Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many biological programs are regulated at the transcriptional level. This is generally achieved by the concerted actions of several transcription factors. Recent findings have shown that, in many cases, transcriptional coactivators coordinate the overall regulation of the biological programs. One of the best-studied examples of coactivator control of metabolic pathways is the peroxisome proliferator-activated receptor coactivator 1 (PGC-1) family. These proteins are strong activators of mitochondrial function and are thus dominant regulators of oxidative metabolism in a variety of tissues. The PGC-1 coactivators themselves are subject to powerful regulation at the transcriptional and posttranslational levels. Recent studies have elucidated the function of the PGC-1 coactivators in different tissues and have highlighted the implications of PGC-1 dysregulation in diseases such as diabetes, obesity, cardiomyopathy, or neurodegeneration.
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PMID:Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. 1701 37

It is widely recognized that obesity and insulin resistance can contribute to an increased risk of coronary disease, but it has also become increasingly apparent that they may contribute directly to cardiac dysfunction even in the absence of significant coronary disease. Recently, obesity, which is frequently accompanied by insulin resistance, has been independently related to clinically diagnosed heart failure. Thus, there is renewed interest in the pathophysiology of myocardial disease related to obesity and insulin resistance, as well as in the specific cellular mechanisms by which obesity may cause detrimental cardiac structural and functional changes. Alterations in hemodynamics, plasma volume, neurohormonal status, and myocardial substrate metabolism all appear to contribute to these changes. Improving our understanding of cardiac dysfunction related to obesity and insulin resistance may provide clues for new strategies to prevent and treat this alarmingly prevalent condition.
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PMID:Obesity and insulin resistance: effects on cardiac structure, function, and substrate metabolism. 1708 55

Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha is a member of a family of transcription coactivators that plays a central role in the regulation of cellular energy metabolism. It is strongly induced by cold exposure, linking this environmental stimulus to adaptive thermogenesis. PGC-1alpha stimulates mitochondrial biogenesis and promotes the remodeling of muscle tissue to a fiber-type composition that is metabolically more oxidative and less glycolytic in nature, and it participates in the regulation of both carbohydrate and lipid metabolism. It is highly likely that PGC-1alpha is intimately involved in disorders such as obesity, diabetes, and cardiomyopathy. In particular, its regulatory function in lipid metabolism makes it an inviting target for pharmacological intervention in the treatment of obesity and Type 2 diabetes.
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PMID:PGC-1alpha: a key regulator of energy metabolism. 1710 41

The world-wide estimated prevalence of diabetes mellitus for 2025 is of about 300 million, resulting from a higher prevalence of obesity and sedentary lifestyles in the developed world. The group of cardiovascular diseases is responsible for 80% of deaths among diabetic patients. Several authors have suggested that patients with diabetes mellitus have a predisposition to develop a form of cardiomyopathy, known as <<diabetic cardiomyopathy>>, which is not related to ischemic heart disease or hypertension, and may progress to cardiac failure. Such condition is known to be associated with a poor prognosis in patients with diabetes mellitus. The prevalence appears to be high. Thus, tissue Doppler techniques added to conventional echocardiography assessment have estimated it to be as high as 75%. However, the use of echocardiography as a screening tool in the asymptomatic diabetic population is problematic. Biomarkers of cardiac dysfunction have been proposed for diagnosis. In this article, we have assessed the role of biomarkers in the diagnosis of this condition and proposed a diagnostic algorithm that may be useful for the assessment of asymptomatic patients with diabetes.
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PMID:[Diabetic miocardiopathy]. 1714 17

Hypertension, obstructive sleep apnea, and coronary artery disease all contribute to the myocardial dysfunction in obesity. However, the development of sensitive cardiac imaging techniques has enabled detection of myocardial structural and functional changes independently attributable to obesity, at the preclinical stage. This review will evaluate the evidence for myocardial disease in this setting, its significance, important mechanisms, preclinical detection, and possible therapeutic implications.
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PMID:Alterations in myocardial characteristics associated with obesity: detection, mechanisms, and implications. 1721 Apr 70

