Lipid Metabolism in Obesity, Exercise, and Weight Loss Grant uri icon

abstract

  • 40 kg/m2) is increasing at a disproportionate rate and associated with elevated health care costs. We have reported that fatty acid oxidation (FAO) is depressed in the skeletal muscle of severely obese patients, which may predispose these individuals to ectopic lipid accumulation. This decrement is retained in human skeletal muscle cells (HSkMC) raised in culture indicating an epigenetic or genetic component. Our preliminary findings suggest that this reduction in FAO is due to a reduction in mitochondrial content which may be linked with an inability to appropriately induce mitochondrial biosynthesis with severe obesity. For example, when subjected to elevated lipid presence (high fat diet, lipid incubation) FAO and indices of mitochondrial content do not increase in the skeletal muscle of the severely obese to the extent seen in lean individuals (metabolic inflexibility). Together, these data are indicative of an underlying ?metabolic program? with severe obesity which favors positive lipid balance. In contrast exercise training, an intervention/prevention for obesity, increases FAO in severely obese patients to the same extent as in lean subjects. These findings have led to our central hypothesis that the depressed FAO and metabolic inflexibility evident in the skeletal muscle of severely obese individuals is due to a reduction in mitochondrial content which stems, at least in part, from an inability to respond appropriately to conditions that induce mitochondrial biosynthesis, with the notable exception of exercise training. Findings could aid in understanding the underlying biology of this condition and designing effective treatments as well as promoting exercise as an intervention/prevention for severe obesity. Lines in the left margin denote revisions. Aim 1: To determine if the regulation of mtDNA in skeletal muscle is altered with severe obesity in a manner that depresses FAO. Mitochondria are unique in that they contain their own genetic system (mtDNA). We have observed a reduction in mitochondrial transcription factor A (TFAM) content which is a critical regulator of mtDNA replication. This aim will examine TFAM to determine if mtDNA is specifically targeted with severe obesity in a manner that depresses mitochondrial content, metabolic flexibility, and FAO. We will test our hypotheses in HSkMC (Aims a-d) and intact humans (Aim e). a) Is occupancy of the NRF-1 (nuclear respiratory factor -1) binding site on the TFAM promoter reduced with severe obesity? b) Is the reduction in TFAM expression linked with methylation of the TFAM promoter region? c) Can TFAM overexpression ameliorate the metabolic phenotype evident with severe obesity? d) Is insulin-induced mitochondrial biosynthesis impaired in the muscle of severely obese individuals? e) Are the defects discerned in HSkMC evident in-vivo? Aim 2: To determine if there is a coordinated dysregulation of nuclear genes required for mitochondrial biosynthesis with severe obesity. Mitochondrial biosynthesis is a complex process requiring the interaction of the nuclear and mitochondrial genomes. Our preliminary data suggests that the expression of NRF-1 target genes involved with mitochondrial biosynthesis is reduced with severe obesity. The intent of this aim is to use our HSkMC system to determine if there is a coordinated, reduced expression of NRF-1 encoded nuclear genes in human skeletal muscle with severe obesity. a) Is there a coordinated reduction in the expression of NRF-1 target genes with severe obesity? b) Is NRF-1 occupancy on genes linked with mitochondrial biosynthesis reduced with severe obesity? c) Can NRF-1 overexpression rescue the decrements in mitochondrial content, FAO, and metabolic inflexibility evident with severe obesity? Aim 3: To determine if compo

date/time interval

  • February 2006 - March 2014