Cardiac Energy Metabolism in Obesity

Lopaschuk, Gary D.; Folmes, Clifford D.L.; Stanley, William C.

doi:10.1161/circresaha.107.150417

Cited by 251 publications

(227 citation statements)

References 209 publications

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“…[61][62][63] Several studies have shown that systemic insulin resistance is prevalent among patients with cardiac dysfunction, and systemic insulin resistance was reported to be a risk factor for the development of heart failure. 8,[63][64][65][66][67][68][69] Thus, there is evidence of a link between heart failure and systemic metabolic dysfunction, but the underlying molecular mechanisms and the clinical implications have not been clarified. Recently, systemic insulin resistance (hyperinsulinemia), including hepatic insulin resistance, was shown to develop in murine models of chronic heart failure.…”

Section: Link Between Cardiac Aging and Adipose Tissue Dysfunctionmentioning

confidence: 99%

Pathological Role of Adipose Tissue Dysfunction in Cardio-Metabolic Disorders

2015

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SummaryObesity has dramatically increased throughout the world, and has become one of the chief healthcare problems in many societies. Evidence has emerged that adipose tissue dysfunction associated with obesity is critically involved in the development of cardiovascular and metabolic disorders. In this review, we delineate the link between adipose tissue abnormalities and systemic metabolic dysfunction in patients with cardio-metabolic diseases and discuss the underlying mechanisms. (Int Heart J 2015; 56: 255-259) Key words: Aging, Diabetes, Insulin, Heart failure, White adipose tissue, Brown adipose tissue A ging can be characterized as an age-dependent decline of physiological function that leads to an increased risk of death. Chronological aging has been linked to genomic instability, loss of telomeres, epigenetic modifications, alterations of intercellular communication, and cellular senescence, all of which contribute to the pathology of aging and age-related disorders.1) The exact mechanism of aging is yet to be defined, but several factors have been reported to be involved. Calorie restriction and inhibition of insulin signaling are well known to delay the aging process and extend longevity in various species, including monkeys. 2)Obesity and diabetes have dramatically increased throughout world and have become major healthcare problems in many societies.3-6) Obesity has a central role in the development of diabetes and atherosclerotic disease, and being obese increases the risk of death, particularly from cardiovascular disease. 5,7,8) Systemic insulin resistance (hyperinsulinemia) is one of the crucial molecular mechanisms involved in the pathology of obesity and diabetes.9,10) Chronic low-grade sterile inflammation affecting visceral fat leads to systemic insulin resistance.11) Excessive uptake of free fatty acids by visceral fat in obese persons drives the production of reactive oxygen species (ROS) and initiates cellular senescence. Several lines of evidence have clearly shown a pathological role of cellular senescence in the progression of age-related diseases, such as atherosclerosis, obesity, and diabetes. 12,13) Recently, occurrence of cellular senescence in cardiac tissue and adipose tissue was reported to have a causal role in accelerating heart failure and diabetes, respectively. 14,15) Occurrence of cellular senescence in white adipose tissue (WAT) induces inflammation and systemic insulin resistance in a murine heart failure model, thus accelerating cardiac remodeling. Conversely, suppression of cellular senescence in adipose tissue ameliorates inflammation and systemic metabolic dysfunction, inhibiting the progression of heart failure and the development of diabetes via modulation of insulin signaling. 15,16) In addition to WAT, other types of fat are known to be involved in regulating metabolic homeostasis. Brown adipose tissue (BAT) is highly vascular and abundant in mitochondria that are rich in uncoupling protein-1 (UCP-1), which produce heat by uncoupling the respiratory chain invo...

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Section: Link Between Cardiac Aging and Adipose Tissue Dysfunctionmentioning

confidence: 99%

Pathological Role of Adipose Tissue Dysfunction in Cardio-Metabolic Disorders

2015

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“…Obesity and diabetes are associated with insulin resistance and increased cardiac fatty acid oxidation. 125 Therefore, further studies are needed to ascertain the effect of accelerating fat oxidation in heart failure models associated with obesity and diabetes.…”

Section: Approaches To Treat Left Heart Failure Inhibiting Fat Oxidationmentioning

confidence: 99%

Cardiac Energy Metabolic Alterations in Pressure Overload–Induced Left and Right Heart Failure (2013 Grover Conference Series)

Sankaralingam

Lopaschuk

2015

Pulm. circ.

