Excess white adipose tissue (WAT) is a major factor underlying the development of insulin resistance and type 2 diabetes. Several different mechanisms could contribute including altered transcription factor expression/activity, long non-coding RNAs (lncRNAs), alternative splicing/promoter usage and/or changes in enhancer activity. CAGE enables us for the first time to identify and further study all these regulatory mechanisms on a global level.
We have collected WAT biopsies from a large number of non-obese (n=34) and obese subjects (n=60) with varying degree of insulin resistance before and after a 2-hour insulin infusion in vivo. The obese individuals have been reinvestigated two years after marked weight reduction. WAT CAGE libraries are prepared and final data will be available when the postdoc arrives. This is by far the largest prospective study of gene regulation in human WAT and will form the basis to identify novel regulatory candidates involved in insulin resistance.
Specific alterations in the transcriptional machinery explain the development of insulin resistance in human WAT. While some of these changes are secondary to obesity development, others are primary defects and remain after weight loss.
Our overall aim is to identify the primary and secondary mechanisms explaining abnormal in vivo insulin-induced gene regulation in human WAT.
The Uppstore resource will be used by the one Karolinska Institute PhD student and one postdoc.
This storage project is a continuation of the projects b2013047 and b2013050.