MOLECULAR DETERMINANTS OF HUMAN ADIPOSE FUNCTION AND THEIR ROLE IN THE PATHOGENESIS OF OBESITY AND DIABETES

Abstract

ADIPOSE TISSUE (AT) FUNCTIONS AS AN ACTIVE ENDOCRINE ORGAN AND IT?S NOW WELL ACCEPTED THAT AT EXPANDABILITY, REMODELLING AND EFFECTIVE STORAGE OF EXCESS LIPIDS IN THE FORM OF TRIGLYCERIDES (TAGS) PLAY AN IMPORTANT ROLE IN MAINTAINING METABOLIC HOMEOSTASIS. TO UNDERSTAND AT EXPANSION AND FUNCTION, WE USED HUMAN DERIVED IN-VITRO ADIPOCYTE MODELS AND NEXT-GENERATION SEQUENCING METHODS. WE FIRST FUNCTIONALLY CHARACTERIZED TWO GWAS CANDIDATE GENES INVOLVED IN LIPID METABOLISM AND EXPRESSED IN ADIPOSE; FIT2 (FAT STORAGE INDUCING TRANSMEMBRANE PROTEIN 2) AND FTO (FAT MASS AND OBESITY ASSOCIATED). OUR OBSERVATIONS SUGGEST THAT IMPROVED TAG STORAGE VIA FIT2 PROTEIN AS WELL AS IMPROVED MITOCHONDRIAL OXIDATIVE CAPACITY VIA FTO PROTEIN CAN PROMOTE INSULIN SENSITIVITY IN HUMAN ADIPOCYTES. NEXT, WE OBSERVED POSITIVE ENRICHMENT IN THE EXTRACELLULAR-MATRIX AND FIBROSIS COMPONENTS IN OMENTAL AT FROM T2DM WHEN COMPARED TO NT2DM SUBJECTS. OVERALL, OUR WORK CONTRIBUTES INSIGHTS INTO THE MOLECULAR AND TRAN