The principle of 'brain energy on demand' and its predictive power for stress, sleep, stroke, obesity and diabetes.

Does the brain actively draw energy from the body when needed? There are different schools of thought regarding energy metabolism. In this study, the various theoretical models are classified into one of two categories: (1) conceptualizations of the brain as being purely passively supplied, which we call 'P-models,' and (2) models understanding the brain as not only passively receiving energy but also actively procuring energy for itself on demand, which we call 'A-models.' One prominent example of such theories making use of an A-model is the selfish-brain theory. The ability to make predictions was compared between the A- and P-models. A-models were able to predict and coherently explain all data examined, which included stress, sleep, caloric restriction, stroke, type-1-diabetes mellitus, obesity, and type-2-diabetes, whereas the predictions of P-models failed in most cases. The strength of the evidence supporting A-models is based on the coherence of accurate predictions across a spectrum of metabolic states. The theory test conducted here speaks to a brain that pulls its energy from the body on-demand.

Psychological stress, body shape and cardiovascular events: Results from the Whitehall II study.

BACKGROUND AND AIM: It is known that persistent psychological stress predicts changes in body shape in two different ways: some stressed people lose weight, others gain weight. It is also known that persistent psychological stress predicts adverse health events. But it is unknown what role the body shape plays in this particular network of relationships. We therefore analyzed the Whitehall II dataset to relate body shape to stress and health risk. METHODS: Data of 4969 men and 2138 women from the Whitehall II cohort were analyzed. Psychological stress (General Health Questionnaire) was measured three times in the years 1991 till 2001. Body shape (BMI, waist and hip circumferences) was measured in the years 1991 till 1994. Childhood adversities were retrospectively assessed by questionnaire. Outcomes included the incidence of non-fatal or fatal CHD events (coronary heart disease) collected up to the years 2012 and 2013 and all-cause mortality collected up to July 2015. Cox proportional hazard models were conducted to estimate the relation between psychological stress and CHD events or all-cause mortality. RESULTS: There was an increase in the expected hazard to develop CHD with high psychological stress (men: Exp (B) = 1.25 (1.06-1.47); P = 0.008; women: Exp (B) = 1.34 (1.05-1.70); P = 0.017). We found a clear dose-response relationship for the association between psychological stress and CHD events in both genders. That is, subjects with consistently high psychological stress in all assessments had a 2.4-fold (men) or 2.3-fold (women) higher risk for later CHD events compared to never-stressed subjects. Moreover, subjects with a high sum score of all 13 childhood experiences had a 10% increased hazard to develop fatal or non-fatal CHD events in adulthood. Although we could not find stress or BMI linked to all-cause mortality, the waist-to-hip ratio contributed to the risk of all-cause mortality in both genders (Exp (B) = 34.66 (6.43-186.92); P < 0.001 for men; Exp (B) = 60.65 (9.33-394.22); P < 0.001 for women). CONCLUSION: This analysis supports the notion that psychological stress and childhood adversities are associated with the risk of fatal or non-fatal CHD events. When this relationship is analyzed in more detail, the Whitehall II dataset provides further insights into the role of body shape. That is, stress is also related to changes in body shape, with waist size in particular predicting higher all-cause mortality.

Brain Mass (Energy) Resistant to Hyperglycaemic Oversupply: A Systematic Review.

Cerebral energy supply is determined by the energy content of the blood. Accordingly, the brain is undersupplied during hypoglycaemia. Whether or not there is an additional cerebral energy demand that depends upon the energy content of the brain is considered differently in two opposing theoretical approaches. The Selfish-Brain theory postulates that the brain actively demands energy from the body when needed, while long-held theories, the gluco-lipostatic theory and its variants, deny such active brain involvement and view the brain as purely passively supplied. Here we put the competing theories to the test. We conducted a systematic review of a condition in which the rival theories make opposite predictions, i.e., experimental T1DM. The Selfish-Brain theory predicts that induction of experimental type 1 diabetes causes minor mass (energy) changes in the brain as opposed to major glucose changes in the blood. This prediction becomes our hypothesis to be tested here. A total of 608 works were screened by title and abstract, and 64 were analysed in full text. According to strict selection criteria defined in our PROSPERO preannouncement and complying with PRISMA guidelines, 18 studies met all inclusion criteria. Thirteen studies provided sufficient data to test our hypothesis. The 13 evaluable studies (15 experiments) showed that the diabetic groups had blood glucose concentrations that differed from controls by +294 ± 96% (mean ± standard deviation) and brain mass (energy) that differed from controls by -4 ± 13%, such that blood changes were an order of magnitude greater than brain changes (T = 11.5, df = 14, p < 0.001). This finding confirms not only our hypothesis but also the prediction of the Selfish-Brain theory, while the predictions of the gluco-lipostatic theory and its variants were violated. The current paper completes a three-part series of systematic reviews, the two previous papers deal with a distal and a proximal bottleneck in the cerebral brain supply, i.e., caloric restriction and cerebral artery occlusion. All three papers demonstrate that accurate predictions are only possible if one regards the brain as an organ that regulates its energy concentrations independently and occupies a primary position in a hierarchically organised energy metabolism. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=156816, PROSPERO, identifier: CRD42020156816.

