Improved Ejection Fraction after Exercise Training in Obesity Is Accompanied by Reduced Cardiac Lipid Content

Schrauwen‐Hinderling, Vera B.; Hesselink, Matthijs K. C.; Meex, Ruth C. R.; Made, Sanne van der; Schär, Michael; Lamb, Hildo J.; Wildberger, Joachim E.; Glatz, Jan F. C.; Snoep, Gabriël; Kooi, M. Eline; Schrauwen, Patrick

doi:10.1210/jc.2009-2076

Cited by 69 publications

(59 citation statements)

References 34 publications

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“…However, no changes in PUFA content or in PPAR␣ protein and mRNA levels were observed in the heart with AAB-induced hypertrophy. In fact, various studies reported marginal changes, if any, in FA oxidation rates in ex vivo perfused hypertrophied hearts (51,58,75) and unaltered oxygen consumption and substrate uptake rates in the hypertrophied myocardium in situ (59). Moreover, in the early stages of heart failure in the human heart, there is a normal (or slightly elevated) rate of FA utilization, with a dramatic downregulation of FA oxidation in advanced or endstage heart failure (34).…”

Section: Discussionmentioning

confidence: 99%

Expression of lipogenic genes is upregulated in the heart with exercise training-induced but not pressure overload-induced left ventricular hypertrophy

Dobrzyń

Pyrkowska

Duda

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Dobrzyn P, Pyrkowska A, Duda MK, Bednarski T, Maczewski M, Langfort J, Dobrzyn A. Expression of lipogenic genes is upregulated in the heart with exercise training-induced but not pressure overload-induced left ventricular hypertrophy. Am J Physiol Endocrinol Metab 304: E1348 -E1358, 2013. First published April 30, 2013 doi:10.1152/ajpendo.00603.2012.-Cardiac hypertrophy is accompanied by molecular remodeling that affects different cellular pathways, including fatty acid (FA) utilization. In the present study, we show that cardiac lipid metabolism is differentially regulated in response to physiological (endurance training) and pathological [abdominal aortic banding (AAB)] hypertrophic stimuli. Physiological hypertrophy was accompanied by an increased expression of lipogenic genes and the activation of sterol regulatory element-binding protein-1c and Akt signaling. Additionally, FA oxidation pathways regulated by AMPactivated protein kinase (AMPK) and peroxisome proliferator activated receptor-␣ (PPAR␣) were induced in trained hearts. Cardiac lipid content was not changed by physiological stimulation, underlining balanced lipid utilization in the trained heart. Moreover, pathological hypertrophy induced the AMPK-regulated oxidative pathway, whereas PPAR␣ and expression of its downstream targets, i.e., acylCoA oxidase and carnitine palmitoyltransferase I, were not affected by AAB. In contrast, pathological hypertrophy leads to cardiac triglyceride (TG) and diacylglycerol (DAG) accumulation, although the expression of lipogenic genes and the levels of FA transport proteins (CD36 and FATP) were not changed or reduced compared with the sham group. A possible explanation for this phenomenon is a decrease in lipolysis, as evidenced by the increased content of adipose triglyceride lipase inhibitor G0S2, the increased phosphorylation of hormone-sensitive lipase at Ser 565 , and the decreased protein levels of DAG lipase that attenuate TG and DAG contents. The increased TG and DAG accumulation observed in AAB-induced hypertrophy might have lipotoxic effects, thereby predisposing to cardiomyopathy and heart failure in the future. lipogenesis; endurance training; sterol regulatory element-binding protein-1; adipose triglyceride lipase; hormone-sensitive lipase CARDIAC HYPERTROPHY IS ASSOCIATED with extensive remodeling, which in due course will affect cardiac function and ultimately contribute to the transition from compensatory hypertrophy to cardiac failure (70). Molecular remodeling in the heart caused by hypertrophy differs between physiological and pathological stimuli. The physiological cardiac hypertrophy caused by endurance training shows enhancement of cardiac function at rest and during exercise and is not a risk factor for heart failure (19, 29). The adaptations include increases in cardiac mass and dimension, maximum oxygen consumption, and coronary blood flow (35). Additionally, exercise results in a balanced growth of cardiomyocytes with a normal myofibril to mitochondrial ratio (52, 71). Conversely, the hype...

