Obesity, overweight and its consequences are major and growing challenges for health care worldwide. Recently, the first common variants have been identified which influence overall levels of adiposity (measured by body mass index, BMI) and predispose to obesity at the population level. These findings should lead to improved understanding of the mechanisms involved in the regulation of overall obesity and energy balance. However, not all obese individuals are equally vulnerable to diabetes, insulin resistance and the other adverse consequences of obesity, and it has long been appreciated that the distribution of fat (particularly the degree of central or visceral obesity) is an additional and independent determinant of individual risk of metabolic and cardiovascular disease.
The research in the Lindgren group seeks to advance understanding of the mechanisms involved in obesity and the regulation of differential fat accumulation in the belief that an appreciation of these mechanisms will complement advances in understanding of obesity. By applying a range of genetic and genomic approaches, we expect to identify genetic variants influencing various aspects of obesity (overall obesity as well as fat distribution), and to illuminate some of the biological pathways involved. Our specific objectives are:
1. To undertake identification of genetic variants influencing obesity and individual patterns of fat distribution and central obesity through large-scale genome-wide association meta-analysis and fine mapping;
2. To examine the relationships between sequence variation, expression of mRNA, microRNAs, methylation pattern and molecular and physiological phenotypes, in human adipose samples, to identify adipose-specific pathways relevant to individual differences in obesity and central fat distribution;
3. To follow-up of the key findings from genetic, epidemiological and functional perspectives.
These advancements should support translational advances in the management of obesity through development of novel diagnostic and therapeutic options.
Herrara, B.M., et al. 2009. MicroRNA-125a is over-expressed in insulin target tissues in a spontaneous rat model of Type 2 Diabetes. BMC Med Genomics, 2, 54.
Lindgren, C.M., et al. 2009. Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution. PLoS Genet, 5, e1000508.
Lindren, C.M. and McCarthy, M.I. 2008. Mechanisms of disease: genetic insights into the etiology of type 2 diabetes and obesity. Nat Clin Pract Endocrinol Metab, 4, 156-63.
Loos, R.J., et al. 2008 Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet, 40, 768-75.
Willer, C.J., et al. 2009. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet, 41, 25-34.
Obesity, fat distribution, microRNA, mRNA, eQTL, association analysis, meta-analysis, Type-2-diabetes