Proximal Disruption of Brain Energy Supply Raises Systemic Blood Glucose: A Systematic Review.

This work joins a series that methodically tests the predictions of the Selfish-Brain theory. The theory postulates a vital ability of the mammalian brain, namely to give priority to its own energy metabolism. The brain behaves "selfishly" in this respect. For the cerebral artery occlusion studied here, the theory predicts an increase in blood glucose concentration, what becomes the hypothesis to be tested. We conducted a systematic review of cerebral-artery-occlusion papers to test whether or not the included studies could confirm this hypothesis. We identified 239 records, screened 231 works by title or abstract, and analyzed 89 by full text. According to strict selection criteria (set out in our PROSPERO preregistration, complying with PRISMA guidelines), 7 papers provided enough information to decide on the hypothesis. Our hypothesis could be fully confirmed for the 3 to 24 h after the onset of a transient 2 h or permanent occlusion. As for the mechanism, the theory predicts that the energy-deprived brain suppresses insulin secretion via the sympathoadrenal system, thereby preventing insulin-mediated glucose uptake into muscle and fat and, as a result, enhancing insulin-independent glucose uptake via the blood-brain barrier. Evidence from our included studies actually demonstrated cerebral insulin suppression. In all, the current work confirms the second major prediction of the Selfish-Brain theory that relates to a proximal bottleneck of the cerebral supply chain, cerebral artery occlusion. Its first major prediction relates to a distal supply bottleneck, caloric restriction, and is fulfilled as shown by our previous work, whereas the prediction of the long held gluco-lipostatic theory, which sees the brain as only passively supplied, is violated (Sprengell et al., 2021). The crucial point was that caloric restriction elicits smaller changes in mass (energy) in the brain than in the body. Taken together, the evidence from the current and previous work clearly shows that the most accurate predictions are possible with a theory that views the brain as an independently self-regulating energy compartment occupying a primary position in energy metabolism.

Brain More Resistant to Energy Restriction Than Body: A Systematic Review.

The gluco-lipostatic theory and its modern variants assume that blood glucose and energy stores are controlled in closed-loop feedback processes. The Selfish Brain theory is based on the same assumptions, but additionally postulates that the brain, as an independent energy compartment, self-regulates its energy concentration with the highest priority. In some clinical situations these two theories make opposite predictions. To investigate one of these situations, namely caloric restriction, we formulated a hypothesis which, if confirmed, would match the predictions of the Selfish Brain theory-but not those of the gluco-lipostatic theory. Hypothesis: Calorie restriction causes minor mass (energy) changes in the brain as opposed to major changes in the body. We conducted a systematic review of caloric-restriction studies to test whether or not the evaluated studies confirmed this hypothesis. We identified 3,157 records, screened 2,804 works by title or abstract, and analyzed 232 by full text. According to strict selection criteria (set out in our PROSPERO preregistration, complying with PRISMA guidelines, and the pre-defined hypothesis-decision algorithm), 8 papers provided enough information to decide on the hypothesis: In animals, high-energy phosphates were measured by 31P-nuclear magnetic resonance, and organ and total body weights were measured by scales, while in humans organ sizes were determined by magnetic resonance imaging. All 8 decidable papers confirmed the hypothesis, none spoke against it. The evidence presented here clearly shows that the most accurate predictions are possible with a theory that regards the brain as independently self-regulating and as occupying a primary position in a hierarchically organized energy metabolism.

