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Modern life has created a metabolic ‘energy crisis’. Many people seem to have dysfunctional energy metabolism resulting in persistent fatigue, high stress levels, weight gain and long-term metabolic dysfunction. ‘Unexplained’ fatigue is commonplace, comprising 5-7% of primary care appointments1 and is occurring in younger people too.2 Yet medical practitioners struggle to find solutions and are restricted to looking at a limited range of blood tests to identify obvious culprits such as anaemia. In fact, often the symptoms are sub-clinical and wrapped up in the complexities of energy homeostasis and the wider picture of stress and environmental demand.
Is it as simple as ‘energy in = energy out’?
We have developed sophisticated biochemical and endocrine systems to maintain our key physical functions in the face of multiple circumstances. This shapes different degrees of ‘engagement’ with our environment, enabling us to perform everyday tasks and activities, and adapt to constantly changing challenges.
Thus, energy metabolism is a key adaptive interface designed to intelligently modulate the delivery of ‘fuel’ to all body cells in the face of multiple, rapid environmental and physiological challenges. A necessarily complex process, involving a symphony of interlinked chemical, hormonal, and neurotransmitter cascades, namely through the AHPA axis and specifically adrenal and thyroid function, fuelling (mainly blood glucose regulation), and cellular energy production through the mitochondria.
We live in a unique period in human history, where most of us have easy access to a huge variety of food. From an evolutionary perspective, lack of regular access to food and seasonal scarcity of carbohydrates necessitated that we develop efficient pathways to readily store and access body fat for energy. Cells can adapt to different types of substrate that can be used as ‘fuel’ and different cells prefer different substrates. This adaptation is crucial and is achieved through the several regulatory mechanisms involved in controlling energy and its utilisation.3
But, we no longer ‘feast and famine’. Instead, we ‘graze and binge’. An over-abundance of calorie-dense, nutrient-scarce foods has led to a disconnection between hunger and true physiological needs.
Blood Glucose Dysregulation
Diets rich in refined carbohydrates, low in fat/protein and low in micronutrients often result in metabolic maladaptation, ranging from dysglycaemia to insulin resistance. Chronically elevated insulin often correlates with elevated glucose as cells become less sensitive to insulin signalling. Glucose ‘peaks and troughs’ may result in energy dips as a result of reactive hypoglycaemia. Maintenance of plasma glucose under a variety of nutritional conditions and energetic demands must be tightly controlled to ensure that cells are not degraded by high sugar levels and avoid consequent formation of inflammatory Advanced Glycation End products (AGEs).4 It can also lead to dyslipidaemia which increases cardiovascular risk,5 testosterone issues in men and an increased risk of polycystic ovary syndrome (PCOS) in women.6
Blood Glucose Metabolism
Glucagon and insulin exert opposite influences as part of a feedback system that keeps blood glucose levels stable. Glucose stimulates secretion of insulin from the pancreas, promoting uptake of glucose and amino acids from blood into cells. Transport proteins known as glucose transporters (GLUT) facilitate transport of glucose over the cell membrane:
Glucose 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. Insulin also inhibits glucagon secretion, blocking the conversion of non-carbohydrate energy sources into glucose. This is presumably a protective mechanism for periods of fasting. Our bodies seem to prioritise storage of fuel rather than the release of it. A decrease in blood glucose stimulates glucagon causing the release of glucose from glycogen, release of fatty acids from stored triglycerides and stimulation of gluconeogenesis.
Cellular Energy Regulation
Now that we are well fuelled, we need to deliver that fuel to our cells, namely our mitochondria, to turn it into energy. The ultimate goal of delivering fuel substrates, such as carbohydrate, protein or fat, is conversion to adenosine triphosphate (ATP) - often referred to as the ‘molecular currency unit’ of energy transfer. ATP is actually a proton (H+) storage system. Removal of the phosphate group from ATP forms ADP and releases energy. It is this key ‘phosphorylation’ reaction, the coupling and uncoupling of phosphate, which powers the demands of our body. ATP can be synthesised by three different energy systems:
A number of environmental and physiological factors can have a damaging effect on the mitochondria. This includes toxic load and oxidative stress. High or chronic low level exposure to xenobiotics, alcohol, and particulate air pollution can directly interfere with mitochondrial energy production.12This can be more of a problem in a state of low mitochondrial antioxidants; manganese superoxide dismutase (MnSOD) and mitochondrial glutathione (mGSH) which can be caused by nutrient deficiencies (manganese, selenium, cysteine), or genetic polymorphisms e.g. glutathione reductase (GSR).13 Methylation is also a crucial process as the mitochondrial enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase 2) is responsible for producing 20–40% of cellular NADPH.14 As mentioned, ATP production is most efficient in the presence of oxygen, so low oxygen states due to anaemia or poor circulation, can significantly compromise energy production. Lastly, thyroid hormones are a key regulator of mitochondrial biogenesis and function, therefore hypothyroidism can be a contributing factor to mitochondrial dysfunction.
AHPA Axis & Adrenal Function
We also have sophisticated endocrine mechanisms that can further modulate energy production in response to circumstances. If blood sugar falls, or if there is a stress demand, the adrenal glands are normally activated as an essential back-up system to maintain ongoing fuelling. Thus, continual metabolic demand and reduced adaptation with poorly regulated blood sugar may have consequences affecting many systems including the adrenals.
When the brain detects a threat or stressor, excitatory neurons in the amygdalae fire rapidly, increasing the glutamatergic response, leading to higher levels of the neurotransmitter glutamate in the brain and a feeling of panic and fear. This nervous system response then triggers the endocrine system via the AHPA axis and increases dopamine.15 The hypothalamus stimulates the adrenal medulla to secrete the more potent stress hormones adrenaline along with noradrenaline, triggering an immediate sympathetic nervous response. The impact of adrenaline release is characterised by greater blood flow to muscles, increased heart rate, pupil dilation and elevated blood glucose levels.16 The primary role of noradrenaline, like adrenaline, is arousal and increasing overall wakefulness and responsiveness. In a secondary, complementary pathway, the AHPA axis, the hypothalamus releases corticotropin-releasing hormone (CRH) which triggers the anterior pituitary to release adrenocorticotropic hormone (ACTH). This stimulates the adrenal cortex to produce the glucocorticoid cortisol. Cortisol influences, regulates or modulates many of the changes that occur in the body in response to stress. The effects of cortisol are felt over almost the entire body, impacting on homeostatic mechanisms. There is an interplay between these two systems to intelligently manage a range of stressors, with adrenaline exerting a rapid and powerful response and cortisol providing a lower intensity but longer-term response. Elevated levels of adrenaline and cortisol are associated with anxiety states.17Conversely, gamma-aminobutyric acid (GABA) balances the excitatory action of glutamate18 and attenuates excessive sympathetic responses and thus CRH and ACTH. As such, GABA has a calming effect on our emotions and prevents us from becoming overwhelmed in stressful situations,19 by modulating cortisol as well as adrenaline, noradrenaline, dopamine and serotonin levels, and effectively promoting parasympathetic mode.20
Support Energy Adaptation
To some extent, the energy equation is as a simple as energy in = energy out. But energy metabolism is complex and its delicate balance can be easily disrupted, leading to fatigue and chronic disease. If we fuel our body appropriately, without overfeeding, whilst optimising cellular energy metabolism and supporting a balanced AHPA response with adequate time to rest and recuperate, we can improve energy adaptation and overall resilience.
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