Lovisa E Johansson
Obesity results from an interaction between genetic and environmental factors and is a growing health problem associated with development of insulin resistance, type 2 diabetes and cardiovascular disease. This thesis has focused on investigating the genetic contribution in obesity and insulin resistance by both candidate and global gene approaches with focus on the adipose tissue. In the first three studies, the adiponutrin gene and family were investigated. The family consisting of five genes (PNPLA1-5) are nutritionally regulated in the adipose tissue and the gene products show both lipogenic and lipolytic activity. The expression of adiponutrin (PNPLA3) was increased in the adipose tissue of obese subjects with higher expression in visceral adipose tissue compared to subcutaneous. Visceral expression correlated negatively with insulin resistance. In cultured adipocytes, insulin induced the PNPLA3 gene expression in a glucose dependent fashion while free fatty acids had no effect. Genetic variants in the PNPLA3 gene showed association with adult obesity, adipose tissue PNPLA3 mRNA expression, basal lipolysis, insulin secretion and sensitivity. Furthermore, genetic variance in PNPLA1 and PNPLA3, but not PNPLA2, PNPLA4 and PNPLA5, seem to be associated with juvenile obesity. The conclusion was that the PNPLA3 gene might be implicated in the pathogenesis of obesity, possibly via effects on insulin sensitivity. Out of the other members of the adiponutrin gene family only variants in the PNPLA1 gene seems to contribute to pathogenesis of childhood obesity. In the fourth study, the importance of including age, gender and level of physical activity in the analyses of genetic association with obesity was investigated with the Gly482Ser variant in the PPARGC1A gene as an example. Elderly males with low level of physical activity showed association between the 482Ser and obesity while there were no association in the whole population. The conclusion was that it is important to take age, gender and physical activity into account, when possible, when analysing genetic variance in relation to obesity. The last study focused on a global approach, investigating the total gene expression in adipose tissue after weight loss and weight stability trying to find genes that would predict a successful weight reduction. The approximately 100 genes showing concordant regulation after sustained weight loss might be of particular interest and may serve as adipostats, in other words, they might regulate adipose tissue homeostasis.