Metabolic Activity Setpoint Regulation In The Body – Conundrum Of How We All Are So Similar Deep Inside

This week I have had a bad bout of flu, along with the rest of the family, and apart from feeling pretty miserable, everything in my body feels disjointed and not functioning well because of the illness. I have been researching how the brain and body works for more than 25 years, and while the old adage that the more one learns about something, the less one knows about it is certainly true in my case, each journal article I read, or data I examine on how the body and the brain ‘work’ and are regulated, I marvel still at what a brilliant piece of work the human body is, and ‘feeling’ my own body not working well this week reinforced this perception for me. One of the most fascinating things about the body is how all the different organs, systems and metabolic activity are regulated to ensure that all its activity functions in a synchronous way and successfully from an integrative perspective. Even at rest, vast numbers of anatomical and physiological functions are operative and interacting with each other continuously in order to sustain life as we know and ‘feel’ it, whatever life really is. When one moves or performs activity, all these variables and interactions change in both quantitative and temporal domains, with metabolic activity increasing and the interactions between different organs and physiological systems occurring at a faster rate. Given the large number of physiological processes and activities occurring at any one time in the body, one would expect large variability between different individuals for the value of any single substrate, metabolite or regulatory factor operating at the cellular, tissue, organ, or system level in the body. Furthermore, one would expect that this potential inter-individual variability in physiological function would alter continuously with time. But, astonishingly, the range of values for any metabolic variable or its activity, and baseline levels of activity for most physiological variables, is relatively similar in different folk who are healthy. For example, blood glucose concentrations are usually maintained between 4 and 6 mmol/l in all healthy individuals, and breathing rate between 12 and 16 breaths per minute. Therefore, a similar metabolic regulator appears to occur in all individuals, although what sets these similar metabolic ranges in all folk is still currently not well understood.

The first potential regulator of all our metabolic and physiological system setpoints is a control mechanism in the brain or central nervous system. If this is the case, the values of each metabolic setpoint level, and the requirement for every single physiological system at every level in the body, as well as mechanical restraints and cellular architecture are present in the brain. The hypothalamus, a small area of brain tissue at the base of the brain, which has been shown to regulate hormonal function and has signalling connections with the body, has been suggested to be the key area of the brain where metabolic regulation occurs, along with a host of other brain and brainstem regions. These potential areas in the brain have been suggested to have a collection of neural networks that contain a register of the set values for each metabolic and physiological constituent of the body which is ‘stored’ somewhere and somehow in the these brain neural networks. Two innovative researchers, Joseph Parvizi and Antonio Damasio, in the early 2000’s suggested that a ‘proto-self’ exists, as a collection of neural networks that ‘map’ the physical and physiological state of the body. In their theory, the proto-self is a first-order map describing the state of every physiological variable in the body, and when a change to the internal physiological milieu occurs, such as when one moves or performs exercise, these changes become a further first-order map in other neural networks. When the proto-self values in the one neural network is compared to this ‘change map’, the difference between the two become a second-order map, which is used by some regulatory process in the brain to initiate changes at either the psychological, physiological system or cellular level by either sending out efferent neural commands (brain signals flowing out to the muscles or organs of the body) or humoral (blood borne) hormonal changes, both of which would attempt to restore the altered metabolic variables to their proto-self values by reducing pace during physical activity or terminating the physical activity, or ingesting fuel or fluid as required to replace the increase in its use, or changing cardiac output or fuel utilization composition to as near what is routine / ‘normal’ as possible.

This is an attractive idea, but like all things related to the brain, there has been no real development in identifying the mechanisms or components of the brain that would be responsible for the storage of the metabolic proto-self maps and register of all the physiological and metabolic setpoint variables. Two distinct shortcomings of these proto-self and brain storage concepts are firstly, the level of requirement for ‘storage space’ given the huge number of variables that would have to be stored, and the intellectual brain activity required to occur continuously to integrate and manage all the different variables at the same time. Secondly, if the values were ‘stored’ in the neural circuits, one would have expected over the generations there would be slow but substantial changes to these values as part of normal genetic variation that occurs over time, which would create an increasingly diverse array of anatomical brain neural network variations and an associated diverse array of setpoint values with time. Therefore, it is likely that some other mechanism is responsible for the similarity between the metabolic setpoint variables of different folk.

An external agent or force, rather than an internal brain mechanism, may be responsible for establishing metabolic setpoints, either directly or by maintaining similar function in the brains of different individuals by preventing changes which would be produced by the evolutionary pressure of passing time. Each individual would need to respond to the external agent or energy force in the same way, and this similar response would set a similar internal physiological and metabolic state in all individuals. For this type of external regulation to occur, the external energy force would need to be consistently present to allow the physiological response to occur continuously in all individuals. A putative energy force which would fulfil these criteria is the force of gravity. Gravity occurs over the entire surface of the earth, and energy is continuously required by all humans to counteract the effect of gravity on body structures. For example, merely standing upright requires constant force and hence muscle activity, which requires as a result a certain continuous level of metabolic activity. Experiments performed in zero gravity environments show that physiological activity levels are profoundly altered by lack of gravitational force. Therefore, there is a strong possibility that gravity, or other electromagnetic forces around the earth such as the coriolus force, are, at least partly, responsible for maintaining the similar homeostatic setpoints found in all healthy individuals.

