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.

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.

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 mug/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.

Low plasma lactate concentration as a biomarker of an incompetent brain-pull: a risk factor for weight gain in type 2 diabetes patients.

OBJECTIVE: Body weight development is closely regulated by central nervous mechanisms. As has been demonstrated recently, the capability of the brain to actively demand energy from the body (brain-pull) is indispensable for the maintenance of systemic homeostasis. A deficit in this brain-pull may result in compensatory ingestive behavior followed by weight gain in the medium or long term. The aim of this study was to establish a biomarker of such an incompetent brain-pull. Since lactate is an alternative cerebral energy substrate to glucose, we investigated whether low fasting plasma lactate concentrations are associated with weight gain and increased feelings of hunger in patients with type 2 diabetes over a 3-year period. METHODS: In a population based cohort study 134 type 2 diabetes patients were examined at baseline and 3-year follow-up. Plasma lactate concentrations and additional hormones associated with food intake such as e.g. insulin, or leptin, as well as psychological variables like hunger feelings before and after a standardized breakfast were measured. The relation between fasting plasma lactate concentrations and postprandial hunger as well as follow-up weight was analyzed. RESULTS: Low fasting plasma lactate concentrations predicted a higher 3-year follow-up weight (B=-1.268, SE=0.625, p=0.04). Moreover, low fasting plasma lactate concentrations were associated with more pronounced feelings of postprandial hunger (B=-0.406, SE=0.137, p<0.01). CONCLUSIONS: We conclude that low plasma lactate concentrations may represent a biomarker of an incompetent brain-pull, which is associated with weight gain and increased postprandial hunger in patients with type 2 diabetes mellitus. These results are in line with the view that plasma lactate can be used by the brain as an alternative energy substrate and thereby to some extent prevent overeating and obesity.

High-calorie glucose-rich food attenuates neuroglycopenic symptoms in patients with Addison's disease.

CONTEXT/OBJECTIVE: Patients with Addison's disease often suffer from fatigue, faintness, lack of concentration, and memory deficits, i.e. symptoms reminiscent of those of neuroglycopenia. Suspecting that a lack of central nervous glucose contributes to these symptoms, we examined whether they can be attenuated by the intake of palatable food rich in glucose ("comfort food") in these patients and, furthermore, whether comfort food reduces hypothalamus-pituitary-adrenal axis activity as observed in animal studies. Design/Setting/Patients/Outcome: Ten Addison patients with primary adrenal insufficiency and acutely discontinued cortisol substitution and 10 matched healthy controls each participated in two experimental sessions in which they were offered a free-choice high-calorie buffet (comfort food) and green salad, respectively, after a mental stress test. Neuroglycopenic and autonomic symptoms, cognitive function (short-term memory, attention), and hormones of the sympathoadrenal system (ACTH, cortisol, catecholamines) were assessed throughout the sessions. RESULTS: Scores of neuroglycopenic symptoms were persistently higher in Addison patients than in controls and were improved by comfort food in comparison to salad (P < 0.04), whereas control subjects did not show such changes. Attention was generally reduced in patients as compared to controls (P < 0.05) and was slightly improved by comfort food, as was memory (each P < 0.07). Sympathoadrenal hormone concentrations remained unaltered. CONCLUSIONS: High-calorie comfort food reduces symptoms of neuroglycopenia in Addison patients, suggesting that Addison's disease is associated with a deficit in cerebral energy supply that can partly be alleviated by intake of palatable food. It will be important to investigate whether additional oral glucose supply may be helpful in improving patients' well-being.

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.

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.

Increased serum brain-derived neurotrophic factor protein upon hypoxia in healthy young men.

