Open Funding

Institution:

University of Dundee

Recipient:

Dr Hari Hundal

Project:

TUB expression and function in adipose tissue: implications for obesity and insulin resistance.

Summary:

Lay summary of why TUB function is worth investigating - TUB is a very abundant protein in the hypothalamus, a region of the brain involved in regulating appetite and energy balance, but, as yet, we know very little about its precise functional role. Mice with mutations in tub gene produce a non-functional TUB protein that promotes obesity and a diabetic-like syndrome as the animals mature in a manner very similar to that seen for mature-onset obesity in humans. These mice (known as tubby mice) also suffer from poor vision and hearing suggesting that TUB also participates in the control of key sensory functions. A number of studies have tried to establish how TUB may cause obesity in these mice as this may provide valuable insights into the problem of human obesity and insulin resistance. However, many of these studies have chosen to explore the role of hypothalamic TUB in the development of obesity based on the fact that TUB is very prevalent in this region of brain and because the hypothalamus has clear involvement in regulating appetite. No convincing links have thus far been established of how defects in TUB induce an increase in body fat in tubby mice. The role of TUB in tissues other than brain has largely been over looked due to much greater focus on the brain protein. However, we have recently discovered that TUB is also expressed at low levels in fat and its abundance is dramatically altered in this tissue during obesity and diabetes, whereas it remains unaltered in brain. We also find that cultured fat cells (adipocytes) growing in a petri dish show significant changes in TUB as they mature and gain more lipid over several days of culture.
Importantly, we find that TUB is regulated in cultured adipocytes by three very important stimuli: insulin, thyroid hormone and serotonin all of which are known to influence energy stores and metabolism. Collectively, our findings raise the exciting possibility that, in addition to its role in the hypothalamus, TUB may also regulate energy balance, adiposity and insulin sensitivity in the very tissue that is at the heart of the obesity problem. The studies outlined in this application will assess whether TUB in fat cells regulates the production and secretion of proteins influencing adiposity/insulin sensitivity and whether this process is modulated by insulin, thyroid hormone and serotonin. We believe that the findings that will emerge from the work described in this application will shed novel insights into how dysfunction of TUB contributes towards increased obesity, a condition that is a major risk factor for the development of numerous disorders, including coronary heart disease, arthritis and diabetes.

Amount:

£29,944