Christian Hubold

How the Selfish Brain Organizes its Supply and Demand

During acute mental stress, the energy supply to the human brain increases by 12%. To determine how the brain controls this demand for energy, 40 healthy young men participated in two sessions (stress induced by the Trier Social Stress Test and non-stress intervention). Subjects were randomly assigned to four different experimental groups according to the energy provided during or after stress intervention (rich buffet, meager salad, dextrose-infusion and lactate-infusion). Blood samples were frequently taken and subjects rated their autonomic and neuroglycopenic symptoms by standard questionnaires. We found that stress increased carbohydrate intake from a rich buffet by 34 g (from 149 ± 13 g in the non-stress session to 183 ± 16 g in the stress session; P < 0.05). While these stress-extra carbohydrates increased blood glucose concentrations, they did not increase serum insulin concentrations. The ability to suppress insulin secretion was found to be linked to the sympatho-adrenal stress-response. Social stress increased concentrations of epinephrine 72% (18.3 ± 1.3 vs. 31.5 ± 5.8 pg/ml; P < 0.05), norepinephrine 148% (242.9 ± 22.9 vs. 601.1 ± 76.2 pg/ml; P < 0.01), ACTH 184% (14.0 ± 1.3 vs. 39.8 ± 7.7 pmol/l; P < 0.05), cortisol 131% (5.4 ± 0.5 vs. 12.4 ± 1.3 μg/dl; P < 0.01) and autonomic symptoms 137% (0.7 ± 0.3 vs. 1.7 ± 0.6; P < 0.05). Exogenous energy supply (regardless of its character, i.e., rich buffet or energy infusions) was shown to counteract a neuroglycopenic state that developed during stress. Exogenous energy did not dampen the sympatho-adrenal stress-responses. We conclude that the brain under stressful conditions demands for energy from the body by using a mechanism, which we refer to as “cerebral insulin suppression” and in so doing it can satisfy its excessive needs.

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.

Modeling the hypothalamus–pituitary–adrenal system: homeostasis by interacting positive and negative feedback

The hypothalamus–pituitary–adrenal (HPA) system is closely related to stress and the restoration of homeostasis. This system is stimulated in the second half of the night, decreases its activity in the daytime, and reaches the homeostatic level during the late evening. In this paper, we derive and discuss a novel model for the HPA system. It is based on three simple rules that constitute a principle of homeostasis and include only the most substantive physiological elements. In contrast to other models, its main components include, apart from the conventional negative feedback ingredient, a positive feedback loop. To validate the model, we present a parameter estimation procedure that enables one to adapt the model to clinical observations. Using this methodology, we are able to show that the novel model is capable of simulating clinical trials. Furthermore, the stationary state of the system is investigated. We show that, under mild conditions, the system always has a well-defined set-point, which reflects the clinical situation to be modeled. Finally, the computed parameters may be interpreted from a physiological point of view, thereby leading to insights about diseases like depression, obesity, or diabetes.

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.

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.

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 (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’.

Effects of glucose infusion on neuroendocrine and cognitive parameters in Addison disease

Sucrose intake has been shown to suppress increased adrenocorticotropic hormone (ACTH) levels in adrenalectomized rats, suggesting that increased cerebral energy supply can compensate for the loss of glucocorticoid feedback inhibition of the hypothalamo-pituitary-adrenal axis. We hypothesized that glucose infusion might acutely down-regulate increased ACTH secretion in patients with Addison disease. We studied 8 patients with primary adrenal insufficiency (Addison group) with short-term discontinuation of hydrocortisone substitution and 8 matched healthy controls in 2 randomized conditions. Subjects received either intravenous glucose infusion (0.75 g glucose per kilogram body weight for 2.5 hours) or placebo. Concentrations of ACTH, cortisol, catecholamines, growth hormone, glucagon, and insulin were measured; and cognitive functions as well as neuroglycopenic and autonomic symptoms were assessed. The ACTH concentrations were not affected by glucose infusion either in the Addison or in the control group. Likewise, concentrations of cortisol, epinephrine, norepinephrine, growth hormone, and glucagon remained unchanged in both groups. Neurocognitive performance and symptom scores were likewise not affected. Independent of glucose infusion, attention of the Addison patients was impaired in comparison with the control group. Our study in patients with Addison disease was not able to support the assumption of a compensatory effect of intravenous glucose infusion on hormonal parameters and neurocognitive symptoms in states of chronic cortisol deficiency. Further studies should examine whether different regimens of glucose administration are more effective.

High plasma VEGF relates to low carbohydrate intake in patients with type 2 diabetes

Objective:Vascular endothelial growth factor (VEGF) has been suggested to enhance glucose transport across the blood–brain barrier, thereby increasing brain glucose supply. Increased brain glucose concentration is known to suppress food intake and to decrease body mass via action on hypothalamic regulation centers. Based on the crucial role of VEGF on brain glucose supply, we hypothesized that higher VEGF concentrations are associated with lower food intake and body mass in humans.Methods:Intending to investigate subjects with high variance of blood glucose, we examined patients with type 2 diabetes mellitus. Our hypothesis was tested in a population-based cohort of 190 subjects with type 2 diabetes. Plasma VEGF levels in conjunction with other parameters known to modulate food intake were measured and subsequently correlated with food intake patterns at a breakfast buffet as well as with body mass.Results:We found that subjects with higher concentrations of plasma VEGF had 17% less carbohydrate intake (P=0.003) and 4.8% lower body mass (P=0.017) than those with lower VEGF concentrations. Intake of protein and fat did not correlate with VEGF concentrations. These associations of plasma VEGF were confirmed in multiple linear regression analyses controlling for several parameters interacting with food intake.Conclusion:We conclude that high plasma VEGF concentrations are associated with less carbohydrate intake and lower body mass in type 2 diabetes. The role VEGF plays in facilitating glucose access to the brain represents a new aspect of food intake regulation and energy homeostasis, with relevance for diseases with body mass disturbances.

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 β-hydroxybutyrate concentrations and stress hormone profiles. RESULTS Our main finding was that social stress markedly increased concentrations of serum β-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 β-hydroxybutyrate concentrations during stress in obese men. CONCLUSION Normal weight men showed high ketone reactivity to a psychosocial challenge.