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Past and future corollaries of theories on causes of metabolic syndrome and obesity related co-morbidities part 2: a composite unifying theory review of human-specific co-adaptations to brain energy consumption



A composite unifying theory on causes of obesity related-MetS has been formulated and published in an accompanying article (1). In the current article, the historical and recent past, present and future corollaries of this theory are discussed. By presenting this composite theory and corollaries, it is hoped that human evolution and physiology will be viewed and studied from a new vantage point. The politics of management of ecological farming and nutrition will change, a profound reconfiguration of scientific theory generation and advancement in a ‘high-tech’ world can be made, and pathways for solutions recognised.

Metabolic syndrome (MetS) predicts type II diabetes mellitus (TIIDM), cardiovascular disease (CVD) and cancer, and their rates have escalated over the last few decades. Obesity related co-morbidities also overlap the concept of the metabolic syndrome (MetS). However, understanding of the syndrome’s underlying causes may have been misapprehended.

The current paper follows on from a theory review by McGill, A-T in Archives of Public Health, 72: 30. This accompanying paper utilises research on human evolution and new biochemistry to theorise on why MetS and obesity arise and how they affect the population. The basis of this composite unifying theory is that the proportionately large, energy-demanding human brain may have driven co-adaptive mechanisms to provide, or conserve, energy for the brain. A ‘dual system’ is proposed. 1) The enlarged, complex cortico-limbic-striatal system increases dietary energy by developing strong neural self-reward/motivation pathways for the acquisition of energy dense food, and (2) the nuclear factor-erythroid 2-related factor 2 (NRF2) cellular protection system amplifies antioxidant, antitoxicant and repair activity by employing plant chemicals. In humans who consume a nutritious diet, the NRF2 system has become highly energy efficient. Other relevant human-specific co-adaptations are explored.

In order to ‘test’ this composite unifying theory it is important to show that the hypothesis and sub-theories pertain throughout the whole of human evolution and history up till the current era. Corollaries of the composite unifying theory of MetS are examined with respect to past under-nutrition and malnutrition since agriculture began 10,000 years ago. The effects of man-made pollutants on degenerative change are examined. Projections are then made from current to future patterns on the state of ‘insufficient micronutrient and/or unbalanced high energy malnutrition with central obesity and metabolic dysregulation’ or ‘malnubesity’.

Forecasts on human health are made on positive, proactive strategies using the composite unifying theory, and are extended to the wider human ecology of food production. A comparison is made with the outlook for humans if current assumptions and the status quo on causes and treatments are maintained. Areas of further research are outlined. A table of suggestions for possible public health action is included.

Peer Review reports


The degenerative disorders associated with major health problems such type II diabetes mellitus (TIIDM), atherosclerotic cardiovascular disease (CVD) and cancer have increased markedly over the last 100 years or so. Almost all populations suffer from high rates of these diseases in the 21st Century. In the last five decades obesity rates have accelerated and are associated with the above degenerative conditions. They are linked, and predicted by, a cluster of markers comprising hypertension, dyslipidaemia and hyperglycaemia, denoted the metabolic syndrome (MetS).

A change to an individualistic, capitalist, westernised way of life has contributed. High energy, refined, over-appetising food has always been a profitable commodity. Science prioritises high-technology oriented commodities that can be mass produced for high financial returns. However, processed food has little overall nutritional value, and its production also involves significant amounts of anti-nutrient additives. Such high energy refined food is known to influence obesity, but the mechanisms of its contribution to MetS are not understood. Much public health and ecological science has been developed to try to rectify the issues caused by technological production of food.

However, some cultures have been pursuing this pattern of increasingly designing and using new technologies since agriculture and animal husbandry arose. The foraging or a hunter/gatherer way of life was effectively that in which humans evolved and for which they were most adapted. Even primitive farming meant a significant change in nutrition, which may need accounting for.

As effective methods to deal with human obesity, let alone basic causes of MetS, are unknown, a review of human evolution and history is required in order to form a unifying theory. Any such theory is likely to be a composite of various hypothesises and extant or new sub theories. Once such a composite unifying theory is formulated it needs to be ‘tested’ against what we know of all of the changes humans have made or have occurred to them, since they left their time of maximum fitness and health.