Effects of blood glucose on delay discounting, food intake and counterregulation in lean and obese men.

BACKGROUND: Delay discounting as a measure of impulsivity has been shown to be higher in obesity with an association of increased food intake. Moreover, obese humans showed a higher wanting for high-calorie food than lean men when blood glucose concentrations were low. First studies linking blood glucose levels to delay discounting yielded mixed results. We hypothesized that obese people - in comparison to lean men - have a relative lack of energy, especially when blood glucose levels are low, that results in higher levels of delay discounting, food intake and hormonal counterregulation. METHODS: We investigated 20 lean and 20 obese healthy young men in a single-blind balanced cross-over design. With a standardized glucose clamp technique, subjects underwent a hypoglycemic state in one condition and a euglycemic state in the control condition. Regularly, blood was sampled for assessment of hormonal status, and questionnaires were filled out to assess delay discounting and symptom awareness. After normalizing blood glucose concentrations, subjects were free to eat from a standardized test buffet, followed by a snack test. RESULTS: Delay discounting was higher in obese than in lean men throughout experiments (p < 0.03). However, we did not observe significant discounting differences between glucose conditions (p > 0.1). Furthermore, the discounting performance did not correlate with food intake from the test buffet or snack test (p > 0.3). As a response to hypoglycemia, hormonal counterregulation was pronounced in both weight groups (p < 0.03), but responses of ACTH, norepinephrine and glucagon were stronger in obese compared to lean men (p < 0.03). Also, intake from the high-calorie buffet after hypoglycemia compared to euglycemia was higher in obese subjects (p < 0.02) but comparable in lean men (p > 0.5). CONCLUSIONS: Our data suggest that augmented delay discounting is a robust feature in obesity that is not linked to glucose levels or actual food intake. With our systematically controlled approach, combining performance in delay discounting with regard to distinct blood glucose levels, different weight groups, counterregulatory behavior and food intake, our results imply that delay discounting is not susceptible to fluctuations of blood glucose and do not support the assumption that a low body's energy content leads to increased impulsivity. Further replications including women and larger sample sizes are needed to corroborate our data.

Stress-Related Changes in Body Form: Results from the Whitehall II Study.

OBJECTIVE: Stress is associated with body mass gain in some people but with body mass loss in others. When the stressor persists, some people adapt with their stress responses, whereas others do not. Heart rate variability (HRV) reflects autonomic variability and is related to stress responses to psychosocial challenges. It was hypothesized that the combined effects of stress exposure and autonomic variability predict long-term changes in body form. METHODS: Data of 1,369 men and 612 women from the Whitehall II cohort were analyzed. BMI, hip-to-height ratio, and waist-to-height ratio were measured at three time points over a 10-year period. HRV and psychological distress (General Health Questionnaire) were assessed. RESULTS: Men with high psychological distress were at risk of developing an increased waist-to-height ratio (F = 3.4, P = 0.038). Men with high psychological distress and low HRV were prone to develop an increased body mass and hip-to-height ratio (psychological distress: F = 4.3, P = 0.016; HRV: F = 5.0, P = 0.008). Statistical trends showed that women displayed similar patterns of stress-related changes in body form (P = 0.061; P = 0.063). CONCLUSIONS: Assessing psychological distress and autonomic variability predicts changes in body form. Psychological distress was found to be associated with an increased risk of developing the wide-waisted phenotype, while psychological distress combined with low autonomic variability was associated with an increased risk of developing the corpulent phenotype.

Rise of ketone bodies with psychosocial stress in normal weight men.

BACKGROUND: Ketone bodies are known as alternative cerebral energy substrates to glucose. During psychosocial stress, the brain of a normal weight subject demands for extra glucose from the body to satisfy its increased needs. In contrast, the brain of an obese subject organizes its need, supply and demand in a low-reactive manner. The present study aimed at investigating (i) whether psychosocial stress increases ketone body concentrations and (ii) whether ketone reactivity to a psychosocial challenge differs between normal weight and obese people. METHODS: Ten normal weight and ten obese men participated in two sessions (stress induced by the Trier Social Stress Test and a non-stress control session). Blood samples were frequently taken to assess serum ß-hydroxybutyrate concentrations and stress hormone profiles. RESULTS: Our main finding was that social stress markedly increased concentrations of serum ß-hydroxybutyrate by 454% in normal weight men. The increase in ketone bodies during stress in normal weight subjects was associated with an increase in ACTH, norepinephrine and epinephrine concentrations. Interestingly, we could not detect any increase in serum ß-hydroxybutyrate concentrations during stress in obese men. CONCLUSION: Normal weight men showed high ketone reactivity to a psychosocial challenge.

