The traditional view is that cancer cells predominately produce ATP by glycolysis, rather than by oxidation of energy-providing substrates. Mitochondrial uncoupling — the continuing reduction of oxygen without ATP synthesis — has recently been shown in leukemia cells to circumvent the ability of oxygen to inhibit glycolysis, and may promote the metabolic preference for glycolysis by shifting from pyruvate oxidation to fatty acid oxidation (FAO). Here we have demonstrated that pharmacologic inhibition of FAO with etomoxir or ranolazine inhibited proliferation and sensitized human leukemia cells — cultured alone or on bone marrow stromal cells — to apoptosis induction by ABT-737, a molecule that releases proapoptotic Bcl-2 proteins such as Bak from antiapoptotic family members. Likewise, treatment with the fatty acid synthase/lipolysis inhibitor orlistat also sensitized leukemia cells to ABT-737, which supports the notion that fatty acids promote cell survival. Mechanistically, we generated evidence suggesting that FAO regulates the activity of Bak-dependent mitochondrial permeability transition. Importantly, etomoxir decreased the number of quiescent leukemia progenitor cells in approximately 50% of primary human acute myeloid leukemia samples and, when combined with either ABT-737 or cytosine arabinoside, provided substantial therapeutic benefit in a murine model of leukemia. The results support the concept of FAO inhibitors as a therapeutic strategy in hematological malignancies.

Background — Previous studies suggest that the failing heart reactivates fetal genes and reverts to a fetal pattern of energy substrate metabolism. We tested this hypothesis by examining metabolic gene expression profiles in the fetal, nonfailing, and failing human heart. Methods and Results — Human left ventricular tissue (apex) was obtained from 9 fetal, 10 nonfailing, and 10 failing adult hearts. Using quantitative reverse transcription-polymerase chain reaction, we measured transcript levels of atrial natriuretic factor, myosin heavy chain-α and -β, and 13 key regulators of energy substrate metabolism, of which 3 are considered “adult” isoforms (GLUT4, mGS, mCPT-I) and 3 are considered “fetal” isoforms (GLUT1, lGS, and lCPT-I), primarily through previous studies in rodent models. Compared with the nonfailing adult heart, steady-state mRNA levels of atrial natriuretic factor were increased in both the fetal and the failing heart. The 2 myosin heavy chain isoforms showed the highest expression level in the nonfailing heart. Transcript levels of most of the metabolic genes were higher in the nonfailing heart than the fetal heart. Adult isogenes predominated in all groups and always showed a greater induction than the fetal isogenes in the nonfailing heart compared with the fetal heart. In the failing heart, the expression of metabolic genes decreased to the same levels as in the fetal heart. Conclusions — In the human heart, metabolic genes exist as constitutive and inducible forms. The failing adult heart reverts to a fetal metabolic gene profile by downregulating adult gene transcripts rather than by upregulating fetal genes.

Diabetes mellitus (type 2 diabetes) is as much a disease of modern lifestyle as it is a disease of genetic predisposition. Worldwide, there are about 143 million patients with diabetes, almost 5 times more than estimates of 10 years ago.1,2⇓ Heart disease, often presenting as cardiomyopathy, is the leading cause of death among patients with diabetes mellitus (Figure 1).3 Like diabetes, the prevalence of heart failure also continues to rise in Western countries.4 Diabetes, in turn, is the largest comorbidity of patients with heart failure and adversely affects outcomes of cardiovascular disease.5 The trend is unmistakable; both insulin resistance and heart failure have emerged as major worldwide epidemics. It is therefore timely to take a fresh look at the effects of diabetes on the heart. Figure 1. Multiple Risk Factor Intervention Trial (MRFIT). Age-adjusted cardiovascular disease death rates (per 10 000 person-years) by presence of number of risk factors in men with and without diabetes. Reproduced with permission from Stamler et al.3 Copyright 1993 American Diabetes Association ( Diabetes Care . 1993;16:434–444). Reprinted with permission from the American Diabetes Association. The difficulties in making a causal connection between diabetes and heart failure are formidable. Some simple definitions remain elusive. For example, the distinction between the insulin-deficient (type 1) and insulin-resistant (type 2) forms of diabetes on the one hand, and the distinction between systolic and diastolic dysfunction as causes of heart failure, on the other hand, are hard to define. The known trophic and hemodynamic effects of insulin in healthy individuals,6 the well-described endothelial dysfunction, the deposition of advanced glycation end products, and an accelerated progression of atherosclerosis in patients with diabetes add further complexities to the clinical picture of heart failure in diabetes. Nonetheless, diabetes as a primary cause for heart failure …