Heart smart insulin-like growth factor 1.

The prevalence of obesity, metabolic syndrome, and type 2 diabetes mellitus, and the associated cardiac pathologies are rising to alarming levels. Conventional medical therapies for the prevention and treatment of cardiomyopathy are less effective in patients with these metabolic disorders, and this is attributed, at least in part, to a limited understanding of the cellular and genetic mechanisms responsible for the pathology in the heart. The cause(s) underlying the development of obesity and metabolic syndrome have been attributed to several factors including, but not limited to, consumption of a high-fat diet and are often associated with myocardial contractile and metabolic dysfunction.1 The detrimental effects of high-fat diets on the heart are likely to be multifactorial and include lipotoxicity, abnormal fatty acid metabolism, endothelial dysfunction, impaired calcium handling, mitochondrial dysfunction, and disruption of the insulin signaling pathway. Recent evidence also suggests that a high-fat diet induces epigenetic defects in the heart,2 which could potentially result in an increased risk of cardiac pathologies in offspring. A better understanding of the mechanisms underlying the increased propensity for high-fat diets to induce cardiac dysfunction is necessary to develop treatment strategies. Insulin-like growth factor-1 (IGF-1) plays a role in regulating cell proliferation, differentiation, survival, and metabolism and is produced in many tissues, including the heart. Reduced IGF-1 levels are associated with obesity, cardiovascular disease, atherosclerosis, and diabetes mellitus, whereas elevated IGF-1 has been associated with longevity in humans.3 A potential connection between IGF-1 and the effects of high-fat diets has only recently been reported in a study using the IGF-1 deficient Lewis dwarf rat and showed that endothelial dysfunction in this model is exacerbated by consumption of a high-fat diet.4 In the present issue of Hypertension, Zhang et al5 demonstrate a beneficial role for cardiac overexpression of IGF-1 in attenuating or preventing the contractile and metabolic dysfunction induced by high-fat feeding. These findings are consistent with previous work by the same group using a type 1 diabetic mouse model,6 showing that the IGF-1 deficiency observed in conditions such as obesity and diabetes mellitus contributes to abnormal cell signaling and metabolism in heart and that enhancing IGF-1 levels can prevent and perhaps reverse these pathologies (as seen in the high-fat diet group, Figures S4 and S5 in Reference 5). Although there are distinct IGF-1 receptors, there is considerable cross-talk between insulin and IGF-1 actions, and, similar to the insulin receptor, the IGF-1 receptor belongs to a tyrosine kinase receptor superfamily, which undergoes autophosphorylation on ligand binding. Downstream of these receptors are 2 major pathways, mitogen-activated protein kinase/extracellularly regulated kinase and phosphoinositol 3-kinase, which play major roles in cell survival, cellular metabolism, and transcriptional regulation of cell growth. Therefore, it is not entirely surprising that restoration of IGF-1 levels in hearts of high-fat fed animals also prevented abnormalities in cardiac function and metabolism. It is interesting to note that, whereas high-fat diet–induced cardiac dysfunction was alleviated by IGF-1 overexpression, cardiomyocyte hypertrophy was not altered. In cardiac tissue, IGF-1 is associated with physiological hypertrophy through the IGF-1 receptor–phosphoinositol 3-kinase (p110 )–Akt pathway.7,8 Perhaps the hypertrophy in the IGF-1 groups, indicated by cell size in Figure 4 of Reference 5 may represent a physiological hypertrophy that would be consistent with the contractile data. Further assessment of markers for pathophysiological hypertrophy is necessary to make such distinctions. The results of the IGF-1 cardiac-specific transgene used in these investigations are somewhat complicated by the observations that plasma levels of IGF-1 are elevated, as well as cardiac IGF-1 levels (Table 1 in Reference 5). However, similar cardioprotection from type 1 diabetes mellitus has been shown in mice overexpressing IGF-1 receptors,9 thereby supporting the notion that cardiac-specific IGF-1 signaling plays a role, rather than an effect solely due to increased systemic IGF-1 levels. It should be emphasized that overexpression of cardiac IGF-1 did not alter peripheral glucose metabolism or inflammatory markers, confirming that the beneficial effects were unlikely to be the result of normalized systemic metabolism. Collectively, these observations are intriguing in that upregulation of cardiac IGF-1 may be sufficient to block the detrimental cardiac effects of a high-fat diet and have potentially profound implications for our understanding of metabolic dysregulation in the heart. The authors present a scheme to highlight their findings (Figure S6 in Reference 5) and propose that high-fat feeding reduces cardiomyocyte IGF-1 signaling, which, in turn, leads to mitochondrial dysfunction, intracellular Ca dysregulation, The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Program in Nutrition and Exercise Physiology (S.A.M.), College of Pharmacy, Washington State University, Spokane, WA; Biomedical Sciences (A.J.D.), College of Osteopathic Medicine, University of New England, Biddeford, ME. Correspondence to Amy J. Davidoff, Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, 11 Hills Beach Rd, Biddeford, ME 04005. E-mail [email protected] (Hypertension. 2012;59:550-551.) © 2012 American Heart Association, Inc.