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Section: Discussionmentioning

confidence: 99%

Expression of lipogenic genes is upregulated in the heart with exercise training-induced but not pressure overload-induced left ventricular hypertrophy

Dobrzyń

Pyrkowska

Duda

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…Moreover, participants were advised to increase physical activity, which is known to influence cardiac function. 24 Another study recently described negative effects of an 8-week very-low-carbohydrate diet on systemic arterial stiffness. 9 However, our study suggests that modest changes in dietary carbohydrate in the setting of a hypocaloric diet do not translate into a differential blood pressure and LV response.…”

Section: Discussionmentioning

confidence: 99%

Left Ventricular Mass and Function With Reduced-Fat or Reduced-Carbohydrate Hypocaloric Diets in Overweight and Obese Subjects

et al. 2012

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Abstract-In animals, carbohydrate and fat composition during dietary interventions influenced cardiac metabolism, structure, and function. Because reduced-carbohydrate and reduced-fat hypocaloric diets are commonly used in the treatment of obesity, we investigated whether these interventions differentially affect left ventricular mass, cardiac function, and blood pressure. We randomized 170 overweight and obese subjects (body mass index, 32.9Ϯ4.4; range, 26.5-45.4 kg/m 2 ) to 6-month hypocaloric diets with either reduced carbohydrate intake or reduced fat intake. We obtained cardiac MRI and ambulatory blood pressure recordings over 24 hours before and after 6 months. Ninety subjects completing the intervention period had a full cardiac MRI data set. Subjects lost 7.3Ϯ4.0 kg (7.9Ϯ3.8%) with reduced-carbohydrate diet and 6.2Ϯ4.2 kg (6.7Ϯ4.4%) with reduced-fat diet (PϽ0.001 within each group; Pϭnot significant between interventions). Caloric restriction led to similar significant decreases in left ventricular mass with low-carbohydrate diets (5.4Ϯ5.4 g) or low-fat diets (5.2Ϯ4.8 g; PϽ0.001 within each group; Pϭnot significant between interventions). Systolic and diastolic left ventricular function did not change with either diet. The 24-hour systolic blood pressure decreased similarly with both interventions. Body weight change (␤ϭ0.33; Pϭ0.02) and percentage of ingested n-3 polyunsaturated fatty acids (␤ϭϪ0.27; Pϭ0.03) predicted changes in left ventricular mass. In conclusion, weight loss induced by reduced-fat diets or reduced-carbohydrate diets similarly improved left ventricular mass in overweight and obese subjects over a 6-month period. However, n-3 polyunsaturated fatty acid ingestion may have an independent beneficial effect on left ventricular mass. O besity is associated with increased left ventricular (LV) mass, 1,2 a potential contributor to heart failure, cardiovascular events, and mortality. 3,4 Energy-restricted diets decrease LV mass in conjunction with body weight loss. [5][6][7] In addition to caloric intake, dietary macronutrient composition appears to influence cardiac metabolism, structure, and function, 8 as well as vascular compliance. 9 In animals, high-fat feeding attenuated cardiac hypertrophy and remodeling, 10,11 whereas high-carbohydrate feeding accelerated the process. 12 Excessive simple sugars and saturated fatty acid ingestion worsened cardiac structure and function. 13,14 In contrast, n-3 polyunsaturated fatty acid supplementation attenuated cardiac hypertrophy and fibrosis in rats. 15,16 Therefore, in addition to caloric intake, macronutrient content and composition could affect LV mass and ventricular function during energy restricted diets. Carbohydrate-restricted and fat-restricted diets are commonly prescribed. 17 Whether macronutrient content, without changing physical activity, affects hypocaloric diet-induced changes in LV mass and function has not been investigated in humans. The issue is important given the independent prognostic role of LV mass on cardiovascular events. ...

