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The Science of Energy Metabolism The SCIENCE OF ENERGY Metabolism Mark Robertson, Technical Advisor, BioCare®. Energy metabolism involves a symphony of interlinked chemical, hormonal and neurotransmitter cascades, which put in simple terms, provide us with the fuel we need to perform our daily functions. Energy allows the body to perform work and is fundamental for all living organisms. Humans need to obtain potential energy from the foods we eat in the form of carbohydrates, fats and proteins. The modern western diet has lead to a decrease in nutrient intake and an increase in foods such as refined carbohydrates, trans fats and saturated fats. These direct sources of energy expectedly have a profound impact on the energy balance of the body. Furthermore, the current modern lifestyle is ladled with psychological stressors, which can overstimulate the stress response, resulting in negative effects on energy balance. Increasing exposure to potential toxins such as tobacco smoke and xenobiotics, forms a potent cocktail of environmental stressors for the body to cope with. Bodily cells have an exceptional ability to maintain their internal environment in the face of environmental stressors. However when stressors occur over a prolonged period of time they begin to strain the body. Combined with a lack of micronutrients to optimise the function and protection of cells, it becomes difficult to maintain optimum energy metabolism. Chronic strains on energy systems may manifest as one of a number of diseases linked with energy imbalances. Energy metabolism must be considered as a complete, intertwined system where cellular, endocrine, nervous, digestive, and immune systems work in concert to maintain the internal environment of our cells and optimise energy output. ‘Bodily cells have an exceptional ability to maintain their internal environment in the face of environmental stressors. However when stressors occur over a prolonged period of time they begin to strain the body.’ The Energy Metabolism System A fundamental cog in energy metabolism is the ingestion of potential energy and sufficient micronutrients from foods. Optimal digestive function is necessary to digest, absorb and assimilate the constituents of food. Once absorbed, the constituents of food carry potential energy, however the body still has to undertake many steps to metabolise and transfer this energy for its own demands. There are many systems which contribute to energy metabolism, mainly involving endocrine and nervous control of cellular energy production. (Insulin & Glucagon) Cellular Energy Homeostasis (Mitochondria) Thyroid Control (T4 & T3) Adrenal Control (Cortisol & DHEA) Cellular Energy • Glucose. When oxygen is available, glucose is converted by aerobic glycolysis, which results in the release of energy providing compounds ATP and pyruvic acid. A total of 4 ATP molecules are produced during glycolysis and pyruvic acid is converted into acetyl CoA.When activity becomes intense and oxygen is limited, glucose is broken down anaerobically, ATP is produced but pyruvic acid is metabolised into lactic acid, which does not carry the same energy potential as pyruvic acid. • Fats. Fats are stored in the form of triglycerides, these are long term energy stores for the body. Firstly the glycerol backbone of the triglyceride can be used in glycolysis by conversion to glyceraldehyde 3-phosphate by a number of enzymatic conversions. Secondly, fatty acids are metabolised by ‘clipping’ carbons from fatty acid chains and combining them with CoA to form acetyl CoA. Free fatty acid chains require the help of carnitine to transport fats across the mitochondrial membrane where they undergo a degradation process called β-oxidation to produce acetyl CoA. Nervous System Control Pancreatic Control energy to the citric acid cycle under varying environmental conditions by the synthesis of acetyl coenzyme A (acetyl-CoA), an intermediary energy molecule which is essential for energy transfer. All cells in the human body use the same energy currency in the form of adenosine triphosphate (ATP). ATP is an energy storage molecule which provides chemical energy to drive the energy demands of the body. ATP is produced by a number of chemical reactions which take place within the mitochondria, organelles which are present in all cells of the human body. Mitochondrion are more heavily concentrated in skeletal muscles than in other tissues, because muscles require large amounts of energy for mechanical work. The metabolism of glucose, fats and proteins in the mitochondria all have the potential to transfer • Protein (Amino Acids).There are two main forms of amino acids which can be used to provide energy: glucogenic and ketogenic amino acids. ♦ The carbon skeletons of glucogenic amino acids are degraded to pyruvate, or to intermediates of the citric acid