FoxO1 breaks diabetic heart

The incidence of type 2 diabetes is increasing explosively around the world. Both hyperglycemia and insulin resistance can cause myocardial damages with coronary atherosclerosis in type 2 diabetes. In addition, some patients show cardiac functional disorder, characterized by diastolic dysfunction, without ischemia. In a large prospective study in the Framingham cohort, patients with diabetes showed a higher risk of congestive heart failure as compared with those without diabetes after adjusting for coronary artery disease. This cardiac damage found in diabetes is called ‘diabetic cardiomyopathy’. The pathology of diabetic cardiomyopathy was classically characterized by myocellular hypertrophy and myocardial interstitial fibrosis in autopsy specimens. Multiple factors (e.g. impairments of calcium homeostasis, upregulation of the renin–angiotensin system, glycation and metabolic derangements) have been implicated in the pathogenesis of diabetic cardiomyopathy. Impaired energy use and abnormal lipid metabolism have emerged as important contributors to multiple organ damage in diabetes. With regard to heart failure, several diabetic animal models have shown abnormal lipid accumulation in the myocardium. In recent years, proton magnetic resonance spectroscopy enables us to evaluate the myocardial lipid accumulation non-invasively. Several reports have shown that myocardial triacylglycerol accumulation is observed in individuals with diabetes or insulin resistance preceding heart failure. In practice, lipid droplets are observed in the myocardium of patients with diabetes or obesity. The major energy source (approximately two-thirds) of the adult heart is b-oxidation of fatty acids (FAs), with the remainder from glucose and lactate metabolism. FAs are mainly taken into cardiomyocytes through FA transporters (e.g. CD36 and FA transport protein 1 [FATP-1]), and are subsequently converted to acyl-CoA. The intracellular acyl-CoA not used for adenosine triphosphate (ATP) production (b-oxidation in mitochondria) are esterified into triacylglycerols and stocked in the cardiomyocytes. Decreased insulin signaling, based on both insulin resistance and deficiency, characteristically reduces glucose usage and enhances FA metabolism in diabetes. FA overloading and consequent activation of peroxisome proliferator-activated receptor a (PPARa)/PPARc co-activator 1 (PGC-1) accelerate the abnormal substrate usage in the diabetic heart. The imbalance between FA uptake and oxidation, increased uptake exceeding oxidation, gradually induces lipid accumulation, which can lead to various deleterious effects (e.g. mitochondrial uncoupling, reactive oxygen species production, diacylglycerol formation, endoplasmic reticulum stress and insulin resistance), so-called ‘lipotoxicity’. A recent report from the Hill’s laboratory in The Journal of Clinical Investigation provides new in vivo evidence for the important role of forkhead box protein O1 (FoxO1) in myocardial abnormal metabolism in diabetic cardiomyopathy. The FoxO family of transcription factors is expressed almost ubiquitously in mammalian cells, and plays pivotal roles in cell growth, metabolism and survival. Previous studies have shown that activation of FoxO (especially FoxO1) enhances hepatic glucose production, decreases pancreatic insulin secretion, increases white adipose tissue lipolysis and stimulates hypothalamic orexigenic signals. However, the role of FoxO in the diabetic heart has not been established yet. FoxO proteins are well established as important downstream mediators of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in insulin/insulin-like growth factor 1 (IGF-1) signaling. Akt-dependent phosphorylation negatively regulates the ability of FoxO by inducing nuclear exclusion. Meanwhile, Hill et al. have pointed out that FoxO can mediate negative feedback control in insulin signaling at the same time. In a preceding study, Ni et al. showed that FoxO activation contributes to reduced insulin sensitivity and glucose metabolism impairment in primary cardiomyocytes through modulating Akt phosphorylation. In their recent report, Battiprolu et al. further showed that FoxO-mediated feedback regulation of insulin signaling plays a pivotal role in diabetic cardiomyopathy through insulin receptor substrate 1 (IRS-1) inactivation. These findings of the FoxO-mediated vicious cycle of insulin resistance provide new insights into the pathogenesis of diabetic cardiomyopathy and other diabetic complications. Battiprolu et al. initially examined two different experimental models of type 2 diabetes, leptin receptor deficient db/db mice and high-fat diet-induced obese mice, and observed functional and morphological myocardial changes resembling diabetic cardiomyopathy in these models. As expected, they confirmed increased FoxO activity, in terms of decreased phosphorylation of FoxO proteins, increased nuclear localization and increased levels of FoxO’s target genes. Furthermore, myocardium-specific FoxO1 knock-out (KO) mice were resistant to high-fat diet-induced cardiac hypertrophy and dysfunction. Lipid accumulation, as a result of increased lipid uptake relative to utilization, is a major preceding feature of diabetic cardiomyopathy. Relative to wildtype mice, FoxO1 KO mice showed lower lipid accumulation in the myocardium under a high-fat diet by shifting their metabolic substrate usage from FA to glucose. High-fat diet-induced *Corresponding author. Shinichi Oikawa Tel.: +81 3 3822 2131 Fax: +81 3 5802 8153 E-mail address: [email protected] Received 21 August 2012; revised 26 September 2012; accepted 27 September 2012