Nutrient sensing and utilization: Getting to the heart of metabolic flexibility

Abstract

A central feature of obesity-related cardiometabolic diseases is the impaired ability to transition between fatty acid and glucose metabolism. This impairment, referred to as “metabolic inflexibility”, occurs in a number of tissues, including the heart. Although the heart normally prefers to metabolize fatty acids over glucose, the inability to upregulate glucose metabolism under energetically demanding conditions contributes to a pathological state involving energy imbalance, impaired contractility, and post-translational protein modifications. This review discusses pathophysiologic processes that contribute to cardiac metabolic inflexibility and speculates on the potential physiologic origins that lead to the current state of cardiometabolic disease in an obesogenic environment.

Restoring mitochondrial calcium uniporter expression in diabetic mouse heart improves mitochondrial calcium handling and cardiac function

“…The heart is able to metabolize exogenous substrates such as glucose and free fatty acids (FA) to produce ATP, although FA are preferred (60 -70%) (8,9). However, the diabetic heart is energetically almost completely dependent on mitochondrial FA oxidation as a consequence of elevated levels of circulating FA and decreased intracellular glucose availability (10,11). Maintaining dynamic glucose utilization in the presence of FA is essential for optimal cardiac function for the following reasons.…”

“…3) FA are known to have an "oxygen-wasting" effect when compared with carbohydrates, which results in a higher ratio between myocardial oxygen consumption and cardiac work. 4) Glucose utilization is necessary to supply ATP during increased cardiac output following ␤-adrenergic stimulation (10). Glucose and FA oxidation have a reciprocal relationship, described in a process known as the glucose/FA cycle (15).…”

“…In addition to Ca 2ϩ , PDC is regulated by various isoforms of pyruvate dehydrogenase kinase (PDK1, -2, -3, and -4) and phosphatase (PDP1 and -2), with phosphorylation inhibiting enzyme activity. Furthermore, products of FA oxidation (NADH and acetyl-CoA) activate PDKs resulting in PDC phosphorylation and inhibition (10).…”

Emerging role of metabolic signaling in synovial joint remodeling and osteoarthritis

“…Over‐nutrition and insufficient physical activity contribute to a state of metabolic dysregulation characterized by a breakdown of hormonal and metabolite sensing feedback pathways that regulate the delivery and utilization of nutrients (e.g., glucose and lipids) throughout the body. The resulting metabolic inflexibility occurs both systemically and at the cellular level and is considered a key driving force of numerous metabolic pathologies, including type 2 diabetes and cardiovascular disease . The effect of metabolic inflexibility on synovial joint function and OA is poorly understood.…”

The alpha-1A adrenergic receptor agonist A61603 reduces cardiac polyunsaturated fatty acid and endocannabinoid metabolites associated with inflammation in vivo

“…Non-selective α1-AR activation in the heart increases glucose metabolism 6,7 and decreases fatty acid oxidation. 8 This metabolic substrate switch from fatty acid to glucose is a critical component of the heart’s adaptation to stress 9,10 . Despite the central role of catecholamines in cardiac biology, very little is known about their global metabolic effects in the heart.…”