Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease

Abstract

The ability to efficiently adapt metabolism by substrate sensing, trafficking, storage, and utilization, dependent on availability and requirement, is known as metabolic flexibility. In this review, we discuss the breadth and depth of metabolic flexibility and its impact on health and disease. Metabolic flexibility is essential to maintain energy homeostasis in times of either caloric excess or caloric restriction, and in times of either low or high energy demand, such as during exercise. The liver, adipose tissue, and muscle govern systemic metabolic flexibility and manage nutrient sensing, uptake, transport, storage, and expenditure by communication via endocrine cues. At a molecular level, metabolic flexibility relies on the configuration of metabolic pathways, which are regulated by key metabolic enzymes and transcription factors, many of which interact closely with the mitochondria. Disrupted metabolic flexibility, or metabolic inflexibility, however, is associated with many pathological conditions including metabolic syndrome, type 2 diabetes mellitus, and cancer. Multiple factors such as dietary composition and feeding frequency, exercise training, and use of pharmacological compounds, influence metabolic flexibility and will be discussed here. Last, we outline important advances in metabolic flexibility research and discuss medical horizons and translational aspects.

Figure 1.

Systemic response to insulin. Upon glucose sensing, the pancreas increases the insulin/glucagon ratio. The rise in insulin stimulates many metabolic processes in the key metabolic organs: the liver, heart, brain, white adipose tissue, and skeletal muscle. Collectively, these metabolic processes switch metabolism from a preference of fatty acid oxidation to glucose uptake and oxidation.

Figure 2.

Mechanism of reciprocal inhibition of glucose and fatty acid oxidation. When glucose uptake and consumption increases, fatty acid oxidation is suppressed by malonyl-CoA’s allosteric inhibition of CPT-1, and increased pyruvate from glycolysis inhibits PDK, which stimulates glucose oxidation (yellow lines). CPT-1 inhibition increases the concentration of LCFA-CoAs, which then are used for triglyceride synthesis and stored (pink arrow). Vice versa, when fatty acid oxidation is high, glucose uptake, glycolysis, and pyruvate oxidation are decreased (red lines) because rising levels of acetyl-CoA and NADH impede PDH activity. Additionally, increased citrate levels inhibit GLUT4 and PFK-1. PFK-1 inhibition results in increased glucose-6-phosphate concentrations that inhibit HK. A decrease in pyruvate oxidation enables pyruvate to be used as either a gluconeogenic precursor or, in energetically demanding tissues, a substrate for PC, which produces oxaloacetate that is used as anaplerotic substrate (purple arrows). During caloric restriction, the rise in AMP/ATP activates AMPK, which inhibits ACC, stimulating fatty acid uptake by the mitochondria via CPT-1. ACL, ATP-citrate lyase; CACT, carnitine acylcarnitine translocase; CTP, citrate transport protein; CYTO, cytosol; FAS, fatty acid synthase; LCFA, long-chain fatty acid; MITO, mitochondria; MPC, mitochondrial pyruvate carrier; PC, pyruvate carboxylase. Green arrows indicate stimulatory reactions.

Figure 3.

Energy- and nutrient-sensing transcription factor–regulated pathways. During caloric excess and obesity, anabolic processes are stimulated via the insulin/IGF-1 and TOR pathways. Additionally, caloric excess suppresses catabolic processes via a decrease in the AMP/ATP ratio, leading to reduced activation of AMPK and downstream activity of PGC1α, sirtuins, and FOXO. Simultaneously, decreased NAD⁺ levels reduce sirtuin activity, inhibiting PPARγ activity and increasing HIF1α activity. Alternatively, during caloric restriction and fasting, catabolic processes are stimulated by the increase in AMP/ATP ratio and consequential activation of AMPK. AMPK also reduces anabolic processes through TOR inhibition. AKT, v-Akt murine thymoma viral oncogene homolog.

Figure 4.

Circulating factors not produced by specific endocrine glands are involved in metabolic flexibility. Examples include those that are produced by the intestine, adipocytes (adipokines), muscle (myokines), and liver (hepatokines) and released into the bloodstream. These endocrine factors act on metabolism through paracrine and endocrine signaling, and distal organs include skeletal muscle, adipose tissue, liver, pancreas, heart, and brain. Much is currently unknown about these endocrine factors. See “Other endocrine factors affecting metabolic flexibility” for a brief description of some examples and their role in regulation of metabolic flexibility.

Figure 5.

A selection of pharmaceutical compounds that target major players or key nodes in metabolic circuits, such as AMPK and sirtuins. Via altered transcription factors, these compounds act on mitochondrial function and positively affect metabolic flexibility. See “Pharmaceuticals” for a brief description of the examples mentioned here. Ac, acetyl; NA, nicotinic acid; NMN, nicotinamide mononucleotide; NR, nicotinamide riboside; P, phosphate; PARPi, poly (ADP-ribose) polymerase inhibitor; TF, transcription factor.