Exposing animals to brief hypoxic periods leads to neuroprotective ischemic tolerance termed preconditioning. This phenomenon is well documented in the brain, but the underlying mechanisms require further elucidation. As nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important mediators of maintaining homeostatic conditions in the adult nervous system in terms of physiological and pathophysiological processes, we hypothesized that hypoxic preconditioning might modulate serum neurotrophin concentrations. Hypoxia was induced for 30 min in 14 healthy young men resulting in a constant blood oxygen saturation of 75%. Hyperinsulinemic euglycemic clamps were performed and serum concentrations of BDNF and NGF were measured at baseline, directly after the intervention, and at the end of the session. Overall, serum BDNF concentrations decreased over time by maximally 35% (P = 0.001) while in contrast NGF concentrations remained unchanged. Acute hypoxia alleviated the decrease of BDNF resulting in higher BDNF concentrations as compared to normoxic control (P < 0.01). Our findings show that acute hypoxia results in significantly higher serum BDNF concentrations pointing to a potential role of BDNF in the underlying mechanism of hypoxic preconditioning. Based on its neuroprotective properties, BDNF may be of high clinical relevance for therapeutic options in ischemic neurovascular diseases.

Blocking NMDA receptor signaling does not decrease hormonal counterregulation to hypoglycemia in humans.

In animals, blocking of glutamate signaling at the N-methyl-D-aspartate (NMDA) receptor reduces the neuroendocrine counterregulation to hypoglycemia. Hence, it has been proposed that increased excitatory glutamatergic input to the hypothalamus signals enforced central nervous energy demand under conditions of reduced supply. We examined the effect of the NMDA receptor antagonist memantine on hypoglycemia counterregulation in healthy humans. Hypoglycemic clamp experiments were performed in 10 healthy men after oral administration of 20 mg memantine and placebo. Counterregulatory hormones were measured during baseline and a clamp period of 120 min with hypoglycemia of 2.4 mmol/l lasting for 50 min. In addition, symptoms related to glycemic changes were assessed. Unexpectedly, the counterregulatory responses to hypoglycemia of adrenocorticotropin, cortisol and epinephrine were not decreased but tended to be increased by memantine, while norepinephrine and growth hormone were not affected. Glucagon levels were increased by memantine treatment during baseline and throughout the hypoglycemic period. After memantine administration, subjects also experienced more neuroglycopenic symptoms during hypoglycemia, whereas differences in autonomic symptoms did not reach significance. Contrasting with findings in animals, blocking the NMDA receptor does not decrease the counterregulatory responses to hypoglycemia in humans. Our data do not support the view that in humans, enhanced glutamate signaling during hypoglycemia supports the satisfaction of increased central nervous energy demands by enforcing hormonal counterregulation.

Preserved circadian rhythm of serum insulin concentration at low plasma glucose during fasting in lean and overweight humans.

Circadian rhythms in glucose metabolism are well documented. Most studies, however, evaluated such variations under conditions of continuous glucose supply, either via food intake or glucose infusion. Here we assessed in 30 subjects circadian variations in concentrations of plasma glucose, serum insulin, and C-peptide during a 72-hour fasting period to evaluate rhythms independent from glucose supply. Furthermore we assessed differences in these parameters between normal-weight (n = 20) and overweight (n = 10) subjects. Blood was sampled every 4 hours. During fasting, plasma glucose, serum insulin, and C-peptide levels gradually decreased (all P < .001). While there was no circadian variation in plasma glucose levels after the first day of fasting, serum levels of insulin were constantly higher in the morning (8.00 h) than at night (0.00 h) (P < .001), although the extent of this morning-associated rise in insulin levels decreased with the time spent fasting (P = .001). Also, morning C-peptide concentrations were higher compared to the preceding night (P < .001). The C-peptide/insulin ratio (CIR) decreased during prolonged fasting (P = .030), suggesting a decrease in hepatic insulin clearance. Moreover, CIR was significantly lower in the morning than at the night of day 1 and day 2 of fasting (P = .010 and P = .004, respectively). Compared to normal-weight subjects, overweight subjects had higher plasma glucose, as well as serum insulin and C-peptide levels (all P < .03). Data indicate preserved circadian rhythms in insulin concentrations in the presence of substantially decreased glucose levels in normal-weight and overweight subjects. This finding suggests a central nervous system contribution to the regulation of insulin secretion independent of plasma glucose levels.