Over 60% of the US population is overweight and more than 30% is obese and these alarming percentages are increasing yearly, resulting in corresponding increases in multiple chronic disease conditions, since overweight and obesity are known to detrimentally impact a wide range of organ systems.
Adipose tissue of obese subjects is more pro-inflammatory than that of lean subjects, revealing more pro-inflammatory adipokine production, more lipolysis, and less adiponectin secretion, all of which can enhance systemic inflammation and abnormal lipid accumulation in non-adipose tissue, and induce progressive damage to target organs and tissues. In the liver, inflammation and ectopic fat deposition leads to insulin resistance, increased glucose production, and non-alcoholic steatohepatitis (NASH), a major cause of cirrhosis and liver transplantation. Lipid deposition in skeletal muscle can cause insulin resistance, while its accumulation in the heart can promote diastolic dysfunction leading to heart failure. Inflammation and lipid accumulation in pancreatic islets can lead to increased death of insulin-producing β-cells, impaired insulin secretion and type 2 diabetes. Finally, plasma free fatty acid and adipokine increases and adiponectin decreases can also lead to vascular inflammation, endothelial dysfunction and hypertension to promote atherosclerosis development.
On average, obese individuals require 4-fold more healthcare dollars than lean subjects due to the array of complications ensuing from overweight. Despite the dire implications of the obesity epidemic, current approaches to combat obesity and its complications, including diet, exercise, small molecular therapeutics and surgery, have proven inadequate to attenuate their progression in the overall population.
Current research being conducted at the Diabetes Research Center includes:
While overweight is associated with increased risk of several chronic disease conditions, including type-2 diabetes and cardiovascular disease, individuals vary in their response to overweight prompting the need to identify risk factors that predict disease development and progression. Metabolic syndrome, the major diagnostic classification used for this purpose, is based on a cluster of interrelated factors implicated to predict type 2 diabetes and cardiovascular disease risk. However, despite modifications of the diagnostic components of metabolic syndrome by multiple expert organizations around the world, this approach has limited utility for risk prediction. Inflammation is now regarded as a major underlying mechanism in metabolic syndrome, but there is no adequate biomarker of inflammation in the standard repertoire of metabolic syndrome risk factors. Adipose inflammation is also increasingly recognized as a major contributor to insulin resistance and the systemic complications of obesity, but only recently have researchers begun to understand the complex regulation of adipocytes, adipose-resident immune cells and the systemic implications of these interactions. Adipose tissue inflammation Adipose tissue represents a dynamic endocrine tissue, whose size and endocrine output increases weight gain. Obesity-induced changes in adipose tissue T-cells and macrophages are increasingly recognized as important determinants of adipose metabolism, pro-inflammatory cytokine secretion, and, ultimately, whole body insulin sensitivity. Recent evidence suggests that changes in adipose-resident T-cells can impact adipose tissue macrophage phenotypes, and regulate systemic insulin action. Adipocyte regulation of T-cell responses may be a central component of the immunologic alterations in obesity, and is a major focus of our current research, where we study early changes in adipose tissue cell fractions and their relative contributions to the development of local and systemic metabolic and pro-inflammatory changes associated with obesity and its complications. Our recent studies indicate that adipocyte changes occurring early in the development of obesity can directly regulate phenotypic responses of adipose-resident immune cell population, inducing cytokine responses that can feedback to promote more pro-inflammatory adipocyte phenotypes and produce local and systemic changes in metabolism and inflammation.
Overweight and obesity are associated with an increased risk of heart failure, as well as increased risk of left ventricular diastolic dysfunction, an asymptomatic heart condition associated with increased risk of future heart failure. Heart failure patients have a 59% fatality rate within 5 years of diagnosis, similar to the median survival rate for cancer, and while neurohormonal blockade has improved survival rates, advances are still desperately needed.
Diabetes is the most common cause of cardiac dysfunction, and diabetic individuals have a markedly elevated risk of heart failure, even after adjustment for obesity and obesity-associated risk factors such as hypertension, coronary artery disease and dyslipidemia. There is also evidence that diabetic patients suffer from a distinct form of this disease, diabetic cardiomyopathy, a clinical condition diagnosed when ventricular dysfunction develops in patients with diabetes in the absence of coronary atherosclerosis and hypertension. However, the pathological physiology changes and mechanisms underlying cardiomyopathy in obesity and type 2 diabetes are not well understood. Cardiac insulin resistance has been implicated in this process, but studies are inconsistent as to the degree of insulin resistance and the regulatory mechanisms associated with disease development.