cycle that are precursors for gluconeogenesis. They can also be catabolized for energy or converted to glycogen or fatty acids for energy storage. ♦ The carbon skeletons of ketogenic amino acids are degraded to acetyl-CoA, or converted to ketone bodies or fatty acids. They cannot be converted to glucose. Citric Acid Cycle The citric acid cycle is an important stage of energy metabolism within the mitochondria, and one which relies upon many vitamin and mineral cofactors. It involves the transfer of a two-carbon acetyl group from acetyl-CoA to oxaloacetate, forming citric acid. Citric acid then undergoes a series of cofactor dependent oxidative chemical reactions. The citric acid cycle produces energy in the form of ATP and electrons. These energy rich electrons are donated to NAD+ and FAD+ to form the energy carrying molecules NADH and FADH2, derivatives of vitamin B3 and vitamin B2. For each acetyl group that enters the citric acid cycle, three molecules of NADH and one molecule of FADH2 is produced. NADH and FADH2 donate electrons to the electron transport chain, in order to maximise ATP production. Electron Transport Chain 1. Food provides sources of fats, carbohydrates and proteins. Glycolysis (glucose) uses magnesium and vitamins B1, B2, B3 and B5 as cofactors for the formation of acetyl CoA. Fats rely upon magnesium and carnitine to produce acetyl CoA via betaoxidation. Electrons from NADH or FADH2 are donated to the electron transport chain, a process of energy transfer along a linked protein complex chain within the inner mitochondrial membrane to produce ATP. Electrons are passed from electron donors to electron acceptors, generating energy. This energy is used to transport protons (H+) from the inner membrane into the intermembrane space, this flux of protons generates potential energy in the form of a pH gradient and electrical potential. This potential energy is used by allowing protons to flow back across the membrane by the enzyme ATP synthase. ATP synthase catalyses ATP synthesis from ADP and phosphate, generating either 32 or 34 ATP molecules. ATP can then be used as an energy molecule to drive reactions in the body, such as muscular movement by the removal of the phosphate group to release energy. It is this key oxidative phosphorylation reaction, the coupling and uncoupling of phosphate which powers the demands of our body. It is important to note that free radicals are released as a natural by-product of electron transport, and are implicated in a number of diseases and ageing. 2. T he complex cyclical nature of the citric acid cycle requires a healthy supply of cofactors to ensure efficient poduction of ATP, NADH and FADH2. Deficiency of cofactors may inhibit one or more of the enzymatic steps in the cycle, potentially reducing energy production. The key cofactors are iron, magnesium, manganese, glutathione, and vitamins B1, B2 and B3. NADH and FADH2 donate electrons to the electron transport chain, the most efficient form of energy production. Vitamins B1 and B2 are needed for their synthesis. 3. At each protein complex an electron is donated.The proton (H+) efflux creates a proton gradient to catalyse the reaction of ADP to ATP, the key energy storage molecule. The process of cellular energy metabolism is vital for health and all parts of the cycle need to function adequately to maintain ATP production. Lack of cofactors or overstressing pathways may lead to imbalances in energy production. However, control of cellular energy metabolism by the endocrine system is of equal importance. Cellular Energy Metabolism 1. Carbohydrates Fats Pyruvic Acid Mg, B1, B2, B3, B5 Endocrine Control Proteins The endocrine system uses a series of chemical messengers called hormones which govern when, how and where energy is metabolised. Hormone balance exerts a huge impact on energy homeostasis and hormone imbalances can result in impaired energy production. Lactic Acid Amino Acids Mg, carnitine B6, B12 Pancreas & Liver Acetyl CoA Fe,GSH Citric Acid Oxaloacetic Acid NADH Isocitric Acid B3, Mg, Mn 2. B1 Citric Acid Cycle NADH a-ketoglutaric Acid Malic Acid ATP Mg, B1, B2, B3 Fumaric Acid Succinic Acid FADH2 NADH NADH / FADH2 Fe, B2 Electron Transport & Oxidative Phosphorylation H20 Electrons 3. Complex I (S, Fe) Complex II (S, Fe, Cu, CoQ10) Complex III (S, Fe) Complex IV (S, Cu, Se) H+ H+ H+ H+ H2 ATP • Insulin. An increase in blood glucose stimulates insulin secretion, increasing the uptake of glucose and amino acid from the blood in to cells by binding to their receptors and initiating exocytosis. Insulin also inhibits glucagon secretion, blocking the conversion of non carbohydrate energy sources into glucose. Glucose which is not used directly for energy is stored as glycogen in the liver and muscles. When glycogen stores are full, glucose can be converted to fatty acids and triglycerides. • Glucagon. A decrease in blood glucose