My research focus is on determining the link between obesity-induced lipotoxicity and the development of type 2 diabetes mellitus (T2DM) and atherosclerosis. My research has been conducted primarily in humans using exercise and nutritional interventions; however, I have recently incorporated both mouse and cell culture models to answer my research hypotheses.
The high prevalence of obesity threatens to overwhelm the U.S. healthcare system due to the impact that obesity has on the combined pathogenesis of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). In patients with obesity, cardiomyopathies are one of the leading causes of increased morbidity and mortality (From, Leibson et al. 2006; MacDonald, Petrie et al. 2008). It has been estimated that 11% of all cases of heart failure in men and up to 14% in women have been due to obesity-related cardiomyopathy (Kenchaiah, Evans et al. 2002). Furthermore, approximately 60-70% of individuals with T2DM have some form of cardiac dysfunction or cardiomyopathy (Sarwar, Gao et al. 2010). The pathogenesis of obesity cardiomyopathy remains unclear; however, defects in insulin signaling, mitochondrial dysfunction (Park, Yamashita et al. 2007) combined with altered glycogen and lipid metabolism (Stanley, Lopaschuk et al. 1997; Ouwens, Boer et al. 2005) and cardiac steatosis are key factors (Sharma, Adrogue et al. 2004).
The defects in insulin signaling and glucose utilization pathways reduce rates of cardiac glucose metabolism, which results in a complete dependence on fatty acid metabolism for ATP production (Stanley, Lopaschuk et al. 1997). This switch in substrate utilization forces the heart to change its structure and biochemistry to compensate for this imbalance. The reduced rate of glucose metabolism (glycolysis) leads to a two- to three-fold increase in glycogen concentration that down regulates the enzyme activity of 5’-AMP-activated protein kinase (AMPK) potentially lowering the production of ATP (Ravingerova, Stetka et al. 2000). Activation of AMPK by enzymatic phosphorylation results in stimulation of energy production pathways during increasing ratios of AMP to ATP and glycogen depletion, which has been shown to be critical to the heart for survival during energy deficits imposed by cardiac injury (Polekhina, Gupta et al. 2003; Russell, Li et al. 2004).
The heart relies heavily on lipid as a source for fuel to meet its high-energy demands. Free fatty acid (FFA) uptake, storage, and oxidation are tightly coordinated to maintain cardiac myocyte lipid balance while yielding necessary energy supply. The obesity cardiomyopathy demonstrates an increase in fatty acid transport protein (FATP)/CD36 mediated FFA uptake and oxidation, which increases the susceptibility of the heart to ischemia and can lead to excess lipid accumulation (lipotoxicity), energy deprivation (reduced ATP), and worsening insulin resistance (An and Rodrigues 2006). FATP/CD36, as well as lipid storage (regulated by adipose triglyceride lipase, ATGL) and downstream fatty acid oxidation pathways within mitochondria are regulated in large part by the nuclear receptor peroxisome proliferator-activated receptor-α (PPARα) and the transcriptional coactivator PPARγ coactivator 1 (PGC-1) (Haemmerle, Moustafa et al. 2011). PGC-1 is known to trigger mitochondrial biogenesis and increased respiratory function. It remains unclear the effects of obesity and differing dietary lipid compositions on PGC-1 activity and subsequent ATGL activity and fatty acid oxidation.
Dietary guidelines recommend the consumption of a low saturated fat/high complex carbohydrate (CHO) diet to reduce the risk for coronary heart disease. In contrast to these recommendations, during the last 40 years the consumption of fructose and rapidly absorbed CHO have increased in most industrialized countries (Tappy and Le 2010). Moreover, low-fat diets that are high in refined-CHO are associated with elevated blood lipids, glucose, insulin and blood pressure in comparison with high-fat diets that are low in refined-CHO or high in complex-CHO (Appel, Sacks et al. 2005; Schaefer, Gleason et al. 2005). Furthermore, diets high in fructose increase left ventricular dysfunction and mortality due in part to elevated plasma insulin levels (Karason, Sjostrom et al. 2003).
In contrast, diets rich in omega-3 polyunsaturated fatty acids (n-3 PUFA) have been shown to have anti-obesogenic effects that promote reduced fat deposition (Buckley and Howe 2009) and plasma triglyceride concentrations (Musa-Veloso, Binns et al. 2010). In non-obese related heart failure models, n-3 PUFA from marine sources alter cardiac membrane phospholipid composition, reduce the onset of new heart failure, and slow the progression of established heart failure (Stanley, Dabkowski et al. 2012); however, it remains unclear the effects of n-3 PUFA on the treatment of obesity cardiomyopathy.
Given this background, our current reseaerch focus is to determine if a diet rich in n-3 PUFA with and without high-fructose can attenuate the effects of diet-induced obese cardiomyopathy on cardiac AMPK and PGC-1 activities and subsequent glucose and lipid uptake, storage and metabolism.