The adult heart primarily uses fatty acid for energy, but can rapidly switch to other substrates in response to stresses such as exercise, fasting, ischemia, hypertrophy or heart failure. Stressed hearts often shift to use less fatty acid and more glucose, which is more a more favorable substrate under hypoxic conditions, since glucose oxidation produces more energy than fatty acid oxidation for the same amount of oxygen consumed. Due to their reduced glucose uptake capability, insulin resistant hearts must still heavily depend upon fatty acids under stress conditions. However, chronically elevated metabolism of fatty acids by cardiac mitochondria under hypoxic conditions can induce mitochondrial oxidative stress, dysfunction and damage, leading to abnormal cardiac function.
Our recent results in a mouse model of metabolic syndrome and insulin resistance, however, suggest that the heart can remains insulin sensitive in the face of marked systemic insulin resistance. We found that the hearts highly insulin resistant obese mice had a marked increase in cardiac glucose uptake, despite no evidence of cardiac hypertrophy or dysfunction, and had greater mitochondrial oxidation responses than of non-obese insulin-sensitive control mice. Cardiac expression of pro-inflammatory and pro-fibrotic genes was increased, however, suggesting that cardiac inflammation and fibrosis occur prior to mitochondrial and cardiomyocyte dysfunction. Steptozotocin-induced insulin-deficiency, which normalized cardiac glucose uptake to that of insulin-sensitive control mice, decreased mitochondrial and cardiac function, suggesting hyperinsulinemia-induced cardiac glucose uptake can preserve mitochondrial and cardiac function in the of face metabolic stresses associated with obesity and systemic insulin resistance.
Recent results using human heart tissue extend these findings to suggest that mitochondrial function remains intact even during advance heart failure. In these studies, left ventricular heart tissue was obtained from heart failure patients during emplacement of a left ventricular assist device (LVAD) and an average of 1 year post-LVAD emplacement upon LVAD removal for transplant. We found that mitochondria isolated from left ventricles pre-LVAD had increased, but coupled, oxidative capacity for all substrates but succinate, indicating that mitochondrial capacity was not degraded in human heart failure, contrary to consensus opinion. However, pre-LVAD left ventricles had increased pyruvate, and decreases in short chain acyl-carnitine and tricarboxylic acid cycle intermediates, indicating a general reduction in substrate metabolism with heart failure. Pre-LVAD left ventricles also had correspondingly decreased gene expression of mitochondrial enzymes associated with pyruvate transport and metabolism of long chain fatty acids, suggesting that mitochondria from failing left ventricles can function normally, but are severely depleted of substrate in vivo. Strikingly, all these left ventricle substrate phenotypes were reversed post-LVAD, indicating that unloading the failing left ventricle has metabolic benefits that may improve the ability of still highly functional mitochondria to restore cardiac function over time.Based on these results it appears that cardiac mitochondria retain full functional activity during systemic insulin resistance and heart failure, but are subjected to substrate starvation during heart failure, suggesting that approaches that target myocardial energetics and metabolism may be attractive therapeutic approaches to treat heart failure.
Chronic kidney disease Diabetes is the leading cause of cause of end-stage renal disease (ESRD) in the US, where diabetic nephropathy accounts for ~40% of new ESRD cases with an associated yearly treatment cost of >$15 billion. About 20–30% of patients with type 1 or type 2 diabetes develop nephropathy, and despite the fact that fewer type 2 diabetic patients progress to ESRD, these individuals represent more than half of the subjects starting dialysis, due to the much greater prevalence of type 2 diabetes in the US population. Without intervention, about 20–40% of type 2 diabetic patients with early kidney disease will progress to nephropathy, but among these subjects only ~20% will progress to ESRD by 20 years after the onset of overt nephropathy. This paints an alarming healthcare picture, since the current epidemic of obesity and diabetes should be expected to produce a similar future increase in diabetic nephropathy and ESRD patients unless effective interventions are found to attenuate this process of disease progression
Despite extensive study, relatively little is known about the exact mechanisms acting upon specific kidney cell types damaged during the development of diabetic nephropathy. For example, diabetes-induced damage to podocytes, specialized kidney cell that directly regulate protein loss into the urine, is known to play a critical role in the development and progression of kidney disease. However, very little is known about how podocytes respond to diabetes, due to the difficulty of obtaining highly-purified podocyte samples from affected humans or animal models of diabetic kidney injury.
We have found that activation of the nuclear receptor PPARg in the kidney can attenuate the development of diabetes-induced kidney injury through actions on both podocytes and mesangial, attenuating structural changes that lead to podocyte loss and decreased filtration capacity. To better understand the mechanisms acting upon podocytes during diabetic kidney injury, we have recently validated an approach to isolate highly-purified podocyte from mouse models of diabetic kidney disease, during disease progression and before and after interventions known to attenuate diabetes or preserve kidney function.
Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH)
Non-alcoholic fatty liver disease (NAFLD), which strongly correlates with overweight and obesity, is a chronic condition where lipid accumulates in the liver and alters its normal metabolic function. NALFD, now the most common chronic liver disease worldwide, confers increased cardiovascular risk and adverse cardiovascular outcomes independent of traditional risk factors. Currently, about 10-20% of the U.S. population is predicted to have NAFLD, while 2-5% of the population is predicted to have non-alcoholic steatohepatitis (NASH), a more severe form of the disease that can progress to cirrhosis, end-stage liver disease and liver failure. Similar number are seen in pediatric populations. NASH incidence is even greater in the overweight population, where >30% of obese individuals are estimated to have NASH, further increases with metabolic syndrome, and is an increasingly common cause of liver transplantation, accounting for about 10% of adult liver transplants. The prevalence of both NAFLD and NASH are expected to increase with the continuing epidemic of overweight and obesity.
Despite these alarming numbers very little is known about the mechanisms responsible for the NAFLD development and its progression to NASH and cirrhosis, and there are no surrogate biomarkers proven to reflect histologic injury in NASH, and no approved treatment other than weight loss, which has not proven highly effective, to prevent NASH or arrest its progression. Since liver transplantation is currently the only definitive treatment for NASH, this disease has the potential to vastly overload organ allocation and health care systems around the world.
We have recently developed a novel mouse model of NAFLD and NASH where, similar to human disease, diet-induced obesity and age interact to promote the development of NASH that displays all the histological features of human disease. Studies in this mouse model have shown that, similar to a recent human clinical trial, therapeutic intervention with a thiazolidindione PPARg ligand can attenuate the development of NASH. These studies suggest these agents may act by decreasing oxidative stress on the liver, as implied by the human trial, but also by increasing lipid oxidation in the liver. Subsequent studies have suggested that the PPARg ligand effects on liver metabolism may be due to an effect on an intronic PPARγ response element cluster in the PGC-1β locus, since we found that ligand treatment up-regulated the expression of several mitochondrial marker genes, and increased mitochondrial activity in a PGC-1β dependent fashion.
Adipose tissue is a dynamic endocrine organ that secretes a number of factors that are increasingly recognized to contribute to systemic and vascular inflammation. Several of these factors, collectively referred to as adipokines, have now been shown to directly or indirectly regulate multiple processes that contribute to the development of atherosclerosis, including hypertension, endothelial dysfunction, insulin resistance, and vascular remodeling.
Cardiovascular disease, including heart attack and stroke, accounts for >33% of the US mortality rate with an estimated yearly health care cost of >$400 billion or ~16% of all the entire US healthcare budget, while coronary heart disease alone is estimated to account for >$100 billion. These numbers are expected to worsen due both to the ongoing obesity epidemic and the aging of the US population.
Age is an independent, non-modifiable risk factor for cardiovascular disease, type 2 diabetes and insulin resistance. It is associated with increased oxidative stress, which is known to promote vascular injury and metabolic syndrome, suggesting that age-related oxidative stress plays an important role in these processes. However, mechanisms responsible for age-associated oxidative stress and its intersection with cardiovascular disease are unclear.
Current mouse models of atherosclerosis do not fully mimic human disease pathology or address the role of aging in this process, since unlike humans, these mouse models develop predominantly fatty streak lesions that spontaneously regress upon removal of high-fat diet and cover only a small area of their aorta.
We have reported that, after aging for one year, at least one of these mouse models, the LDLR-deficient mice fed 3 months of high-fat diet, has dramatically worse metabolic syndrome and oxidative stress than younger mice, and develops markedly accelerated atherosclerotic lesions containing advanced atherosclerotic plaques that do not spontaneously regress upon diet withdrawal. We have proposed that this accelerated vascular injury likely results from a profound inability to mount an antioxidant response to compensate for diet-induced oxidative stress, a conclusion which is supported by our finding that treatment of these mice with an anti-oxidant compound markedly attenuated atherosclerosis. We hypothesized that increased macrophages cell death in developing lesions of the older mice, due to age- and diet-induced increases in oxidative stress, was at least partially responsible for the development of more advanced atherosclerosis lesions. Our recent studies lend support to this hypothesis, indicating that mice whose macrophages are genetically-modified not to respond to oxidative stress develop more atherosclerosis than mice with normally-responsive macrophages.
Clinical Trials The Methodist Hospital Research Institute is dedicated to research and is deeply committed to finding new ways to prevent and treat illness and improve the health of patients who come to The Methodist Hospital for healthcare.