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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. In order to
even begin understanding the complexities of treating these conditions
we must throw away the view of looking at single causes, single organs,
or single viruses and appreciate the interdependent nature of bodily
systems. Energy regulation works on many levels, so the treatment of
any imbalance in energy metabolism must be considered holistically.
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