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.

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.

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 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.

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 (R² = 0.221, p = 0.02) and ACTH concentrations (R² = 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’.

ObjectiveStress 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 don't. Heart-rate-variability (HRV) reflects ‘autonomic variability’ and is related to stress responses to psychosocial challenges. We hypothesized that the combined effects of ‘stress exposure’ and ‘autonomic variability’ predict long-term changes in body form.MethodsData of 1369 men and 612 women from the Whitehall II cohort were analyzed. Body-mass-index, hip-to-height-ratio and waist-to-height-ratio were measured at three time points over a ten-year period. HRV and ‘psychological distress’ (General-Health-Questionnaire) were assessed.ResultsMen 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). We found statistical trends that women displayed similar patterns of stress-related changes in body form (P=0.061;P=0.063).ConclusionAssessing ‘psychological distress’ and ‘autonomic variability’ predicts changes in body form. Psychological distress was found 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’.

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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?