Chen. 1 computer file (PDF); vii, 141 pages.
Understanding The Regulation Of Adipogenesis And Adipocyte Metabolism In Obesity.
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