Obesity-related diabetes mellitus leads to increased myocardial uptake of fatty acids (FAs), resulting in a form of cardiac dysfunction referred to as lipotoxic cardiomyopathy. We have shown previously that chronic activation of the FA-activated nuclear receptor, peroxisome proliferator-activated receptor alpha (PPARalpha), is sufficient to drive the metabolic and functional abnormalities of the diabetic heart. Mice with cardiac-restricted overexpression of PPARalpha (myosin heavy chain [MHC]-PPARalpha) exhibit myocyte lipid accumulation and cardiac dysfunction. We sought to define the role of the long-chain FA transporter CD36 in the pathophysiology of lipotoxic forms of cardiomyopathy. MHC-PPARalpha mice were crossed with CD36-deficient mice (MHC-PPARalpha/CD36-/- mice). The absence of CD36 prevented myocyte triacylglyceride accumulation and cardiac dysfunction in the MHC-PPARalpha mice under basal conditions and following administration of high-fat diet. Surprisingly, the rescue of the MHC-PPARalpha phenotype by CD36 deficiency was associated with increased glucose uptake and oxidation rather than changes in FA utilization. As predicted by the metabolic changes, the activation of PPARalpha target genes involved in myocardial FA-oxidation pathways in the hearts of the MHC-PPARalpha mice was unchanged in the CD36-deficient background. However, PPARalpha-mediated suppression of genes involved in glucose uptake and oxidation was reversed in the MHC-PPARalpha/ CD36-/- mice. We conclude that CD36 is necessary for the development of lipotoxic cardiomyopathy in MHC-PPARalpha mice and that novel therapeutic strategies aimed at reducing CD36-mediated FA uptake show promise for the prevention or treatment of cardiac dysfunction related to obesity and diabetes.
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PMID:CD36 deficiency rescues lipotoxic cardiomyopathy. 1746 25

Type 1 and type 2 diabetic patients are at increased risk of cardiomyopathy and heart failure is a major cause of death for these patients. Cardiomyopathy in diabetes is associated with a cluster of features including decreased diastolic compliance, interstitial fibrosis and myocyte hypertrophy. The mechanisms leading to diabetic cardiomyopathy remain uncertain. Diabetes is associated with most known risk factors for cardiac failure seen in the overall population, including obesity, dyslipidemia, thrombosis, infarction, hypertension, activation of multiple hormone and cytokine systems, autonomic neuropathy, endothelial dysfunction and coronary artery disease. In light of these common contributing pathologies it remains uncertain whether diabetic cardiomyopathy is a distinct disease. It is also uncertain which factors are most important to the overall incidence of heart failure in diabetic patients. This review focuses on factors that can have direct effects on diabetic cardiomyocytes: hyperglycemia, altered fuel use, and changes in the activity of insulin and angiotensin. Particular attention is given to the changes these factors can have on cardiac mitochondria and the role of reactive oxygen species in mediating injury to cardiomyocytes.
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PMID:Causes and characteristics of diabetic cardiomyopathy. 1748 34

Obesity is becoming a worldwide phenomenon. Myocardial changes associated with the obese state are increasingly recognized, independent of hypertension, obstructive sleep apnea and coronary artery disease. The existence of a cardiomyopathy of obesity is supported by a range of evidence: epidemiologic study findings, which have shown an association between obesity and heart failure; clinical studies that have confirmed the association of adiposity with left ventricular dysfunction, independent of hypertension, coronary artery disease and other heart disease; and experimental evidence of structural and functional changes in the myocardium in response to increased adiposity. The most important mechanisms in the development of obesity cardiomyopathy are metabolic disturbances (insulin resistance, increased free fatty acid levels, and also increased levels of adipokines), activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, myocardial remodeling, and small-vessel disease (both microangiopathy and endothelial dysfunction). In the first part of this two-part Review, we seek to evaluate the emerging evidence for the existence of a cardiomyopathy of obesity and clarify the responsible mechanisms.
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PMID:Obesity cardiomyopathy: pathogenesis and pathophysiology. 1765 16

Obesity is associated with an increased risk of heart failure. Apparently healthy obese individuals can, however, exhibit subclinical left ventricular dysfunction. The use of myocardial imaging techniques to detect this subclinical change could have important management implications with respect to initiating prophylactic therapy. In this Review, we evaluate possible pharmacologic and nonpharmacologic strategies for treating obesity cardiomyopathy in the context of currently understood mechanisms, including myocardial remodeling and small vessel disease, and more speculative mechanisms such as insulin resistance, and activation of the renin-angiotensin-aldosterone and sympathetic nervous systems.
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PMID:Obesity cardiomyopathy: diagnosis and therapeutic implications. 1771 61

The goal of pharmacogenetics is to define the genetic determinants of individual drug responsiveness, and thereby provide personalized treatment to each individual. The peroxisome proliferator-activated receptors (PPARs) are polypeptide products of a set of related genes functioning to regulate several cellular processes that are central to cardiovascular health and disease. Given their pleiotropic roles in lipid and glucose homeostasis, cardiac energy balance and regulation of adipocyte release of circulating inflammatory factors, it is not surprising that PPARs represent an attractive target for clinical investigation and intervention in disease states, such as diabetes, obesity, atherosclerosis, cardiomyopathy, cardiac hypertrophy and heart failure. Research into the manipulation of PPAR function by pharmacologic agents has already resulted in important advances in the treatment of diabetes mellitus and cardiovascular disease. It follows that PPAR pharmacogenetics promises important advances in the personalized treatment of cardiovascular disease.
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PMID:Pharmacogenetics of the PPAR genes and cardiovascular disease. 1803 23


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