Original articleFunctional brown adipose tissue limits cardiomyocyte injury and adverse remodeling in catecholamine-induced 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.
References (54)
- et al.
Acute changes in circulating natriuretic peptide levels in relation to myocardial ischemia
J Am Coll Cardiol
(2004) - et al.
Relationship of systolic dysfunction to area at risk and infarction size after ischemia–reperfusion in mice
J Am Soc Echocardiogr
(2004) - et al.
Biomarker panel of cardiac and skeletal muscle troponins, fatty acid binding protein 3 and myosin light chain 3 for the accurate diagnosis of cardiotoxicity and musculoskeletal toxicity in rats
Toxicology
(2012) - et al.
The uncoupling protein UCP: a membraneous mitochondrial ion carrier exclusively expressed in brown adipose tissue
Int J Biochem
(1991) - et al.
Impaired cytosolic NADH shuttling and elevated UCP3 contribute to inefficient citric acid cycle flux support of postischemic cardiac work in diabetic hearts
J Mol Cell Cardiol
(2015) - et al.
Influence of sex on ventricular remodeling after myocardial infarction in mice
J Am Soc Echocardiogr
(2003) - et al.
Gender differences of echocardiographic and gene expression patterns in human pressure overload left ventricular hypertrophy
J Mol Cell Cardiol
(2009) - et al.
Thermogenic activation induces FGF21 expression and release in brown adipose tissue
J Biol Chem
(2011) - et al.
Influence of the diabetic state on isoproterenol-induced cardiac necrosis
J Mol Cell Cardiol
(1985) - et al.
Heart disease and stroke statistics—2015 update. A report from the American Heart Association
Circulation
(2014)
Adrenergic signaling in heart failure: a balance of toxic and protective effects
Pflugers Arch
Changes in autonomic nervous system activity: spontaneous versus balloon-induced myocardial ischaemia
Eur Heart J
Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes
J Clin Invest
A heart-adipose tissue connection in the regulation of energy metabolism
Nat Rev Endocrinol
Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat
Nat Med
Cold-activated brown adipose tissue in healthy men
N Engl J Med
High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity
Diabetes
Brown adipose tissue: function and physiological significance
Physiol Rev
Cellular bioenergetics as a target for obesity therapy
Nat Rev Drug Discov
Brown adipose tissue: recent insights into development, metabolic function and therapeutic potential
Adipocytes
Thermogenic mechanisms in brown fat
Physiol Rev
Adaptive thermogenesis and thermal conductance in wild-type and UCP1-KO mice
Am J Physiol Regul Integr Comp Physiol
Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese
Nature
In vivo noninvasive characterization of brown adipose tissue blood flow by contrast ultrasound in mice
Circ Cardiovasc Imaging
Brown adipose tissue activity controls triglyceride clearance
Nat Med
Brown adipose tissue regulates glucose homeostasis and insulin sensitivity
J Clin Invest
Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans
Diabetes
Cited by (56)
Inosine: novel activator of brown adipose tissue and energy homeostasis
2024, Trends in Cell BiologyImplantation of CPT1AM-expressing adipocytes reduces obesity and glucose intolerance in mice
2023, Metabolic EngineeringManipulation of beta-adrenergic receptor in pressure-overloaded murine hearts mimics adverse and reverse cardiac remodeling
2020, Biochemical and Biophysical Research CommunicationsAdenosine A<inf>2A</inf> receptor activation prevents DOCA-salt induced hypertensive cardiac remodeling via iBAT
2020, Biochemical and Biophysical Research CommunicationsCitation Excerpt :In the last decade, data generated in both rodents and humans reveal the therapeutic potential of BAT in cardiovascular disease [13]. BAT transplantation improved cardiomyocyte injury in mice [16]. In previous study, we detected that DOCA-salt treatment induced a significant increase of A2AR in BAT, but an unconspicuous change in heart [17].