Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Obesity is a serious global health challenge. Understanding obesity as a progressive disease and the factors involved in its development will help with management and even prevention. One of the factors that is severely reduced in obesity is growth hormone (GH), which plays an essential role in maintaining a healthy balance of the body's fat supply. Normally another hormone, insulin, is highly elevated in obesity and favors use of sugar over stored fat, however GH offers balance by increased use of fat. So, the more GH you make, the less you tend to be obese. Recently, a study showed that GH is rapidly lowered in healthy non-obese individuals who overate for three days, suggesting GH production is affected at the very early stages of developing obesity. Interestingly, the increase in insulin seen with overeating is believed to be responsible for low GH levels. I am interested to study when, how and why GH is reduced in individuals who are on their way to become obese. We believe that the fundamental changes in GH production are happening at the level of the gene, but until recently there have been difficulties in studying human GH gene regulation. These include: (i) a lack of normal human pituitary samples availability until after death; and (ii) that human GH is distinct from mouse, rat or pig GH, so animal pituitaries are likely to represent a partial solution. Thus, we generated a mouse containing the human GH gene and enough DNA information for it to be made specifically in GH-producing pituitary cells. Using pituitary cells from these mice we observed that the human GH gene switches off in response to insulin excess. My proposed project is to use these humanized mice, to model overeating and obesity in humans. Specifically I will examine the effect of high fat diet-induced obesity on GH levels at progressive stages of obesity. My hope is to increase our knowledge of the causes and consequences of abnormal GH levels, a hormone with strong anti-obesity function.