? DESCRIPTION (provided by applicant): The goal of this randomized, controlled clinical trial is to investigate whether decreasing obesity through a weight loss intervention induces beneficial changes in the cholesterol gene network in monocytes and adipocytes that are associated with whole body glycemic changes. Recent studies suggest that interaction of monocyte-derived macrophages and adipocytes in adipose tissue plays a crucial role in adipose tissue inflammation, which may link obesity to insulin resistance. Disruption of intracellular cholesterol homeostasis in cells, such as monocytes/macrophages and adipocytes, is one of the cell-intrinsic factors shown to be responsible for insulin resistance in animal experimental studies. Our recent transcriptomic study of purified human monocytes extends these findings to humans, and specifically identifies a network of co-expressed cholesterol metabolism genes whose altered expression is associated with type 2 diabetes mellitus (T2DM) (p- trend: 5.07x10-10), as well as two important risk factors for T2DM - obesity (p: 1.6 x10-18) and inflammation (p: 2.0x10-7 for interleukin-6). Furthermore, weight loss appeared to reverse these alterations of the cholesterol metabolism genes in monocytes in our pilot study of 16 obese persons without a control group. We hypothesize that obesity and inflammation alters the cholesterol metabolism gene network in monocytes to increase intracellular cholesterol accumulation, and these changes along with related changes in adipocytes increase insulin resistance and disrupt glucose regulation, which subsequently lead to T2DM. To illustrate the role of this cholesterol gene network in weight loss-induced glycemic improvements, we will randomly assign 200 obese and prediabetic adults aged 40-60 years to diet-induced weight loss intervention (Diet, N=100) or healthy lifestyle education intervention (Control, N=100). We will achieve our goal through the following specific aims: 1) To test whether weight loss intervention rebalances methylomic/transcriptomic profiles in monocytes and adipocytes from obese persons; and 2) To determine whether weight loss-induced methylation and transcriptional changes in human monocytes and adipocytes correlate with whole body glycemic improvements. We will also explore whether the observed molecular changes in human monocytes alter glucose metabolism in human adipocytes, skeletal myocytes, and hepatocytes using in vitro models. The integration of epigenetic, transcriptional, and clinical data from the clinical trial and in viro experimental studies, carried out by a team of scientists with expertise in genetic epidemiology, molecular biology, and bioinformatics, will provide novel insights concerning the regulation of cellular cholesterol metabolism, and susceptibility to T2DM, potentially leading to new treatment and prevention targets.

R01DK103531

2016-04-09

2021-03-31