Control of Fatty Acid Oxidation by the Sympathetic Nervous System in the Diabetic Heart: Implications for Both Heart Failure and Cancer

Abstract

Diabetic cardiomyopathy and cancer are both diseases which can be understood from an evolutionary perspective as a maladaptive response of the tissue or organ to a change in its local environment. Diabetic cardiomyopathy is an example of a stressor, diabetes, producing a shift in the phenotype from one which is adaptive to one which is maladaptive, thereby impairing function. Cancer represents the maladaptive re-expression of an ancient pre-programmed trait which evolved hundreds of millions of years ago, before the advent of multicellularity, a trait which shares many common pathways with the maladaptive phenotype of heart failure and diabetes, many of which are in the metabolic pathways but some of which may be in the pathways of \(\beta\)-adrenergic signalling. If diabetic cardiomyopathy and cancer share in common reaction norms which have become maladaptive, restoring the norm back to a truly adaptive phenotype is the goal of therapy, and there is the opportunity for therapeutic insights gleaned from one disease to be applied to the other. Carnitine palmitoyltransferase-1 (CPT-1) provides one such opportunity. Our studies of CPT-1 in the diabetic heart provided a number of novel insights into the regulation of CPT-1 and its complex interactions with \(\beta\)-adrenergic signalling. In cancer, CPT-1 has emerged as a prognostic marker and therapeutic target in a number of cancers including breast, prostate and colon cancer. Further novel aspects of CPT-1 regulation have emerged from the cancer field. For example, it is now known that there is a splice variant of CPT-1A which translocates to the nucleus and acts as an epigenetic regulator. The signalling web we unravelled in the diabetic heart may therefore find new therapeutic value in the setting of cancer as well. The human body cannot survive without energy, and it is in the understanding of energy flow, and how that flow is disturbed, that we will glean many effective and powerful treatments in the years to come.