The composite unifying theory has been developed [1]. It states that human physiology, in addition to anatomy, changed during the evolution of the proportionately large, energy-demanding human brain. Such co-adaptive mechanisms were required to provide or conserve more energy for the brain. There are a number of human specific mechanisms that may be contributing to human obesity. However, two co-dependent, but unrelated co-adaptive systems or a ‘dual system’ is proposed: 1) the enlarged, complex cortico-limbic-striatal system increases dietary energy by developing strong neural self-reward/motivation pathways for the acquisition of energy dense food, and 2) the nuclear factor-erythroid 2-related factor 2 (NRF2) cellular protection system amplifies antioxidant, antitoxicant and repair activity by employing plant chemicals, becoming highly energy efficient in humans.

These two systems may have come to interact in a negative way since technologies advanced.

The complex human cortico-limbic-striatal system generates strong behavioural patterns, based on neural rewards, for energy dense food procurement, including motivating the development of agricultural technologies and social systems to augment the process. Once significant amounts of this high energy, refined food are produced for communities, the cortico-limbic-striatal reward system tends to an extreme, ‘overdrive’ setting or addiction in many individuals. Aspects of addiction include lack of control of the behaviour and over-consumption of the salient item, and neglect of healthy behaviours such as eating nutritious but less appetising ‘common or garden’ food.

Insufficient consumption of food micronutrients, such as secondary plant food micronutrients, prevents optimal human NRF2 function. In humans, the micronutrient dependant, hyper-functioning NRF2 appears to protect long lived cells, such as cardiomyocytes and neurones, from oxidative stress, thus conferring many decades of excess functional longevity. Additionally, the human NRF2 protects fast turnover immune/endocrine or other epithelial cells from toxins, stabilises and controls replication, which decreases rates of neoplastic change and cancer. If there are insufficient food micronutrients, inefficient oxidation of excess energy forces central and non-adipose cells to store excess toxic lipid. Lack of detoxification of foreign or unnecessary (xenobiotic) chemicals exposes cells to toxins which poison many cell processes, introducing dysfunction or apoptosis. Ensuing oxidative stress and metabolic inflammation (metaflammation) allows susceptibility to infectious, degenerative atherosclerotic cardiovascular, autoimmune, neurodegenerative and dysplastic diseases.

Corollaries of the composite unifying theory on the metabolic syndrome

This composite unifying theory has a number of corollaries which modify current ideas on why human health has changed over the ages since agriculture began, what is occurring now, and what the future could bring.

Nutrition through the ages - agriculture, industrialisation and migration

The health effect of the cortico-limbic-striatal system’s driving humans to attain a high energy diet can be traced over the last few millennia. As food processing technologies developed, low micronutrient to macro-nutrient ratio diets became more frequent rendering the high micronutrient dependant energy efficient antioxidant NRF2 system increasingly dysfunctional.

The archaeology of pre-agricultural era humans confirms that they were taller, more muscular and robust [2]. Although the average life span was only 40 years, it seems to have been kept lower by high infant mortality. Healthy old age did occur [3].

The advent of farming technologies dates from about 10,000y ago [2]. Energy dense, storable and transportable, starchy foods increased to 50-70% of the diet and the diminishment of variety was significant [4]. Such diets allowed rather more predictable, year round energy supplies, and humans to breed, migrate and colonise much of the world. However, there was a health cost to the loss of a widely varied, whole food diet [2]. There is evidence that many, but not all, agricultural populations became stunted; even brain size decreased [3].

The mean height of pre-19th Century European women was approximately 155 cm, and of men, 166 cm, with men losing more highly nutritionally-demanding, lean tissue [5]. European mediaeval city dwellers became more disease, particularly infection, prone,[2] with average life expectancy of 18 years [3].

