The overall purpose of this research training project is to study the regulation of lipoprotein lipase (LPL) as it relates to physical inactivity and muscle free fatty acids. In addition, because of the high association and purported role of elevated free fatty acids (FFA) in development of the metabolic syndrome (e.g., insulin resistance, dyslipdemia, hypertension, CAD) and the large role muscle plays in the metabolism of fatty acids, a major goal of this project is to study the effect of fatty acids on global gene expression in muscle to gain a better understanding of gene regulation that underlies the effects of fatty acids on health and disease.
Aim I will determine how acute physical inactivity effects LPL activity and how restoration of ambulatory activities effects LPL activity.
Aim 2 will describe the time course for changes in muscle FFA with inactivity and relate it to the time course of LPL activity.
Aim 3 will use models known to manipulate muscle FFA to best determine the association between muscle LPL activity and muscle FFA.
Aim 4 will determine the effect of elevated muscle FFA on global gene expression using unbiased oligonucleotide array technology. Physical inactivity in Aims 1-3 will be achieved with the use of the hind limb suspension of rats while control rats will be ambulatory. Heparin releasable and intracellular LPL activity will be determined as measured with enzymatic assays at a range of time points between 1 hr and 14 days of hind limb suspension and after short term restoration of ambulatory activities. Manipulations of dietary glucose and fat will be used to manipulate muscle FFA in Aim 3 to determine relationship between muscle FFA and LPL activity. In order to study the direct effects of specific fatty acids on skeletal muscle gene expression, the in vitro model of hind limb perfusion will be employed to determine the specific effect of elevating muscle fatty acids on global gene expression.
| Hamilton, Marc T; Hamilton, Deborah G; Zderic, Theodore W (2014) Sedentary behavior as a mediator of type 2 diabetes. Med Sport Sci 60:11-26 |
| Hamilton, Marc T; Hamilton, Deborah G; Zderic, Theodore W (2007) Role of low energy expenditure and sitting in obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Diabetes 56:2655-67 |
| Zderic, Theodore W; Hamilton, Marc T (2006) Physical inactivity amplifies the sensitivity of skeletal muscle to the lipid-induced downregulation of lipoprotein lipase activity. J Appl Physiol 100:249-57 |
