Original article
Functional brown adipose tissue limits cardiomyocyte injury and adverse remodeling in catecholamine-induced cardiomyopathy

https://doi.org/10.1016/j.yjmcc.2015.05.002Get rights and content

Highlights

  • Brown adipose tissue (BAT) modulates cardiovascular risk factors.

  • UCP1-deficiency exacerbates isoproterenol-induced myocardial injury.

  • BAT transplantation in UCP1−/− mice is cardioprotective.

Abstract

Brown adipose tissue (BAT) has well recognized thermogenic properties mediated by uncoupling protein 1 (UCP1); more recently, BAT has been demonstrated to modulate cardiovascular risk factors. To investigate whether BAT also affects myocardial injury and remodeling, UCP1-deficient (UCP1−/−) mice, which have dysfunctional BAT, were subjected to catecholamine-induced cardiomyopathy. At baseline, there were no differences in echocardiographic parameters, plasma cardiac troponin I (cTnI) or myocardial fibrosis between wild-type (WT) and UCP1−/− mice. Isoproterenol infusion increased cTnI and myocardial fibrosis and induced left ventricular (LV) hypertrophy in both WT and UCP1−/− mice. UCP1−/− mice also demonstrated exaggerated myocardial injury, fibrosis, and adverse remodeling, as well as decreased survival. Transplantation of WT BAT to UCP1−/− mice prevented the isoproterenol-induced cTnI increase and improved survival, whereas UCP1−/− BAT transplanted to either UCP1−/− or WT mice had no effect on cTnI release. After 3 days of isoproterenol treatment, phosphorylated AKT and ERK were lower in the LV's of UCP1−/− mice than in those of WT mice. Activation of BAT was also noted in a model of chronic ischemic cardiomyopathy, and was correlated to LV dysfunction. Deficiency in UCP1, and accompanying BAT dysfunction, increases cardiomyocyte injury and adverse LV remodeling, and decreases survival in a mouse model of catecholamine-induced cardiomyopathy. Myocardial injury and decreased survival are rescued by transplantation of functional BAT to UCP1−/− mice, suggesting a systemic cardioprotective role of functional BAT. BAT is also activated in chronic ischemic cardiomyopathy.

Introduction

Cardiomyocyte injury leading to cardiac remodeling and subsequent progression to heart failure represents a major cause of human morbidity and mortality [1]. To maintain adequate cardiac output in the face of decreased ventricular pump function, reflex pathways including the sympathetic nervous system are activated, in turn leading to increased catecholamine release from the heart and endocrine tissues. This exposure to excess catecholamines increases cardiomyocyte death and augments myocardial adverse remodeling [2].

Sympathetic nervous system activation and norepinephrine release [3], concomitant with the release of natriuretic peptides [4] occur after myocardial injury and during the development of adverse left ventricular (LV) remodeling. Interestingly, these molecules are also major contributors to the growth and stimulation of brown adipose tissue (BAT) [5], [6]. Brown adipose tissue, a relatively sparse brownish-colored adipose tissue well recognized in rodents and children, has recently been detected in adult humans [7], [8], [9]. Upon activation of BAT, the brown adipocytes consume glucose and lipids and convert the energy from free fatty acids and glucose oxidation into heat (thermogenesis) [10]. The unique metabolic and thermogenic properties of BAT have generated substantial research interest in exploring its potential therapeutic applications for obesity and type II diabetes [6], [11], [12].

The thermogenic capacity of BAT is mediated by the mitochondrial proton transporter uncoupling protein 1 (UCP1), which disperses the proton motive force generated by oxidative phosphorylation, generating heat as a by-product of this futile cycle [13]. Mice deficient in UCP1 (UCP1−/− mice) display impaired activation of BAT in response to cold and beta-adrenergic agonists, characterized by a mildly decreased thermogenic capacity [14], [15], and reduced local blood flow [16].

Recently, several lines of evidence indicated that BAT and related tissues are capable of modulating several endocrine and cardiovascular risk factors. BAT activation or transplantation normalized both glucose tolerance and insulin resistance in obese or old mice [17], [18]. Moreover, the beneficial effect on glucose metabolism was also extended to humans: in healthy volunteers Chondronikola et al. demonstrated that activated BAT increased insulin sensitivity [19]. In addition, perivascular and epicardial adipose tissue depots, which share characteristics of BAT [20], are implicated in the modulation of atherosclerosis and blood pressure [21].

Although BAT may be activated after myocardial injury and during ventricular remodeling, whether this activation has an effect on these processes is unknown. The objectives of the present study were to evaluate whether BAT was activated after myocardial injury and whether this activation was cardioprotective. To approach this question we first used a model of cardiac injury in which the activation of BAT is well recognized. The model we chose, chronic catecholamine (isoproterenol) exposure, leads to cardiac injury and cardiomyopathy [22]. Using this model, we compared the cardiac response of wild-type (WT) and UCP1−/− mice (with functional and dysfunctional BAT respectively). In a series of separate experiments, we then investigated whether BAT was also activated in a clinically translatable model of ischemic cardiomyopathy.

Section snippets

Material and methods

Additional material and methods are detailed in the Supplemental Data.

Adverse LV remodeling after catecholamine exposure is aggravated in UCP1−/− mice

At baseline, LV dimensions and fractional shortening were similar in WT and UCP1−/− mice for both genders (Fig. 2 and Table 1 for males, Table S1 for females). Isoproterenol infusion for 14 days induced LV concentric hypertrophy (increases in wall thickness, H/R, LV mass) in both WT and UCP1−/− mice (Fig. 2A-C, Tables 1, S1), detected both by echocardiography and at necropsy. However, isoproterenol induced greater hypertrophy in both male and female UCP1−/− mice than in WT mice (Fig. 2A–C,

Discussion

The present study provides the first experimental evidence that functional BAT remotely protects against cardiomyocyte injury and maladaptive remodeling in vivo. Although previous studies have suggested a potential role for BAT and BAT-secreted factors in regulating cardiovascular risk factors [6], [17] no study has addressed the ability of BAT to protect cardiomyocytes.

Our results suggest that the absence of UCP1 is associated with increased cardiomyocyte injury and cardiac remodeling in a

Funding

This work was supported by grant R21-DK092909 and a SPARK award from the Massachusetts General Hospital (both to M.S-C.) and a training grant from the French Federation of Cardiology (to L.E.)

Disclosures

None.

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