The lack of vitamin D, for instance predisposed humans to the chronic infections of tuberculosis, leprosy and syphilis [6], in addition to rickets, but has probably had unrecognised nutrition-related metabolic influence in the liver [7]. It is worth noting, at this point, that neoplastic tumours were rare in non-industrialised communities [8]. In addition, the development of the Northern Hemisphere human’s minimally pigmented skin was probably an adaptation to lack of skin sun exposure for synthesis of vitamin D [9]. Infection and bone dysplasia probably also exerted epigenetic, if not genetic, selection [10].

Lack of micronutrients was likely to have profound effects on human health, and recently realised now that analytical techniques have advanced, is that of dietary quality (energy and micronutrient type, variety and volume) on intestinal microbiota [11]. A few studies have associated not only the energy content, and energy harvest, of diets with more or less beneficial microbiota dominance, but also the type of food culture, ethnicity and degree of westernisation [12].

Interestingly, there are a number of other genetic adaptations which may have occurred in response to humans occupying self-made niches, and cultural practices [13].

Early in the 20th century, an increasing understanding of microbiology led to improved public sanitation and nutrition in some westernised populations. Later in the century, antibiotics were developed and significantly decreased puerperal and infant infection, contributing to increased maternal and infant survival [14], and increased average life span. In addition, the discovery of the requirement for most vitamins and minerals reassured consumers that they just needed a few supplements for health. The rapid escalation and success of supplement supplier and advertising industries followed and continues [15]. Processed, highly palatable fortified foodstuffs, along with synthetic supplements, including infant formulae, became preferable to previous low processed diets. The convenience and sophisticated advertising of refined energy foods are strong cues, and cues feed into, or are a part of, addictive behaviours [16]. Finally well entrenched habits form [17].

Nutrition and lifestyle, and medical and surgical, treatments for obesity and metabolic syndrome

Early, and recent, TIIDM and CVD public health research and ‘lifestyle’ messages focussed on behaviours related to decreasing dietary energy and increasing physical activity [18]. However, various low energy, set-item diets, often commercially formulated as high dairy protein, vitamin and mineral fortified meal replacements, only work well in the obese if they are well below the average adult daily energy requirements, and then with much health professional support. ‘Calorie counting’ by individuals in the community on ad libitum diets usually fails in the long term, which is possibly due to the retention of addictive, refined energy foods, and insufficient fruit and vegetable intake.

In those with MetS who do make the change to a whole food type of diet, or even a 'higher fruit and vegetable and lower salt' diet such as the Dietary Approaches to Stop Hypertension (DASH [19]), weight loss and improvement in many metabolic biomarkers can be shown [20]. Further, the long running Mediterranean intervention PREDIMED study (including groups where olive oil and nuts were provided), was recently stopped early as CVD events and death rates were unacceptably high in the low-fat control group participants [21].

In almost all clinical studies, humans who habitually consume diets, such as from the traditional Mediterranean region, tend to maintain normal weight with decreased risk of CVD and cancer [22]. These type of traditional whole food diets are higher in low-processed, synthetic-chemical ‘free’ , hardy, old varieties of fruit and vegetables, which make their own secondary or defence chemicals. Such diets include mixed protein from plant and free range animal sources. These diets do not have to be low energy, and notably, the Mediterranean diet is proportionately high in energy from cold pressed, high polyphenol-content oil, in addition to fats in dairy, meat, fish, and nuts. The typical traditional Mediterranean contains approximately 38% of olive oil, equivalent to the fat percentage of a typical western diet [23]. Note that saturated fat has been present in our diets for millions of years [24]. It appears high ‘fat to carbohydrate’ ratio, and even ketogenic, diets are physiologically not a problem generally or in obesity [25].

Many researchers have concluded that a narrow range of olive oil and wine polyphenolic metabolic activity was the main or only mechanism for the Mediterranean diet’s health properties [26], rather than the total nutrient content and proportion. This belief possibly spurred on the super-food and nutraceutical industry in its search for one or a few commercialisable food extracts to marketeer. With each new piece of research published, individuals are buffeted back and forth on how to make nutrition choices [27]. Humans have minimal awareness of micronutrient deficits, although they may overeat refined energy food as they seek protein [28].