Energy allocation between brain and body during ontogenetic development.

OBJECTIVE: We here studied how energy is allocated between brain and body both during the ontogenetic development from a child to an adult and during weight loss. METHODS: We investigated 180 normal weight female and male children and adolescents (aged 6.1-19.9 years) as well as 35 overweight adolescents undergoing weight reduction intervention. 52 normal weight and 42 obese adult women were used for comparison. We assessed brain mass by magnetic-resonance-imaging and body metabolism by indirect calorimetry. To study how energy is allocated between brain and body, we measured plasma insulin, since insulin fulfils the functions of a glucose allocating hormone, i.e., peripheral glucose uptake depends on insulin, central uptake does not. We used reference data obtained in the field of comparative biology. In a brain-body-plot, we calculated the distance between each subject and a reference mammal of comparable size and named the distance "encephalic measure." With higher encephalic measures, more energy is allocated to the brain. RESULTS: We found that ontogenetic development from a child to an adult was indicated by decreasing encephalic measures in females (r = -0.729, P < 0.001) and increasing plasma insulin concentrations (F = 6.6, P = 0.002 in females and F = 8.6, P < 0.001 in males). Weight loss of about 5 kg in females and about 9 kg in males resulted in reduced insulin concentrations and increased encephalic measures. CONCLUSION: Our results indicate that the share of energy allocated to the brain increased with weight loss, but decreased during the ontogenetic development from childhood to adolescence. These developmental changes in brain-to-body energy allocation appear to be driven by increasing plasma insulin concentrations.

The corpulent phenotype-how the brain maximizes survival in stressful environments.

The reactivity of the stress system may change during the life course. In many-but not all-humans the stress reactivity decreases, once the individual is chronically exposed to a stressful and unsafe environment (e.g., poverty, work with high demands, unhappy martial relationship). Such an adaptation is referred to as habituation. Stress habituation allows alleviating the burden of chronic stress, particularly cardiovascular morbidity and mortality. Interestingly, two recent experiments demonstrated low stress reactivity during a mental or psychosocial challenge in subjects with a high body mass. In this focused review we attempt to integrate these experimental findings in a larger context. Are these data compatible with data sets showing a prolonged life expectancy in corpulent people? From the perspective of neuroenergetics, we here raise the question whether "obesity" is unhealthy at all. Is the corpulent phenotype possibly the result of "adaptive phenotypic plasticity" allowing optimized survival in stressful environments?

Rise in plasma lactate concentrations with psychosocial stress: a possible sign of cerebral energy demand.

OBJECTIVE: It is known that exogenous lactate given as an i.v. energy infusion is able to counteract a neuroglycopenic state that developed during psychosocial stress. It is unknown, however, whether the brain under stressful conditions can induce a rise in plasma lactate to satisfy its increased needs during stress. Since lactate is i) an alternative cerebral energy substrate to glucose and ii) its plasmatic concentration is influenced by the sympathetic nervous system, the present study aimed at investigating whether plasma lactate concentrations increase with psychosocial stress in humans. METHODS: 30 healthy young men participated in two sessions (stress induced by the Trier Social Stress Test and a non-stress control session). Blood samples were frequently taken to assess plasma lactate concentrations and stress hormone profiles. RESULTS: Plasma lactate increased 47% during psychosocial stress (from 0.9 ± 0.05 to 1.4 ± 0.1 mmol/l; interaction time × stress intervention: F = 19.7, p < 0.001). This increase in lactate concentrations during stress was associated with an increase in epinephrine (R(2) = 0.221, p = 0.02) and ACTH concentrations (R(2) = 0.460, p < 0.001). CONCLUSION: Plasma lactate concentrations increase during acute psychosocial stress in humans. This finding suggests the existence of a demand mechanism that functions to allocate an additional source of energy from the body towards the brain, which we refer to as 'cerebral lactate demand'.

The brain's supply and demand in obesity.