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“…Lipid accumulation in cardiac muscle and liver in patient 2, measured with 1 H-magnetic resonance spectroscopy, 6 also seemed to decrease over the 28-week intervention period ( Figure D). Because of the presence of an implantable cardioverter defibrillator, these magnetic resonance spectroscopy measurements could not be performed in patient 1.…”

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confidence: 89%

Effects of Bezafibrate Treatment in a Patient and a Carrier With Mutations in the PNPLA2 Gene, Causing Neutral Lipid Storage Disease With Myopathy

Weijer

Havekes

Bilet

et al. 2013

Circulation Research

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Despite a marked decrease in tissue lipid accumulation and an improvement in oxidative metabolism, no major changes were (yet) found in clinical parameters. Handgrip strength was low in NLSDM patients and did not change on bezafibrate treatment in either subject (data not presented). However, both patients did show an improvement in a leg extension test, a measure of leg muscle strength (Figure E). Although this did seem to consistently improve, the values for both patients remained low compared with age, body mass index, and sex-matched controls ( Figure E, dotted lines).Cardiac function at baseline was impaired in patient 1 and normal in patient 2 (Table). Patient 1, who is known to have frequent arrhythmias before treatment, only had 1 episode with a nonsustained ventricular tachycardia during the intervention period, as registered by the implantable cardioverter defibrillator. Still, neither the ultrasound nor the ECG could detect marked changes in cardiac function in both patients after 28 weeks of treatment (Table).Consistent with the findings in mice lacking ATGL,4 bezafibrate treatment resulted in a marked lowering of cardiac and muscle fat content and an increase in fat oxidative capacity. In healthy subjects, fibrates were shown not to affect ectopic lipid content, 7,8 suggesting that fibrates may reduce the extreme lipid accumulation that characterizes NLSDM by upregulating and normalizing oxidative metabolism. Haemmerle et al 4 showed recently that the lack of ATGL prevents liberation of fatty acids (or fatty acid intermediates) for PPAR signaling from the lipid droplet, hence resulting in an impaired fat oxidative capacity. As a consequence, oxidation of circulatory fatty acids taken up in muscle, liver, and heart is compromised, and these fatty acids will be more readily directed to storage. By providing synthetic PPAR agonists to ATGL-deficient mice, fat oxidative capacity could be increased, ectopic fat storage was blunted, and cardiac dysfunction was completely restored. The results presented here indicate that, in humans with compromised ATGL activity, PPAR treatment results in similar improvements in fat oxidation and tissue lipid storage, as in ATGL-deficient mice. However, unlike ATGL-deficient mice, the improvements in lipid accumulation and oxidative metabolism observed in our patients did not (yet) result in pronounced clinical changes. Leg muscle strength did improve but was not paralleled by a decrease/normalization of creatine kinase levels or a change in handgrip strength. Furthermore, cardiac function seemed unaltered. Whether the lack of clinical changes are attributed to the relative short duration of the treatment or the fact that treatment could only be started in patients who are in a later stage of the disease (note that ATGLdeficient mice were treated from early age onward) cannot be deduced from the present study and needs further investigation.In conclusion, our results suggest that, similar to mice lacking ATGL, NLSDM patients may also benefit from bezafibrate treatment wit...

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Improved Ejection Fraction after Exercise Training in Obesity Is Accompanied by Reduced Cardiac Lipid Content

Cited by 69 publications

References 34 publications

Expression of lipogenic genes is upregulated in the heart with exercise training-induced but not pressure overload-induced left ventricular hypertrophy

Expression of lipogenic genes is upregulated in the heart with exercise training-induced but not pressure overload-induced left ventricular hypertrophy

Left Ventricular Mass and Function With Reduced-Fat or Reduced-Carbohydrate Hypocaloric Diets in Overweight and Obese Subjects

Effects of Bezafibrate Treatment in a Patient and a Carrier With Mutations in the PNPLA2 Gene, Causing Neutral Lipid Storage Disease With Myopathy

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