Energy metabolism is the general process by which all living cells acquire and use the energy needed to stay alive, to grow, and to reproduce. By coupling oxidation of nutrients with high-energy compounds synthesis, particularly ATP which works as the main chemical energy carrier in all cells, cells become able to capture the released energy while breaking the chemical bonds of nutrient molecules.

The human body uses three types of molecules to yield the necessary energy to drive ATP synthesis: fats, proteins, and carbohydrates. Lipids are broken down into fatty acids, proteins into amino acids, and carbohydrates into glucose.

There are two main mechanisms of ATP synthesis:

oxidative phosphorylation/ATP synthesis, the process by which ATP is synthesized from ADP and inorganic phosphate (Pi) that takes place in mitochondrion

– substrate-level phosphorylation, in which ATP is synthesized through the transfer of high-energy phosphoryl groups from high-energy compounds to ADP. The latter occurs in both the mitochondrion, during the tricarboxylic acid (TCA) cycle, and in the cytoplasm, during glycolysis.

Most cells use glucose for ATP synthesis, but there are other fuel molecules (fatty acids, proteins) that are equally important for maintaining human body’s equilibrium or homeostasis. However, some cells rely only on glucose for ATP synthesis as they are devoid of functional mitochondria (red blood cells, cancer cells,…) and unable to oxidize neither fatty acids nor amino acids. But, even in cells that can use all nutrients, the type of food substrate that is oxidized changes according to the physiological situation of the cell, such as the fed and fasting states.

Although fatty acids, amino acids, and glucose oxidation pathways begin differently, all these mechanisms ultimately converge onto a common pathway, the TCA cycle, occurring within the mitochondria. The ATP yield obtained from lipid oxidation is over twice the amount obtained from carbohydrates and amino acids.

Over a hundred ATP molecules are synthesized from the complete oxidation of one molecule of fatty acid, and almost forty ATP molecules result from amino acid and pyruvate oxidation. Only two ATP molecules are synthesized in the cytoplasm via the glycolytic conversion of glucose molecules to pyruvate.

Fuel utilization strongly varies from cell to cell, according to the repertoire of glucose transporters (GLUT) present on their plasma membranes. The presence of high affinity GLUTs in the membrane may increase the rate of glucose uptake by twenty- to thirtyfold in tissues, hence increasing the amount of glucose available for oxidation.

After meals, glucose is the primary source of energy for adipose tissue and skeletal muscle. As the breakdown of glucose, in addition to contributing to ATP synthesis, generates compounds that can be used for biosynthetic purposes, the choice of glucose as primary oxidized substrate is very important for cells that can grow and divide fast (white blood cells, stem cells, some epithelial cells…).

Between meals, cardiac and skeletal muscle cells meet 90% of their ATP demands by oxidizing fatty acids. Although these proportions may fall to about 60% depending on the nutritional status and the intensity of contractions, fatty acids may be considered the major fuel consumed by cardiac muscle during rest or mild-intensity exercise. As exercise intensity increases, glucose oxidation will surpass fatty acid oxidation. Other organs that use primarily fatty acid oxidation are the kidney and the liver. The cortex cells of the kidneys need a constant supply of energy for continual blood filtration, and so does the liver to accomplish its important biosynthetic functions.

During fasting, the use of adipose fatty acids from adipose tissue, the storehouse of body fat, clearly contributes to the maintenance of adequate blood glucose concentration to meet the demands of cells that exclusively or primarily rely on glucose as a fuel molecule. Among these cells figure the central nervous system (CNS) cells as blood-brain barrier prevents the access of lipids to these cells. Thus, in prolonged fasting, however, ketone bodies released in the blood by liver cells as part of the continual metabolization of fatty acids are used as fuels for ATP production by CNS cells.

Human cells and tissues adapt to internal metabolic demands in many ways, mostly in response to hormones and/or nervous stimuli. Demands by one cell type can be met by the consumption of its own reserves and by the uptake of fuel molecules released in the bloodstream by other cells. Thus, energy use is tightly regulated so that the energy demands of all cells are met simultaneously

Blood glucose levels are regulated by different hormones: insulin and glucagon from the pancreas, and T3 and T4 from the thyroid.
– When blood glucose levels rise, insulin is secreted by the pancreas. Insulin will lower blood glucose by increasing its uptake in target cells. It will also stimulate liver to convert glucose to glycogen that will be stored.
– When blood glucose levels fall, glucagon is secreted by the pancreas, which increases blood glucose levels by stimulating glycogen breakdown into glucose and glucose formation from amino acids.
– Basal metabolic rate (BMR) of the body is controlled by T3 and T4 thyroid hormones,in response to anterior pituitary thyroid stimulating hormone (TSH). T3 and T4 bind to receptors on the mitochondria, causing an increase in the production of ATP, as well as increase in the transcription of genes that help utilize glucose and produce ATP. Thus, the resulting effect will be a higher metabolism of the cell.

Glycogen stores are found in the liver (6% of its mass) and in muscles (1% of muscle mass that represents 3 to 4 times the amount found in liver). However, only the liver is able to supply blood with glucose by degrading its glycogen stores. This reserve is not large, and during overnight fasting glycogen reserves fall severely. As blood glucose concentration is kept within narrow limits under most physiological conditions, another mechanism do exist to supply blood glucose. Indeed, glucose can be synthesized from amino acid molecules. This process is called de novo synthesis of glucose, or gluconeogenesis. Amino acids, while being degraded, generate several intermediates that are used by the liver to synthesize glucose. Alanine and glutamine are the two amino acids whose main function is to contribute to glucose synthesis by the liver. The kidneys also possess the enzymes necessary for gluconeogenesis and, during prolonged fasting, contribute to some extent to the supply of blood glucose. Since de novo glucose synthesis comes from amino acid degradation and because depletion of protein stores can be life-threatening, this process must be tightly regulated. Insulin, glucagon, and glucocorticoids play important roles in controlling the rate of protein degradation and, therefore, the rate of glucose production by the liver.

Any alterations in factors that control food intake and regulate energy metabolism will induce cell dysfunction and thus pathological states such as obesity, type II diabetes, metabolic syndrome, and some kinds of cancer.