Nutrient Stress Activates Inflammation and Reduces Glucose Metabolism by Suppressing AMP-Activated Protein Kinase in the Heart

Ko, Hwi Jin; Zhang, Zhiyou; Jung, Dae Young; Jun, John Y.; Ma, Zhong; Jones, Kelly E.; Chan, Sook Y.; Kim, Jason K.

doi:10.2337/db08-1361

Cited by 137 publications

(126 citation statements)

References 47 publications

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“…Consistent with our findings in these mice, nontransgenic models of lipid overload using long-term high-fat diet or streptozotocin treatment have also demonstrated increased numbers of macrophages within the hearts of insulin resistant and/or diabetic mice (13,30). However, assessing the influence of cardiac macrophages on LV function using cell depletion strategies with these models is confounded by the concomitant role of macrophages in promoting the primary dysregulation of systemic metabolism, which is further modified by macrophage depletion (16,21).…”

Section: Discussionsupporting

confidence: 68%

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

Schilling

Machkovech

Kim

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Schilling JD, Machkovech HM, Kim AH, Schwedwener R, Schaffer JE. Macrophages modulate cardiac function in lipotoxic cardiomyopathy. Am J Physiol Heart Circ Physiol 303: H1366 -H1373, 2012. First published October 5, 2012; doi:10.1152/ajpheart.00111.2012.-Diabetes is associated with myocardial lipid accumulation and an increased risk of heart failure. Although cardiac myocyte lipid overload is thought to contribute to the pathogenesis of cardiomyopathy in the setting of diabetes, the mechanism(s) through which this occurs is not well understood. Increasingly, inflammation has been recognized as a key pathogenic feature of lipid excess and diabetes. In this study, we sought to investigate the role of inflammatory activation in the pathogenesis of lipotoxic cardiomyopathy using the ␣-myosin heavy chain promoter-driven long-chain acylCoA synthetase 1 (MHC-ACS) transgenic mouse model. We found that several inflammatory cytokines were upregulated in the myocardium of MHC-ACS mice before the onset of cardiac dysfunction, and this was accompanied by macrophage infiltration. Depletion of macrophages with liposomal clodrolip reduced the cardiac inflammatory response and improved cardiac function. Thus, in this model of lipotoxic cardiac injury, early induction of inflammation and macrophage recruitment contribute to adverse cardiac remodeling. These findings have implications for our understanding of heart failure in the setting of obesity and diabetes. heart failure; diabetes; inflammation OBESITY AND DIABETES ARE SIGNIFICANT risk factors for the development of heart failure (11). In many diabetic patients, this can occur in the absence of underlying coronary artery disease or hypertension, a phenomenon known as diabetic cardiomyopathy (1). The pathogenesis of diabetic cardiomyopathy is complex; however, myocardial lipid overload is a pathologic feature of this condition in humans and in animal models (6,7,12,25). The observation that cardiac myocyte lipid overload causes cardiomyopathy in genetic mouse models, without systemic abnormalities of insulin or glucose metabolism, supports the notion that excess lipids can be cardiotoxic (4,5,7,32). Membrane lipid remodeling, endoplasmic reticulum and oxidative stress, and production of toxic lipid species, such as ceramides, have been implicated as potential mechanisms of cardiac lipotoxicity (12,23).Systemic inflammation is another hallmark of obesity and diabetes and has been shown to correlate with the risk of heart failure in patients with these metabolic conditions (2). This raises the intriguing possibility that lipid-induced inflammatory responses might contribute to cardiac dysfunction in obesity and diabetes. Much of what is known regarding the link between diabetes and inflammation has come from investigations of adipose tissue. In humans and animals, obesity triggers the recruitment of macrophages to white adipose tissue, which is followed by release of inflammatory mediators and the onset of insulin resistance (26,29). When this response is interrupted in mice fed...

