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

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(definition), 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.(Endocrine Reviews 39: 489 -517, 2018) H uman physiology evolved during times of dramatic fluctuations in energy supply and demand.Coping with these changes has entrained the human body with the ability to manage energy metabolism for optimal substrate storage and use during states of either food surplus or famine, and periods of either rest or increased energy demand.The ability to efficiently adapt metabolism depending on demand or supply is known as metabolic flexibility ().In general, the human body can aptly use moderate amounts of carbohydrates, fatty acids, and amino acids.The modern era, however, is characterized by unprecedented levels of food supply ().This near continuous intake of calorically dense processed foods, combined with physical inactivity, reduces a predilection for, and directly impedes, metabolic flexibility ().This is caused by substrate competition and metabolic insensitivity, characterized by distorted nutrient sensing, blunted substrate switching, and impaired energy homeostasis ().Importantly, this metabolic inflexibility may underlie the epidemic changes in metabolic disease that affect all demographic groups and burden health-care systems (, ). Defining Metabolic FlexibilityMaintaining energy homeostasis requires substrate sensing, trafficking, storage, and utilization, dependent on substrate availability (push concept) and energy requirement (pull concept).Metabolic plasticity (or adaptability) was recognized in  by Saltin and Gollnick () when they reviewed the metabolic adaptations of skeletal muscle to exercise (see "Physical exercise").The term metabolic flexibility was coined by Kelley et al. () in  when they studied fuel selection in skeletal muscle in lean and obese individuals after an overnight fast.Specifically, they discovered that skeletal muscle of lean individuals showed a remarkable ability to adapt fuel preference to fasting and insulin infusions and were therefore designated as