Epidemiological studies show dietary intakes of whole foods, including their antioxidants, are associated with better health [29]. However, there is accruing evidence that mono or multi-vitamins have neutral-to-negative effects [30] including mineral supplements [31], when given therapeutically. Antioxidant supplements can perturb important, controlled, ‘positive pro-oxidant effects’ , including mitohormesis (cellular regeneration due to small negative stimuli) in post-exercise muscle [32, 33], infection response or inflammation and, recently realised, cancer prevention [30]. In spite of the lack of evidence of efficacy [34], a multibillion dollar a year supplement industry flourishes for humans and animals [15].

Modestly increasing fruit and vegetables in the diet has gained some traction and become a widespread health message. However, it coexists with muddled information from researchers, clinicians and public health professionals, let alone the refined energy food industry, on how much grain and tuber starch, fruit sugars, hydrogenated oils and animal fat should be consumed.

In addition, a vast pharmaceutical and medical device manufacturing industry flourishes for the treatment of blood pressure, lipid and carbohydrate markers of MetS [35], which further distracts from problems with human metabolism and nutrition in the current environment.

Bariatric surgery should be mentioned as it is often held up to be the ‘gold standard’ of weight loss. It is available to relatively few [36] and can result in massive weight loss, although early and late surgical problems do occur and can require revision. However, the post-surgical diminished volume/energy diets are rarely high in whole food micronutrients. Patients are prescribed unproven multi-vitamins supplements, although this practice, and compliance, is highly variable [37]. Total nutrient malabsorption and micronutrient deficiencies can be the cause, or result, of metabolic derangements [37]. Decreased morbidity and mortality is not assured in bariatric patients with established MetS [38].

Long term follow-up in many reports is patchy, and weight regain is not rare [36]. In the short term, as bariatric patients recover from variably extensive surgery, cell triglyceride mobilisation and ‘downsizing’ cell organelle components (molecules and minerals) are recycled (autophagy). The released cell molecules increase micronutrient to macronutrient ratios. This may be the reason for the (often temporary) improved insulin sensitivity and general metabolism, including regression of TIIDM, rather than the proposed “lower intestinal hypothesis”. This hypothesis is ‘based on the documented substantial changes in incretin and other entero-endocrine responses’ [36]. Note that incretin treatment may increase pancreatic hyperplasia and sequelae [39].

However, for bariatric patients who do make significant changes to appropriately-prepared whole food diets, and who develop regular physical activity patterns, the regain of health can be gratifyingly long-term, and significant.

The above discussions revolve around 1) modestly low food micronutrient to macronutrient ratios with deficient overall food volumes contributing to stunting in the past few hundreds to thousands of years, and 2) the extremely low food micro to macronutrient ratios with overall excess energy food associating with central obesity pandemic in the last few decades to the present. However, between these two ‘eras’ , another type of degenerative problem appeared.

Toxicity as a cause of metabolic syndrome – cardiovascular disease and cancer

From the early 1920’s to the 1960’s, as infectious disease rates plummeted, another significant disease markedly increased. MetS, without (obvious) central obesity and specifically atherosclerotic ischaemic heart disease (IHD), rates became epidemic. Lifestyle change data has not explained all of the increase in CVD. An alternative explanation is possible for IHD which escalated in incidence in studies of lower middle to middle-class men from westernised countries during the late 19th and early-mid 20th century [40]. Over this period widespread war and work with vastly increased heavy industrial machines and materials were associated with increased smoking rates, stress, poor sanitation, sub-standard nutrition and crowding.

Importantly, and probably under-recognised, was the general and specific exposure to new synthetic persistent chemicals. All of the above factors probably contributed to traumatic, toxic and infective death rates, particularly in men. Is posited here that MetS and sequelae may be a partial response to variably toxic man-made pollutants which were released with few controls, and importantly coupled with diets insufficient in micronutrients [41]. It is likely that the problem started in towns of the industrial revolution, and later moved into industrialised agriculture and warfare.

