Dietary effects on gene regulation and function in human adipose tissue in obesity

Abstract

Obesity is an excess of body fat that develops from both genetic and environmental factors, leading to a disturbed balance between energy intake and energy expenditure. It is closely associated with insulin resistance, type 2 diabetes, hyperlipidemia and atherosclerosis. Its increasing prevalence has reached epidemic proportions worldwide. Adipose tissue produces and secretes a number of important factors that are involved in the regulation of adipose tissue metabolism. These factors could also be of importance in the development of insulin resistance.

Previous research has shown that a number of genes seem to be involved in both the development of obesity and different functions of adipose tissue. It is not clear if, and how, weight loss or the energy content and the macronutrient composition of the diet affect the expression of these genes. More knowledge about intracellular pathways and mechanisms underlying the metabolic regulation in adipose tissue is essential for a better understanding of the pathogenic importance of this tissue.

The aims of this thesis were to define dietary effects on the secretory function of, and gene expression in, human adipose tissue, to identify and characterize novel nutrient-sensitive candidate genes in obesity and to study the functional role of one of these novel genes in vitro.

In Papers I and II, we investigated the influence of weight loss and macronutrients on protein secretion and gene regulation in white adipose tissue (WAT). Forty women were randomized to two different ten-week hypoenergetic diets. In Paper I, the changes in secretion were compared with the changes in circulating levels and adipose tissue mRNA expression. The effect of energy restriction on different secreted proteins varies. There were no differences between the diet groups and we therefore conclude that the energy supply per se and not the macronutrient composition is of importance for the regulation of the protein secretory function and gene expression in human adipose tissue, at least during energy restriction. Furthermore, there was no difference in weight loss between the diet groups.

In Paper II, we used microarrays to study the changes in gene expression induced by the two hypoenergetic diets. Key results were confirmed using real-time quantitative PCR. There were no differences between the diet groups, although in both groups, marked effects were obtained on genes regulating the production of polyunsaturated fatty acids and genes regulating obesity in experimental models. Cell death-inducing DFFA-like effector A (CIDE-A) was the most up-regulated gene after weight loss.

In Paper III, we investigated the function(s) of CIDE-A in human adipose tissue. We found that CIDE-A is expressed in human, as opposed to mouse, WAT. The gene appears to be protective against obesity and several features of the metabolic syndrome and an important regulator of basal lipolysis in human WAT, most likely through interactions with tumour necrosis factor ���� (TNF-����) signalling and/or perilipin.

In Paper IV, we tried to elucidate the possible mechanism(s) by which CIDE-A regulates basal lipolysis in white adipocytes. We studied effects of over-expression of CIDE-A and interaction between CIDE-A and different nuclear receptors. We found that CIDE-A interacts with the liver X receptors (LXRs) in human adipocytes. We also found that activation of the LXRs stimulates lipolysis, possibly via down-regulation of perilipin. We suggest that CIDE-A mediates its antilipolytic effect via modulation of LXR-regulated gene expression.