There are of course times and conditions when metabolic setpoint variables alter, and can be altered. After long term physical training, a number of setpoint levels are altered associated with increased ‘fitness’ induced by training. For example, resting heart rate is reduced, blood lipid and cholesterol profiles are reduced, and muscle enzymatic and mitochondrial setpoint functions are altered. These changes are probably due to adaptations in protein regulatory function at the genetic and molecular level, which alters the physical and neural structures associated with physiological activity by changing their size, number and efficiency of function. But, these alterations are maintained only as long as the training bouts are continued. Once the training stimulus is removed, the metabolic setpoint levels in the different physiological systems return to their original values associated with the ‘untrained’ state, and these reversions occur at a faster rate than do the changes associated with training, indicating that it is easier to return metabolic setpoint values to their untrained values, then it is to alter the setpoint values away from their untrained state.

Chronic disease can also alter resting metabolic values, and in a permanent manner, if the disease is permanent and related to some cellular death. For example when an individual suffers a big heart attack, there is permanent loss of heart tissue in the affected area, which results in the contractile state of the heart changing, which leads to a number of other changes occurring, such as increased (or decreased) heart rate or stroke volume, blood pressure changes, and alterations in the flow of blood and fluids between organs. If the body can tolerate these changes, the individuals will survive in this damaged state for a substantial period of time, with altered resting metabolic variables and setpoint values, until death occurs from some other pathology / disease process. One could describe this as being a functionally different setpoint state, and in complex system research terminology / parlance this is known as a functional bifurcation from the resting state, but it is an artificial state related to illness, and the individual is in effect not functioning in an optimal state, but rather in state of chronic systemic compensation. In diseases such as diabetes mellitus, there appears to be marked changes in the concentrations of blood glucose, with levels measured at different times of the day either being higher or lower than the concentrations present in healthy individuals. However, these changes appear to be caused by the increased variation in blood glucose concentration associated with changes in the gain (the capacity of the system to return to baseline), and time constant of the gain, of the blood glucose control system in individuals with diabetes, rather than by changes in the metabolic setpoint values themselves.

The metabolic setpoints can also alter in response to acute infection, as happened to my body this week, with increased baseline temperature levels, heart rate and cardiac output. Interestingly, in what has been called the ‘setpoint controversy’, during a bout of fever such as I have had, changes occur which are not immediately corrective and which return the core temperature to previous homeostatic setpoint levels, but rather create conditions which would lead to further increases in temperature, or maintenance of the raised temperature away from the routine setpoint levels. These include seeking a warm environment, increased vasoconstriction, and shivering, all which increase metabolic rate and increase generation of heat, despite the individual already having an increased core temperature. The usual response to an increased core temperature when one is in a hot environment, or when the body’s core temperature increases due to exercise or physical exertion (hyperthermia), would be to seek out a cold environment, reduce locomotion, increase vasodilation and reduce metabolic rate. Therefore the responses to hyperthermia and fever, which similarly cause core temperature to increase above baseline setpoint levels, induce directly opposite effects, which in the case of hyperthermia lead to a reduction in core temperature, and in fever, maintains the increase in core temperature, and these different responses are the nub of the setpoint controversy. The teleological value of the responses to fever would be to allow optimal function of the inflammatory and immune response to remove the threat caused by the organism or process (in my case a flu virus) which induced the fever. The teleological value of the responses to hyoperthermia would be to prevent catastrophic overheating of physiological systems. How the ‘decision’ is made by the brain and body to initiate either of these different metabolic setpoint related strategies in response to an increase in core temperature is not currently known.

In summary therefore, one of the most fascinating aspect of our hugely complex bodies, is that despite this complexity, the setpoint values for each metabolic or physiological function appears to be very similar across all individuals, unless there are differences in fitness or health levels. While these setpoint values may be determined in brain structures and circuits, it is more likely that they are set in response to an external system force, likely to be gravity or other such forces that operate in a chronic and continuous manner similarly in all of us. In a world where our perceived external individual differences are often used politically and socially to differentiate and define us, it is a surety that deep inside we are all very much the same, and all are responding to the same challenges and forces we face, and are all so similar in all aspects of our bodies makeup and physical function because of this. So apart from being fabulously complex and mechanistically brilliant, perhaps the deep workings of our bodies, in all their brilliance, can teach us also something socially from how they are made, and how they are operate, reacting to external stimuli in the same way, responding internally in a host of different physiological systems in the same way, and returning to the same baseline values in the same way. No matter how different we or others think we are, deep inside, we are all very much the same, and this similarity is perhaps the fundamental tenet which allows the ongoing existence of life as we know it. Who would ever have believed that gravity would perhaps be the ultimate force potentially underpinning all of our body’s functions, and ensuring the physiological similarity of all us residing on this planet of ours, as we rotate daily around the sun and go about our daily business, if indeed this is the case. Sadly though, it wasn’t able to prevent me developing an illness as a result of a nasty flu virus, which appears to have knocked everything out of kilter this week, including most of my metabolic setpoints, to say nothing of my psychic harmony!


About Alan (Zig) St Clair Gibson

Professor Alan (Zig) St Clair Gibson MBChB PhD MD - Deputy Dean (Research), Faculty of Science and Health, University of Essex, Colchester, United Kingdom View all posts by Alan (Zig) St Clair Gibson

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