The most well-known association of toxins and CVD and cancer is, of course, with chemicals from burnt plant derivatives: coal, oil and tobacco. A famously recognised early example is scrotal cancer in chimney sweeps [42]. Tobacco smoking has persistently and unequivocally been shown to associate with all degenerative disease [43]. The peak CVD rates in men occurred after the second world war [44], with significant declines in this same group of men not starting until the late 1960’s [45]. Interestingly, smoking was proven to cause both CVD and cancer in the same period. The United States of America (USA) Surgeon General [46] announced this finding and that smoking cessation was to be encouraged. Concurrently, awareness of the need to control the environmental release of acute and persistent pollutants was popularised by publications such R Carson’s ‘Silent Spring’ [47]. Increased numbers of, and more effective, pollution control measures were instigated thereafter [48]. Environmental toxins, including smoking, may explain why nearly half of the decline in CVD cannot be attributed to low fat and sugar diets, new MetS pharmaceuticals and CVD interventions [49, 50].

The association of industrial chemicals on associated acute illness [51] and cancer development [52] has been investigated. However, most research on cancer has been concentrated on non-industrial exposures such as domestic fires and aflatoxin [53], especially in less developed countries. There is little emphasis on long term persistent chemical exposure and CVD in the general medical literature, even now [54, 55].

Currently, a high proportion of the world’s communities are exposed to modest to significant doses of thousands of types of persistent (organic) pollutants and other xenobiotics [5456] and the lowest micronutrient to macronutrient ratio in human evolution. Scientists are often under political pressure to commercialise research to produce various technologies that support industry, and food science is a very active area [57, 58]. Chemical and mechanical technologies are constantly being developed for food: preservation, travel, shelf-life, acceptable look and size, energy content and palatability, rather than nutrition. Nutrition science is perhaps a poor cousin of food science, and toxicology is often not prioritised [59]. Whilst there is a long history of clinicians who profit from industry involvement [60], it is likely that most public health nutrition scientists and physicians believe that they are trying to advance science in good faith. Public health researchers are often under considerable pressure from governments to not upset industry. However, there are a few public health units and directors who have managed to maintain hard hitting, unbiased research that reveals the extent of the influence of industry on nutrition [61, 62]. Data on the effects of sugary drinks and their contribution to obesity and poor health are conclusive, as are the marketing tactics of Big Food [61].


The current cohort of humans has been unable to efficiently oxidase their excess energy. This leads to ectopic, toxic lipid accumulation [63] in perivisceral, upper body and organ tissue, as seen with central obesity. This state of excess oxidative stress and ineffectively detoxified xenobiotics [64] in the suboptimal, micronutrient-deprived NRF2 system leads to the inability of cells to perform maintenance and autophagic repair work [65]. Fast-turnover cell replication loses its strict regulation and tends to dysplasia, with immune cells particularly being prone to acquired DNA damage; dysfunction or malignancy rates increase [30].

Metabolic inflammation (metaflammation [66]) occurs, especially in the arterial endothelium (as atheroma containing oxidised, pro-thrombotic, lipid engulfed by cytokine-secreting foam-cells), endocrine epithelium (dysplasia), liver (production/secretion of inflammatory proteins & dysplasia), cardiomyocytes (ischaemia/lipotoxicity [63])) and central nervous system protein damage by glycation and misfolded protein (neurodegeneration [65, 67]). Many other related mechanisms occur, often overlapping in different tissues. This could be called malnutritive obesity or malnubesity [68].

Future scenarios

As can be seen, many researchers and practitioners have undertaken work in multiple fields that relate to the problem of MetS. Some have known that there are many unsolved issues relating to human evolution and development. Evolutionary studies and basic science, especially cancer bioscience and addiction research on the NRF2 and cortico-limbic-striatal systems respectively, have unwittingly provided plenty of evidence for the ‘dual system’ idea. These, and many other disciplines contributing information on, for example, the human propensity to gain fat and develop slowly, allowed for the pulling together of the many parts of the composite unifying theory.

There is still research to do in rigorously studying the effects of an ad libitum whole food diet in humans under controlled conditions on MetS and other markers. Mathematical modelling and energy balance studies in obese humans on whole food diets are required to deduce how much of the whole food diet contributes to the NRF2 energy efficiency effect and how much is a vegetable fibreenergy dilution effect. Field trialling is required to study various models of ecologically-sustainable, healthy, mixed crop and stock farming using traditional and historic, as well as current smart technologies and techniques (Table 1). This type of farming should produce decreased volumes of lower energy/higher nutrient-value food [69].