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Pressure overload of the heart, such as seen with pulmonary hypertension and/or systemic hypertension, can result in cardiac hypertrophy and the eventual development of heart failure. The development of hypertrophy and heart failure is accompanied by numerous molecular changes in the heart, including alterations in cardiac energy metabolism. Under normal conditions, the high energy (adenosine triphosphate [ATP]) demands of the heart are primarily provided by the mitochondrial oxidation of fatty acids, carbohydrates (glucose and lactate), and ketones. In contrast, the hypertrophied failing heart is energy deficient because of its inability to produce adequate amounts of ATP. This can be attributed to a reduction in mitochondrial oxidative metabolism, with the heart becoming more reliant on glycolysis as a source of ATP production. If glycolysis is uncoupled from glucose oxidation, a decrease in cardiac efficiency can occur, which can contribute to the severity of heart failure due to pressure-overload hypertrophy. These metabolic changes are accompanied by alterations in the enzymes that are involved in the regulation of fatty acid and carbohydrate metabolism. It is now becoming clear that optimizing both energy production and the source of energy production are potential targets for pharmacological intervention aimed at improving cardiac function in the hypertrophied failing heart. In this review, we will focus on what alterations in energy metabolism occur in pressure overload induced left and right heart failure. We will also discuss potential targets and pharmacological approaches that can be used to treat heart failure occurring secondary to pulmonary hypertension and/or systemic hypertension.

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“…It has been confirmed that disturbances in cardiac substrate metabolism and energetics are the key contributors to DCM (Anderson et al., 2009; Lopaschuk, Folmes & Stanley, 2007). In diabetes, cardiac palmitate oxidation doubles and glucose oxidation decreases by 30%–40% relative to the levels observed in nondiabetic patients (Anderson et al., 2009; Rijzewijk et al., 2009).…”

Section: Introductionmentioning

confidence: 99%

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

Wang

et al. 2018

Aging Cell

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SummaryLipotoxicity cardiomyopathy is the result of excessive accumulation and oxidation of toxic lipids in the heart. It is a major threat to patients with diabetes. Glucagon‐like peptide‐1 (GLP‐1) has aroused considerable interest as a novel therapeutic target for diabetes mellitus because it stimulates insulin secretion. Here, we investigated the effects and mechanisms of the GLP‐1 analog exendin‐4 and the dipeptidyl peptidase‐4 inhibitor saxagliptin on cardiac lipid metabolism in diabetic mice (DM). The increased myocardial lipid accumulation, oxidative stress, apoptosis, and cardiac remodeling and dysfunction induced in DM by low streptozotocin doses and high‐fat diets were significantly reversed by exendin‐4 and saxagliptin treatments for 8 weeks. We found that exendin‐4 inhibited abnormal activation of the (PPARα)‐CD36 pathway by stimulating protein kinase A (PKA) but suppressing the Rho‐associated protein kinase (ROCK) pathway in DM hearts, palmitic acid (PA)‐treated rat h9c2 cardiomyocytes (CMs), and isolated adult mouse CMs. Cardioprotection in DM mediated by exendin‐4 was abolished by combination therapy with the PPARα agonist wy‐14643 but mimicked by PPARα gene deficiency. Therefore, the PPARα pathway accounted for the effects of exendin‐4. This conclusion was confirmed in cardiac‐restricted overexpression of PPARα mediated by adeno‐associated virus serotype‐9 containing a cardiac troponin T promoter. Our results provide the first direct evidence that GLP‐1 protects cardiac function by inhibiting the ROCK/PPARα pathway, thereby ameliorating lipotoxicity in diabetic cardiomyopathy.

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Cardiac Energy Metabolism in Obesity

Cited by 251 publications

References 209 publications

Pathological Role of Adipose Tissue Dysfunction in Cardio-Metabolic Disorders

Pathological Role of Adipose Tissue Dysfunction in Cardio-Metabolic Disorders

Cardiac Energy Metabolic Alterations in Pressure Overload–Induced Left and Right Heart Failure (2013 Grover Conference Series)

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

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