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Section: Discussionsupporting

confidence: 68%

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

Schilling

Machkovech

Kim

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…These results indicate that exercise-specific effects possibly involving AMPK may be involved in the improvement of muscle glucose metabolism following exercise. Moreover, our recent study found activation of inflammatory response in the heart following HFDinduced obesity, and this was associated with cardiac insulin resistance (18). In the current study, high-fat feeding increased myocardial levels of MCP-1 and IFN␥, and weight loss following a LFD switch or exercise attenuated myocardial inflammation.…”

Section: E973 Weight Loss Improves Inflammation and Insulin Sensitivitysupporting

confidence: 50%

“…A horseradish peroxidase-conjugated secondary antibody (Bio-Rad) was used for staining at room temperature for 1 h. After being washed three times, metal enhanced 3,3-diaminobenzidine-tetrahydrochloride substrate was added to tissue and incubated for 15 min. Tissue was also counterstained with hematoxylin stain for 1 min, washed with ultrapure water, and mounted with mounting medium (Thermo Fisher Scientific, Waltham, MA) (18). Local levels of cytokines (IL-6, TNF␣, IL-1␤, IFN␥, and IL-10) and chemokine [macrophage chemoattractant protein (MCP-1)] in white adipose tissue, skeletal muscle, liver, and heart, as well as serum cytokines (IL-1␣, IL-5, IL-6, and IL-10), were measured using multiplexed Luminex.…”

Section: E966 Weight Loss Improves Inflammation and Insulin Sensitivitymentioning

confidence: 99%

Short-term weight loss attenuates local tissue inflammation and improves insulin sensitivity without affecting adipose inflammation in obese mice

Jung

Lichtman

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Obesity is a major cause of insulin resistance, and weight loss is shown to improve glucose homeostasis. But the underlying mechanism and the role of inflammation remain unclear. Male C57BL/6 mice were fed a high-fat diet (HFD) for 12 wk. After HFD, weight loss was induced by changing to a low-fat diet (LFD) or exercise with continuous HFD. The weight loss effects on energy balance and insulin sensitivity were determined using metabolic cages and hyperinsulinemic euglycemic clamps in awake mice. Diet and exercise intervention for 3 wk caused a modest weight loss and improved glucose homeostasis. Weight loss dramatically reduced local inflammation in skeletal muscle, liver, and heart but not in adipose tissue. Exercise-mediated weight loss increased muscle glucose metabolism without affecting Akt phosphorylation or lipid levels. LFD-mediated weight loss reduced lipid levels and improved insulin sensitivity selectively in liver. Both weight loss interventions improved cardiac glucose metabolism. These results demonstrate that a short-term weight loss with exercise or diet intervention attenuates obesity-induced local inflammation and selectively improves insulin sensitivity in skeletal muscle and liver. Our findings suggest that local factors, not adipose tissue inflammation, are involved in the beneficial effects of weight loss on glucose homeostasis.

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“…The characteristics observed in both mouse and human models of diabetic cardiomyopathy, such as lipid accumulation, oxidative stress, mitochondrial dysfunction, and cardiomyocyte cell death, have been shown to trigger inflammation. [122][123][124][125] Cardiac inflammation and leukocyte recruitment, as observed in the setting of diabetic cardiomyopathy, seems to be mediated in part through the NLRP3 inflammasome in a similar fashion to MI. 68,[126][127][128][129][130] It has been hypothesized that the mechanism of inflammasome activation in diabetic cardiomyopathy is dependent on the combination of oxidative stress and reactive oxygen species production, as a result of mitochondrial dysfunction.…”

Section: Diabetic Cardiomyopathy and Chronic Inflammationmentioning

confidence: 99%

Chronic Heart Failure and Inflammation

Dick

Epelman

2016

Circulation Research

525

380

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As a greater proportion of patients survive their initial cardiac insult, medical systems worldwide are being faced with an ever-growing need to understand the mechanisms behind the pathogenesis of chronic heart failure (HF). There is a wealth of information about the role of inflammatory cells and pathways during acute injury and the reparative processes that are subsequently activated. We discuss the different causes that lead to chronic HF development and how the sum of initial inflammatory and reparative responses only sets the trajectory for disease progression. Unfortunately, comparatively little is known about the contribution of the immune system once the trajectory has been set, and chronic HF has been established—which clinically represents the majority of patients. It is known that chronic HF is associated with circulating inflammatory cytokines that can predict clinical outcomes, yet the causative role inflammation plays in disease progression is not well defined, and the majority of clinical trials that target aspects of inflammation in patients with chronic HF have largely been negative. This review will present what is currently known about inflammation in chronic HF in both humans and animal models as a means to highlight the gap in our knowledge base that requires further examination.

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Nutrient Stress Activates Inflammation and Reduces Glucose Metabolism by Suppressing AMP-Activated Protein Kinase in the Heart

Cited by 137 publications

References 47 publications

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

Short-term weight loss attenuates local tissue inflammation and improves insulin sensitivity without affecting adipose inflammation in obese mice

Chronic Heart Failure and Inflammation

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