Table 1 Public health responses to the composite unifying theory for decreasing metabolic syndrome & obesity related co-morbidities

A negative projection

Without understanding the likely cause of MetS, the future prospect will be to continue on the current trajectory. One American public health publication warned of the current scenario of a degenerative disease epidemic 60 years ago [70]. Furthermore, a report was recently published on the ‘Shorter Lives, Poorer Health’ in the USA. The USA compared poorly with 17 other wealthy countries over the last 30 years, in spite of massive health spending. The report underlines nine areas of attention, five areas of which are: adverse birth outcomes, obesity/diabetes, CVD, lung disease and disability, and possibly two more; drug-abuse mortality and HIV/AIDS, which may relate to the composite unifying theory [71]. We know the ‘developing countries’ have escalating food and general pollution problems [55].

Increases in refined energy food and industrial toxin production will cause further ecological degradation, deforestation, desertification, pollution and acidification of the waterways including global climate change, indicating that MetS is an environmental problem [72, 73].

In poor countries or communities with few industrial regulations, high levels of environmental and occupational toxic chemical exposure [55, 74, 75] are telescoped in time and coincide with addictive, extremely micronutrient depleted westernised refined energy diets, as well as other poverty stresses. This combination of general westernisation and nutrition transition escalates MetS, CVD and cancer rates [62, 75].

Most humans, particularly in less wealthy populations, are now dependant on food products derived from chemically supported and engineered agribusiness monocultures, often grown in low socioeconomic countries [55]. These are at increasing risk of catastrophic failure, often as weakened crops or stock predictably fall prey to rogue microbes [76]. Global climate change is another area of environmental damage, and should be factored into public health action [77].

Individuals will increasingly be exposed to maternal malnubesity and circulating pollutants in utero [54]. They are at risk of suffering cognitive deficits and behavioural dysfunction [78], early MetS (TIIDM in teens), disturbance with reproduction (polycystic ovary syndrome and male hypogonadism) [79], and early degenerative CVD and cancer [78].

A positive projection

Good science on nutrition, the environment and sociology, for example, is available to the public. Civil society groups are already collating ground swells of public opinion via the internet and other communication channels. These can influence governments to reduce corruption [80], warfare (death, injury, starvation, destruction, pollution) and unfair public or government subsidies to large agribusiness [81] and related industries (Table 1). Transparent regulation is required to make the profiteering refined energy food conglomerates provide minimum standards of nutrition, and be progressively taxed on products that do not meet these requirements [62].

Perhaps the most important area is for public health money to be diverted to work with all pregnant women, and help feed poverty stricken mothers and children healthy, non toxic food [71].

Preventing some of the world’s already grown and harvested food, of which half is estimated to go to waste [82], would solve the problem of converting further natural ecologies into unsustainable resource ‘mines’.

It is imperative to stop the rapid nutrition transition to westernised food of cultures which are still farming and foraging traditional whole foods, and protect their land and way of life. This also serves to protect food patterns and environments from westernising exploitation, often destruction, and conserves world resources and knowledge. In fact, for the western or European populations, which have taken generations to industrialise their food, it is time for them to quickly reverse their own nutrition transition back to traditional and forager whole foods.

There is plenty of evidence for scientifically smart, technologically assisted, sustainable mixed organic, ecological farming [69], and even sustainable industry [83]. Many of the traditional food - farming and preparation – methods [84] may be able to be reclaimed and reinstituted, especially by low income countries. Increased types and numbers of programmes to construct more new, simple but smart, environmental already-designed-technologies can be introduced to these areas. Labourers on such farms producing food for the local community should be much healthier than industrial factory workers making components from toxic chemical for arguably unnecessary items.

Major media will be exposed as being owned by large industrial magnates [85] where reporting on much science, medicine and technology is designed to encourage consumption and investment, rather than health. If local and national media can be freed from influence of the wealthy conglomerates [85], then non-environmental agribusiness will no longer be framed as the more positive pathway [86]. Education and promotion of more ecological methods of food production that are likely to lead to better farming, healthy food and less obesity [87]. Media framing of the ordinary, low income family, where obesity is common, would no longer be pejorative [88, 89] (Table 1).