stimulates glucagon secretion, which has opposing effects to insulin. Causing release of glucose from glycogen, release of fatty acids from stored triglycerides and stimulation of gluconeogenesis. Diets rich in refined carbohydrates, low in protein and low in micronutrients often results in an irregular insulin balance, leading to constant peaks and troughs in energy. After an insulin spike, blood glucose levels become depleted, this often results in fatigue or tiredness due to the lack of glucose entering brain cells for energy production. Blood glucose regulation has profound effects upon adrenal function. Adrenals ATP Synthase H+ The pancreas and liver have a major role to play in endocrine regulation of blood glucose. As we look back to cellular respiration it is clear that the use of glucose as an energy source is extremely important, even more so as it is the primary source of fuel for brain cells because glycogen cannot be stored in the brain. This means that blood glucose must be tightly regulated to ensure the brain can function.The liver acts to store energy sources such as glycogen and the pancreas is responsible for the production of hormones which directly regulate how glucose is used. Two important hormones made by beta and alpha cells in the pancreas’s Islets of Langerhans are insulin and glucagon, which maintain a delicate balance of blood glucose levels. ADP+ P The adrenal glands are responsible for the synthesis of the hormones; cortisol, dehydroepiandrosterone (DHEA), aldosterone and the sex hormones, testosterone and oestrogen. Two important hormones with regards to energy balance are cortisol and DHEA. • Cortisol is a hormone released in response to stress (following adrenaline release). Its primary functions are to increase blood glucose through gluconeogenesis for immediate energy; suppress the immune system; and aid in fat, protein and carbohydrate metabolism. Cortisol counteracts insulin by binding to β-adrenergic receptors. This triggers glucagon secretion in the pancreas, increased adrenocorticotropic hormone (ACTH) secretion by the pituitary gland, and increased lipolysis by adipose tissue.Together, these effects lead to increased blood glucose and fatty acids, providing substrates for energy production within cells throughout the body. the hypothalamus, and mediates cortisol secretion in response to acute stress. Other neuro-hormones such as serotonin also exert systemic effects over energy metabolism, which is associated with changes in the hippocampus, prefrontal cortex and HPA axis in neurodegenerative disease [6]. • DHEA counteracts the negative effects of prolonged high cortisol levels such as immune suppression and damage to brain cells through over stimulation. CFS is a debilitating disease involving persistent fatigue which is not relieved by rest and is often triggered by viral infection. CFS is a complex multifactorial disease, but one school of thought suggests that mitochondrial dysfunction may play a significant role in the aetiology of this condition [7]. Recent research has focused on providing synergistic cofactor support for mitochondrial function, achieving favourable results [8] [9]. Cortisol is secreted in a circadian rhythm, the cortisol surge in the morning is responsible for the initial burst of energy in the morning by increasing blood glucose and cellular energy metabolism as a result. If this cortisol pattern is altered through chronic stimulation of the stress response, it may affect sleep and energy levels throughout the day. Adrenal hormones also interact closely with the thyroid, each exerting effects over the other. Thyroid The thyroid gland produces vital thyroid hormones, the principal ones being thyroxine (T4) and triiodothyronine (T3). The thyroid hormones control how quickly the body metabolises energy at the cellular level, by increasing ATP production in the mitochondria [1]. Key Protocols For Nutritional Treatment Chronic Fatigue Syndrome (CFS) A key variable to normal mitochondrial function is the availability of cofactors. Psychological stress and physical activity are known to stress the biochemical pathways involved in the metabolism of cofactors [10] [11] [12]. A logical first step is to ensure the availability of key cofactors for enzymatic reactions within glycolysis, the citric acid cycle and oxidative phosphorylation. The importance of vitamin B1, B2 and B3 in energy metabolism is well known and they have all been shown to provide mitochondrial stimulating benefits, normalising energy production [13] [14] [15]. ‘NADH is a high energy compound which may be particularly useful for individuals with energy metabolism dysfunction and has been shown to improve symptoms of chronic fatigue syndrome.’ T3 is the most bioactive thyroid hormone and is produced through the metabolism of T4 by 5’-iodinase which requires selenium, zinc and copper as cofactors. T3 exerts its metabolic stimulatory effects on nearly all bodily cells. Furthermore, the thryroid hormones are highly dependent on adrenal function. Cortisol reduces thyroid activity by reducing stimulation of the thyroid gland through decreased output of TSH from the pituitary [2]. If thyroid function is impaired, adrenal output must also be considered. The thyroid and endocrine system also interacts with the executive control of the brain and nervous system. NADH is a high energy compound which may be particularly useful for individuals with energy metabolism dysfunction and has been shown to improve symptoms of chronic fatigue syndrome [16]. Nervous System L-carnitine deficiency is common in CFS [23] and is required for β-oxidation of fatty acids [24]. L-carnitine also contributes to increased capacity for physical and cognitive activity by reducing fatigue and improving cognitive functions [25] . The hypothalamus in the brain exerts executive control to the pituitary, the ‘master gland’ which coordinates the control of the endocrine system. Although functionally classified as hormones, ghrelin and leptin have profound interactions between the endocrine and nervous systems and are directly involved in central nervous system regulation of energy metabolism. • Ghrelin interacts with hypothalamic neurones to regulate satiety. Increased levels increases the respiratory quotient, decreasing utilisation of lipids for the generation of energy [3]. Furthermore, ghrelin increases the expression of fat storage enzymes. • Leptin has direct effects on the same hypothalamic neurons engaged by ghrelin.However, leptin’s effects are counter to those of ghrelin’s.Leptin impacts the energy balance equation by decreasing intake and increasing energy expenditure [4]. Leptin also increases insulin sensitivity as evidenced by increased peripheral glucose uptake and decreased hepatic glucose production through effects exerted on the neuroendocrine network [5]. Key neurotransmitters which exert nervous interactions are adrenaline and noradrenaline. Adrenaline release is stimulated by Magnesium is an essential cofactor for energy metabolism and complexes with ATP, it is commonly insufficient in CFS sufferers [17] and supplementation may help to reduce muscle weakness [18]. CoQ10 supports energy release and forms part of complex III in the electron transport chain [19]. CoQ10 also acts as a potent antioxidant and immunomodulator in the mitochondria [20] [21] [22]. Other beneficial nutrients include N-acetyl cysteine, which has been shown to significantly support mitochondrial protection and function [26] [27] [28] [29].This could be through its role in increasing intracellular glutathione, another mitochondrial protective antioxidant [30]. Panax ginseng may provide a more naturopathic approach to mitochondrial support, which has a traditional usage to support energy balance. Scientific evidence shows it provides antioxidant properties and can improve energy metabolism, glycaemic control and adrenal hormone balance [31] [32] [33] [34] [35] [36]. Another potential nutraceutical, D-ribose provides a key building block of ATP, which can become depleted following overexertion. In clinical trials D-ribose significantly reduces clinical symptoms of chronic fatigue syndrome [37], improves energy restoration in muscles [38] and speeds up regeneration of ATP in muscle cells of animals [39] [40] [41] [42]. Furthermore it may increase ventilatory efficiency, improve peak exercise performance [43] [44] and modulate glucose levels [45]. Supporting the mitochondria is only one facet of treating CFS, the energy metabolism system illustrates the importance of supporting the body holistically. For example, many sufferers display abnormal outputs of the adrenal hormones cortisol and DHEA [46] [47]. Siberian Ginseng is an adaptogenic herb, meaning it can provide resistance to over stimulation of the adrenal response. Research shows that Siberian ginseng enhances mental acuity and physical endurance [69]. Dysglyceamia Licorice is known to support adrenal function through stimulating cortisol and DHEA production [70] [71]. Dysglycaemia is the abnormal control of blood glucose levels. It is heavily reliant upon diet and the actions of insulin and glucagon. It has a direct effect on daily energy levels and is heavily linked with fatigue. A controlled diet with a low glycaemic load and high nutrient density are key considerations to ensure a healthy blood glucose balance. A balanced glycaemic response is important for weight balance and normal metabolism. Hypothyroidism Whey Protein accelerates lipolysis, and effects nutrient partitioning between adipose tissue and skeletal muscle [48] and increases satiety [49] [50]. Compared to other food proteins, whey contains the highest concentration of the branched-chain amino acids, especially L-leucine [51]. Leucine acts as the stimulator of the downstream