During psychosocial stress, the brain demands extra energy from the body to satisfy its increased needs. For that purpose it uses a mechanism referred to as "cerebral insulin suppression" (CIS). Specifically, activation of the stress system suppresses insulin secretion from pancreatic beta-cells, and in this way energy-particularly glucose-is allocated to the brain rather than the periphery. It is unknown, however, how the brain of obese humans organizes its supply and demand during psychosocial stress. To answer this question, we examined 20 obese and 20 normal weight men in two sessions (Trier Social Stress Test and non-stress control condition followed by either a rich buffet or a meager salad). Blood samples were continuously taken and subjects rated their vigilance and mood by standard questionnaires. First, we found a low reactive stress system in obesity. While obese subjects showed a marked hormonal response to the psychosocial challenge, the cortisol response to the subsequent meal was absent. Whereas the brains of normal weight subjects demanded for extra energy from the body by using CIS, CIS was not detectable in obese subjects. Our findings suggest that the absence of CIS in obese subjects is due to the absence of their meal-related cortisol peak. Second, normal weight men were high reactive during psychosocial stress in changing their vigilance, thereby increasing their cerebral energy need, whereas obese men were low reactive in this respect. Third, normal weight subjects preferred carbohydrates after stress to supply their brain, while obese men preferred fat and protein instead. We conclude that the brain of obese people organizes its need, supply, and demand in a low reactive manner.

The selfish brain: stress and eating behavior.

The brain occupies a special hierarchical position in human energy metabolism. If cerebral homeostasis is threatened, the brain behaves in a "selfish" manner by competing for energy resources with the body. Here we present a logistic approach, which is based on the principles of supply and demand known from economics. In this "cerebral supply chain" model, the brain constitutes the final consumer. In order to illustrate the operating mode of the cerebral supply chain, we take experimental data which allow assessing the supply, demand and need of the brain under conditions of psychosocial stress. The experimental results show that the brain under conditions of psychosocial stress actively demands energy from the body, in order to cover its increased energy needs. The data demonstrate that the stressed brain uses a mechanism referred to as "cerebral insulin suppression" to limit glucose fluxes into peripheral tissue (muscle, fat) and to enhance cerebral glucose supply. Furthermore psychosocial stress elicits a marked increase in eating behavior in the post-stress phase. Subjects ingested more carbohydrates without any preference for sweet ingredients. These experimentally observed changes of cerebral demand, supply and need are integrated into a logistic framework describing the supply chain of the selfish brain.

Why doesn't the brain lose weight, when obese people diet?

OBJECTIVE: As has been shown recently, obesity is associated with brain volume deficits. We here used an interventional study design to investigate whether the brain shrinks after caloric restriction in obesity. To elucidate mechanisms of neuroprotection we assessed brain-pull competence, i.e. the brain's ability to properly demand energy from the body. METHODS: In 52 normal-weight and 42 obese women (before and after ≈10% weight loss) organ masses of brain, liver and kidneys (magnetic resonance imaging), fat (air displacement plethysmography) and muscle mass (dual-energy X-ray absorptiometry) were assessed. Body metabolism was measured by indirect calorimetry. To investigate how energy is allocated between brain and body, we used reference data obtained in the field of comparative biology. We calculated the distance between each woman and a reference mammal of comparable size in a brain-body plot and named the distance 'encephalic measure'. To elucidate how the brain protects its mass, we measured fasting insulin, since 'cerebral insulin suppression' has been shown to function as a brain-pull mechanism. RESULTS: Brain mass was equal in normal-weight and obese women (1,441.8 ± 14.6 vs. 1,479.2 ± 12.8 g; n.s.) and was unaffected by weight loss (1,483.8 ± 12.7 g; n.s.). In contrast, masses of muscle, fat, liver and kidneys decreased by 3-18% after weight loss (all p < 0.05). The encephalic measure was lower in obese than normal-weight women (5.8 ± 0.1 vs. 7.4 ± 0.1; p < 0.001). Weight loss increased the encephalic measure to 6.3 ± 0.1 (p < 0.001). Insulin concentrations were inversely related to the encephalic measure (r = -0.382; p < 0.001). CONCLUSION: Brain mass is normal in obese women and is protected during caloric restriction. Our data suggest that neuroprotection during caloric restriction is mediated by a competent brain-pull exerting cerebral insulin suppression.