Obesity management and prevention must target the most at risk groups – who are impoverished, deprived of all resources, including good education, often treated unjustly, and often of non-dominant cultures. World efforts need to be increased to regulate corrupt human, environmental and resource exploitation by large multinational corporations, as a first step [90]. This would have an effect on resource wars. Serious new global health modelling on new ecological ways of running economies needs considering. Communities can regroup if left alone. Plans on managing obesity and inequity are appearing [91].

Government public health initiatives can work towards making it easier for individuals in communities by regulating local food producing, processing and marketing industries. Another initiative would be to show the community the value of whole food to health by subsidising fruit and vegetables at least to the levels of other consumables [92]. City councils can provide spare land for community gardens (Table 1).

Healthy, inexpensive whole foods can largely replace refined energy food. This, together with minimising the exposure to persistent pollutants, significantly alters the micro to macronutrient balance and normalises NRF2 metabolism. These environmental and behavioural life status (rather than lifestyle) changes can effect a surprising amount of metabolic repair [93] at any age or stage of disease. Centrally obese individuals with minimal end organ damage can reverse, or bring into remission, TIIDM.

Some specialist addiction management principles and practices will need to be used for the already overweight, possibly with medical and pharmaceutical interventions [94].

Addiction counselling techniques should be used in most cases. Long term assistance in a low stress, non-judgemental, therapeutic environments should be provided [95]. Once individuals have been overweight or obese for some time, and are distressed, most are relieved to classify the problem as addiction. They easily understand that the current environment is pushing most people to overeat ‘junk food’ and that the metabolic problems are due to a lack of food micronutrients. This is especially so when reasons for the types of foods that engender addiction, and other components of addiction, are explained [94, 96] – and often patients recognise them. The next step is explaining that the brain pathways that lead to addiction do not link with logic - ‘addiction can’t be reasoned with’. Thoughts around guilt are usually misplaced and unhelpful, but are encouraged by external influences such as media [89]. Experimenting with new reality testing behaviours, especially with regards to self-worth, can be helpful. Working with patients on advance planning to set rules for abstinence and replacement with non-addictive but healthy, medium energy, pleasant food can work. Practice and repetition over time to establish new patterns or habits is important. However, as most patients know, stress can lead back to ‘comfort eating’ – a euphemism for addiction [97]. Withdrawal symptoms and relapse can often be predicted and managed.

Anti-addictive medication is likely to be helpful for many who are already overweight. Phentermine, an old but understudied medication [94, 98, 99], partially and selectively dampens appetite for rich foods, which along with naloxone [100] and lorcaserin [101], have adrenergic, antiopiate, serotonergic and ultimately dopaminergic effects [102]. The fright, fight or flight response appears to be activated, which tends to decrease saliva flow, and appetite possibly selectively for refined energy food (Table 1).

Metabolic medication has been shown to augment basic energy pathways. Metformin has ‘antioxidant’ [103] type effects, which decreases insulin resistance [103]. It is associated with modest weight loss and confers a significant degree of improvement in MetS and prevention of CVD and possibly cancer [30]. Allopurinol decreases the pro-oxidant enzyme xanthine oxidase [104], directly or indirectly via the NRF2 system. Medications to primarily ‘normalise’ blood pressure, glucose and lipids, MetS markers, can only be temporary measures. When hyperinsulinaemia is already present, the hypoglycaemics, high dose insulin and insulin secreteagogues, sulphonylureas, can have the adverse effects, worsening other aspects of MetS, such as central obesity.

Once individuals are on a whole food diet, daily physical activity will cause normal muscle microdamage and minor arterial endothelial shear disruption-associated oxidative stress [105]. This slight stress will stimulate repair (hormesis [32] again), effectively signalling total body upkeep [29].

Educated primary care health professionals should be leading general and specific patient support, coaching and monitoring of healthy food and physical activity plans.