signal control of protein synthesis in the insulin signalling pathway, maintaining a stable level of glucose and insulin [52] . Furthermore it may aid liver detoxification and heavy metal chelation [53] [54] . Hypothyroidism is an increasingly prevalent disease which involves the malfunction or insufficient production of thyroid hormones. By general definition it is an over production of TSH, and an underproduction of T4. This definition does not adequately consider the aetiology of this disease from a nutritional point of view. Lack of regular quality protein intake and essential cofactors such as selenium and zinc, may be partly responsible for an increasing prevalence in sub clinical and clinical hypothyroidism. Although providing adequate nutrition and blood glucose control is essential, adrenal fatigue requires a change in lifestyle if already overloaded with stressors. Relaxation techniques and education on sleep hygiene prove invaluable tools in managing stress levels. ‘Supporting the mitochondria is only one facet of treating CFS, the energy metabolism system illustrates the importance of supporting the body holistically.’ L-carnitine seems to increase overall glucose elimination. It shows independent effects, improving insulin resistance with a post receptor mechanism and may improve skeletal muscle function and athletic performance in healthy individuals [55]. Increased environmental exposures to halides elements such as fluoride and chloride may induce competitive inhibition of the mineral iodine, which represents a key part of the structure of thyroid hormones. Conjugated Linoleic Acid has been found to reduce fat deposition in obese mice, possibly through increased fat oxidation and decreased triglyceride uptake in adipose tissue [56]. Iodine is an essential component of the thyroid hormones,T3 and T4, and is therefore essential for normal thyroid function [72] [73]. Chromium improves glycaemic control through its action on cell insulin receptors [57]. Supplementary chromium has been shown to increase lean body mass and basal metabolic rate [58] [59]. Additionally, a recent study reported that chromium picolinate supplementation attenuated body weight gain in type 2 diabetic patients [60]. Other important nutrients to consider for insulin function and glycaemic control are magnesium [61], manganese [62] and vitamin B3 [63]. Adrenal Fatigue Adrenal fatigue is usually caused by chronic strains to the body by psychosocial, physical, or environmental (e.g. infection, exposure to toxins, inadequate nutrition) stressors. Although not recognised by general medicine, it is accepted that over stimulation of the stress response is known to have detrimental effects on health. Adrenal fatigue occurs when the adrenal glands are no longer able to adequately control the stress response, resulting in an abnormal balance of cortisol and DHEA. This can result in a long list of symptoms, including severe fatigue and mood disturbances. Adrenal hormones can become depleted through strained biochemical pathways, therefore it is important to provide the building blocks and cofactors to these hormones. Combinations of B vitamins, vitamin C, calcium, magnesium, and zinc have been shown to improve fatigue [64] and psychological stress [65], possibly through their importance in cortisol synthesis. Vitamins C, B1, B5 are cofactors for the synthesis and balance of cortisol. Ensuring normal cortisol balance directly influences energy metabolism at a cellular level [66] [67] [68]. Selenium is an essential element for normal development, growth, and metabolism because of its role in the regulation of thyroid hormones. Selenium is responsible for the production and regulation of active thyroid hormone T3 from T4. Three different seleniumdependent iodothyronine deiodinases (types I, II, and III) can both activate and inactivate thyroid hormone by acting on T3, T4, or other thyroid hormone metabolites [73] [74]. Selenium deficiency can exacerbate the effects of iodine deficiency. Zinc and copper should also be considered, they require a delicate balance and have been shown to be involved in thyroid regulation [75]. Tyrosine is an amino acid precursor to thyroid hormones, adrenocortical hormones and dopamine, which supports adaptation to stressful situations [76]. Concluding Remarks Although some of the core areas of energy metabolism are mentioned above it is still essential that digestion, liver function, immune integrity, antioxidant protection and physical activity are all considered, as they also feed into the energy metabolism system. It is also wise to consider boundaries of treatment, genetic predispositions and medical treatments when addressing disorders of energy metabolism. Complex equations usually require complex solutions, perhaps this is why diseases such as CFS puzzle the medical profession. 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