Lowering Body Weight in Obese Mice With Diastolic Heart Failure Improves Cardiac Insulin Sensitivity and Function: Implications for the Obesity Paradox

Abstract

Recent studies suggest improved outcomes and survival in obese heart failure patients (i.e., the obesity paradox), although obesity and heart failure unfavorably alter cardiac function and metabolism. We investigated the effects of weight loss on cardiac function and metabolism in obese heart failure mice. Obesity and heart failure were induced by feeding mice a high-fat (HF) diet (60% kcal from fat) for 4 weeks, following which an abdominal aortic constriction (AAC) was produced. Four weeks post-AAC, mice were switched to a low-fat (LF) diet (12% kcal from fat; HF AAC LF) or maintained on an HF (HF AAC HF) for a further 10 weeks. After 18 weeks, HF AAC LF mice weighed less than HF AAC HF mice. Diastolic function was improved in HF AAC LF mice, while cardiac hypertrophy was decreased and accompanied by decreased SIRT1 expression, increased FOXO1 acetylation, and increased atrogin-1 expression compared with HF AAC HF mice. Insulin-stimulated glucose oxidation was increased in hearts from HF AAC LF mice, compared with HF AAC HF mice. Thus lowering body weight by switching to LF diet in obese mice with heart failure is associated with decreased cardiac hypertrophy and improvements in both cardiac insulin sensitivity and diastolic function, suggesting that weight loss does not negatively impact heart function in the setting of obesity.Obesity is a recognized risk factor for heart failure (1,2). Obesity is associated with left ventricular (LV) hypertrophy and dilatation, features that are known to precede the development of overt heart failure (3,4). For every increase in BMI by 1, the risk of heart failure increases by 5% in men and 7% in women (5). In a prospective study of 21,094 men, every 1 kg/m 2 increase in BMI was associated with an 11% increase in heart failure risk (6). Compared with lean subjects, overweight and obese individuals have a 49 and 180% increased risk of developing heart failure, respectively.Despite the fact that obesity increases the incidence of heart failure, several studies suggest that there is a protective effect of being obese in patients with heart failure, known as the obesity paradox (7-13). A low BMI in heart failure patients is associated with decreased survival. This paradoxical association is found in patients with preserved and reduced ejection fraction, with a nadir of mortality in one individual patient meta-analysis (n = 23,967) of 34.0-34.9 kg/m 2 (8). A number of experimental studies have also shown favorable effects of high-fat (HF) diet on cardiac function and survival in different disease states such as myocardial infarction, heart failure, and hypertension (see ref. 14 for review).The obesity paradox would suggest that intentional weight loss in obese heart failure patients could have a detrimental effect on cardiac function. However, weight loss can decrease cardiac hypertrophy and improve LV systolic and diastolic filling in obese heart failure patients (15,16).

Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

“…Based on the unaltered expression of SIRT3 but increased expression of GCN5L1, we propose that GCN5L1 may be a key modulator of protein acetylation in the heart during maturation. This notion is supported by our recent studies in which increased GCN5L1 contributes to an increase in acetylation of LCAD in obese mice with heart failure, which, in turn, enhances fatty acid oxidation rates (52). As a proof of the concept, we further demonstrated that the inhibition of GCN5L1 in H9c2 cells via siRNA attenuated the levels of acetylated LCAD and ␤-HAD, as well as total protein acetylation, in parallel with suppressed activities of both enzymes.…”

“…For instance, hyperacetylated LCAD has been suggested to reduce enzymatic activity in the liver and the heart from SIRT3-deficient mice (9,19), and LCAD Lys 42 , Lys 318 , and Lys 322 were detected as a critical active site for the regulation of LCAD enzymatic activity by SIRT3 (2, 4). However, we have demonstrated that increased acetylation of LCAD and ␤-HAD is associated with an increase in fatty acid ␤-oxidation rates in hearts from mice with SIRT3 deficiency, as well as in mice with a high-fat diet-induced obesity, and in mice with heart failure (1,52). Because previous studies were carried out in males and similarly aged animals, gender or age effects are unlikely to occur in those experimental settings (1,10,52).…”

“…However, we have demonstrated that increased acetylation of LCAD and ␤-HAD is associated with an increase in fatty acid ␤-oxidation rates in hearts from mice with SIRT3 deficiency, as well as in mice with a high-fat diet-induced obesity, and in mice with heart failure (1,52). Because previous studies were carried out in males and similarly aged animals, gender or age effects are unlikely to occur in those experimental settings (1,10,52). With regard to assay condition in LCAD activity, other groups applied the anaerobic electron transferring flavoprotein fluorescence reduction assay (2, 9, 10), whereas we performed a sensitive aerobic assay in which electron transferring flavoprotein is replaced by the ferricenium ion, a readily obtainable organometallic oxidant.…”

Cardiac mTOR rescues the detrimental effects of diet-induced obesity in the heart after ischemia-reperfusion

“…At 6 wk of age, mice were placed on pellets of either a normal chow diet (NCD) consisting of 24.7% energy from protein, 63.4% carbohydrate, and 4.6% fat (PicoLab rodent diet 5053, 339.5 kcal/100 g, TestDiet, Richmond, IN) or a HFD consisting of 14.9% energy from protein, 26.0% carbohydrate, and 59.0% fat (S3282, 549.0 kcal/100 g, Bio-Serv, Frenchtown, NJ) for 12 wk. Previous studies have demonstrated that a 60% fat diet induces insulin resistance as well as obesity and creates a reasonable model for studying pathophysiological features of the cardiovascular system in diet-induced obesity (8,25,41). To evaluate HFD-induced glucose intolerance and insulin resistance, we performed glucose tolerance tests (GTTs) and insulin tolerance tests (ITTs) after 12 wk of NCD or HFD feeding as previously demonstrated (4,36).…”

Weight loss enhances cardiac energy metabolism and function in heart failure associated with obesity

“…Interestingly, caloric restriction‐induced cardioprotection has been suggested to be mediated through an age‐independent manner . In a model of high fat (HF) diet‐induced obesity and diastolic dysfunction, we recently reported that lowering body weight by switching mice to a low fat (LF) diet improves cardiac insulin sensitivity and function . However, the impact of weight loss by CR on cardiac hypertrophy, energy metabolism and function in heart failure associated with obesity is not known.…”