In summary, it is proposed that as the human brain became enlarged, which increased its energy demands on the body, a human specific ‘dual system’ and other co-adaptations were required to provide extra energy for the brain.

To increase energy uptake, the cortico-limbic-striatal system, an expanded neural network, has driven humans to devise wide-ranging technologies to make available extremely refined energy food for the brain. The same system is probably involved in addiction, initially to refined energy food, but also in compulsions to seek and maintain power over resources (and other humans).

Ultimately, food technologies have processed food until it is unregognisable, largely eliminating micronutrients, leaving refined energy dense foods. However, humans depend on micronutrient dense food for their health and longevity. The NRF2 system’s power to maintain an extremely high level of antioxidant cell protection and (partially) detoxify persistent man-made chemicals depends on relative and absolute food micronutrient sufficiency.

There has been a progression of modest micro to macronutrient ratio decline, with the transitions to agrarian based cultures over the ages, leading to stunting. This was aggravated by work and residence in crowded, sunless habitations, with poor access to fresh fruit and vegetables. In towns, on voyages, and during and after migration, especially with insufficiencies of in vitamin intake, infectious plagues became frequent.

In the industrial age the above continued, but became combined with additional large, uncontrolled releases of toxic man-made environmental pollutants. These initially caused acute toxicity, with significant morbidity and mortality. Over time, pollutants released were less acutely toxic but more numerous, with subacute oxidative stress and metaflammation occurring. The largest organ of the body, the endothelium, especially, was damaged, with atherosclerotic plaques accreting on the large, shear stressed arteries of the aorta, heart and brain, and lower limbs causing CVD; IHD, stroke and peripheral vascular disease.

Early in the 20th century CVD incidence and prevalence increased rapidly, although it is still a leading cause of illness, disability and death in the 2010’s. Over longer lead times still, from the mid-20th century on, cancers developed from accumulated DNA damage associated, at best estimates, with constant low grade epithelial exposure to xenobiotics, and low food micronutrient intake. Cancer incidence increased, with increasing prevalence but less mortality, possibly due to palliative, and some curative, care.

In the later 20th to the early 21st century arose populations who made an extremely rapid nutrition transition to westernised food with extreme micronutrient to macronutrient imbalance, and chronic exposure to myriads of persistent man-made environmental pollutants; they tend to develop extreme central obesity-related MetS. CVD rates and cancers are increasing again in proportion to central obesity-related MetS.


The composite unifying theory includes the ‘dual system’ theory and other co-adaptations, as an explanation for malnubesity, a condition of excess fat accumulation but with concomitant insufficiency of vitamins, minerals and plant and other micronutrients. An understanding of the composite unifying theory can be used as a basis to remediate the current MetS epidemic.

Public health and primary health care professionals can help with refined energy food addiction, utilising current addiction management techniques modified from alcohol and drug programmes, as well as and general education and support for generally unlimited whole food intake, without calorie counting. Non-judgemental coaching for healthy eating together with adequate physical activity will improve health to a large degree (Table 1).

Government public health and environmental defence departments need strengthening and protection from private company lobbying to reduce or influence their charters (Table 1).

Enabling more families to grow and prepare healthy whole food in community gardens or ‘buying local’ from environmentally sound and sustainable, ‘smart’ farmed food, which has minimal synthetic chemicals added, will also be important.

Town planning including public transport engineering and architecture regulations can be improved for more environmentally appropriate structures, accessible parks and active transport systems.

It could be hoped that a number of public health, primary care, human nutrition, evolutionary medicine specialists, and traditional farmers and environmentalists will be interested in the current discussion, and not surprised. Many have known that MetS management, in all areas, is inadequate. Ideally health, environmental and wider economic cost benefit modelling will convince some powerful countries’ governments that regulating and reigning in the global exploitative industries, to make way for sustainable industries and a healthy food culture, will be well worth their while.


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Correspondence to Anne-Thea McGill.

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McGill, AT. Past and future corollaries of theories on causes of metabolic syndrome and obesity related co-morbidities part 2: a composite unifying theory review of human-specific co-adaptations to brain energy consumption. Arch Public Health 72, 31 (2014).

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