Identification of a novel obesity gene: The BTBR mouse strain is predisposed to increased body weight gain when fed a high fat compared to the C57BL/6 strain. Previous studies (Stoehr et al, Diabetes 2004) have identified regions of the genome that contain genes that cause these differences in body weight. A major focus of the lab is the identification of one of these genes. We have created several congenic mouse strains for the fine-mapping of this gene. Current studies include physiological analyses of these mouse strains to determine the mechanism by which this gene alters body weight, the creation of additional strains for fine-mapping, and molecular analysis of the region and the genes it contains. This work is supported by the American Heart Association and the Heart and Stroke Foundation of BC and the Yukon.
Diabetes in wild-derived inbred strains: The identification of novel genes for obesity and diabetes in humans is difficult because of the large influence lifestyle and environmental factors over one’s lifetime can have on determining risk. These factors can all be controlled in laboratory animals, so that we can specifically study the effects of genes on the development of obesity and diabetes. Many mouse strains have been used for studies to identify genes predisposing to obesity and diabetes, however they suffer from the drawback that most of the strains used are all highly related to each other. Thus, they have limited genetic diversity to capture the entire spectrum of variants that could contribute to disease susceptibility. The wild-derived inbred strains are newly created strains that do not share a common ancestry with the others. Furthermore, their genome sequence is available, which will greatly facilitate genetic studies. We are currently examining the development of obesity and diabetes in these strains (PWD/PhJ and WSB/EiJ) to understand their risk at a very detailed physiological level. Both strains appear resistant to the development of obesity but have phenotypes that may predispose them to the development of type 2 diabetes. In addition to further physiological analysis of these strains, we will perform genetic studies to identify the genetic factors contributing to these physiological differences. This work is supported by the Canadian Diabetes Association.
Adipocyte size and function: During the development of obesity, adipose tissue expands by increasing both the size and number of adipocytes (fat storing cells) it contains. Many other changes also occur in adipose tissue, including increased infiltration of macrophages, tissue remodelling and new blood vessel development. Adipose tissue from obese individuals is “dysfunctional” compared with that of lean individuals, which can lead to metabolic disturbances throughout the individual. But, the molecular causes of this dysfunction are unknown. We are interested in determining the functional changes that occur in adipocytes as they enlarge during the development of obesity. We want to understand which aspects of adipose tissue dysfunction come first and trigger the others, which changes occur specifically in enlarged adipocytes, and which changes occur in all adipocytes in response to the changing metabolic status of the individual. Characterization of these changes at the cellular level will be followed by profiling at the transcriptional and translational levels to identify the genetic and molecular mechanisms underlying these changes. These findings will have relevance for all states of increased fat accumulation. By identifying the molecular cause of the dysfunction, we hope to be able to design treatments to prevent it and the complications associated with obesity.
Mouse Obesity and Metabolic Phenotyping Core: Through funding from the Canada Foundation for Innovation and the BC Knowledge Development Fund, we have developed a platform for detailed phenotyping of mouse models of obesity and metabolism including calorimetry, energy expenditure and physical activity, food intake, drinking behaviour, body weight and body fat.
