Compact energy metabolism model: Brain controlled energy supply

The regulation of the energy metabolism is crucial to ensure the functionality of the entire organism. Deregulations may lead to severe pathologies such as obesity and type 2 diabetes mellitus. The decisive role of the brain as the active controller and heavy consumer in the complex whole body energy metabolism is the matter of recent research. Latest studies suggest that the brain's energy supply has the highest priority while all organs in the organism compete for the available energy resources. In our novel mathematical model, we address these new findings. We integrate energy fluxes and their control signals such as glucose fluxes, insulin signals as well as the ingestion momentum in our new dynamical system. As a novel characteristic, the hormone insulin is regarded as central feedback signal of the brain. Hereby, our model particularly contains the competition for energy between brain and body periphery. The analytical investigation of the presented dynamical system shows a stable long-term behavior of the entire energy metabolism while short time observations demonstrate the typical oscillating blood glucose variations as a consequence of food intake. Our simulation results demonstrate a realistic behavior even in situations like exercise or exhaustion, and key elements like the brain's preeminence are reflected. The presented dynamical system is a step towards a systemic understanding of the human energy metabolism and thus may shed light to defects causing diseases based on deregulations in the energy metabolism.     

An adipocyte-central nervous system regulatory loop in the control of adipose homeostasis.

Mounting evidence supports a 'lipostatic' model for the regulation of adipose mass. In such a model, signals are generated in the periphery in proportion to adipose mass that act on hypothalamic control centers in the brain to regulate food intake and energy expenditure. Two such signals, leptin and insulin, have been identified and found to dramatically lower food intake and body weight. Several signalling molecules in the effector pathways that mediate the response to these signals in the brain have also been identified. The regulation of these factors and the nature of the adipose-CNS regulatory loop will be discussed.     

Iron and mechanisms of emotional behavior

Iron is required for appropriate behavioral organization. Iron deficiency results in poor brain myelination and impaired monoamine metabolism. Glutamate and γ-aminobutyric acid homeostasis is modified by changes in brain iron status. Such changes produce not only deficits in memory/learning capacity and motor skills, but also emotional and psychological problems. An accumulating body of evidence indicates that both energy metabolism and neurotransmitter homeostasis influence emotional behavior, and both functions are influenced by brain iron status. Like other neurobehavioral aspects, the influence of iron metabolism on mechanisms of emotional behavior is multifactorial: brain region-specific control of behavior, regulation of neurotransmitters and associated proteins, temporal and regional differences in iron requirements, oxidative stress responses to excess iron, sex differences in metabolism, and interactions between iron and other metals. To better understand the role that brain iron plays in emotional behavior and mental health, this review discusses the pathologies associated with anxiety and other emotional disorders with respect to body iron status.     

An integrated mathematical model of the dynamics of blood glucose and its hormonal control

An integrated whole-organism model of the short-term blood glucose regulation system is presented. The model is of the comprehensive type, is nonlinear, and evidences the major crucial processes of glucose, insulin, and glucagon dynamics per se and their interrelationships. Validation of the model has been performed by dealing simultaneously with different kinds of test inputs in a variety of normal and pathological states and by looking not only at plasma accessible variables, but also at the behavior of unit processes. Current practical uses of the model in the area of carbohydrate metabolism regulation are briefly outlined.     

Energy compensation and metabolic adaptation: “The Biggest Loser” study reinterpreted

“The Biggest Loser” weight-loss competition offered a unique opportunity to investigate human energy metabolism and body composition before, during, and after an extreme lifestyle intervention. Here, I reinterpret the results of “The Biggest Loser” study in the context of a constrained model of human energy expenditure. Specifically, “The Biggest Loser” contestants engaged in large, sustained increases in physical activity that may have caused compensatory metabolic adaptations to substantially decrease resting metabolic rate and thereby minimize changes in total energy expenditure. This interpretation helps explain why the magnitude of persistent metabolic adaptation was largest in contestants with the greatest increases in sustained physical activity and why weight-loss interventions involving lower levels of physical activity have not measured similarly large metabolic adaptations. Additional longitudinal studies quantifying the interrelationships between various components of energy expenditure and energy intake are needed to better understand the dynamics of human body weight regulation.     

Checking of some hypotheses of the pathogenesis of diabetes mellitus by mathematical modeling

A mathematical model of normal regulation of carbohydrate metabolism by the pancreas endocrine apparatus is presented. In a numerical experiment the model imitated changed levels of sucrose, insulin glucagon and gastrointestinal hormones in the blood in response to the ingested 50 g of glucose. The model of normal regulation was damaged in the way which theoretically should result in diabetes development. Then an estimation was made to what extent the disturbances of carbohydrate metabolism characteristic of diabetes were reproduced by the changed model. It has been shown that disturbances specific for diabetes appear when the sensitivity of beta-cells to glucose stimulus or hyperproduction of glucagon decreased. No changes in the behaviour of blood glucose typical of diabetes were obtained in the model when a decrease of the sensitivity of insulin receptors due to hyperinsulinemia in insulin-dependent tissues was imitated, as well as an increased activity of liver insulinase or hyposecretion of gastrointestinal hormones. These results point to the necessity of further development of these hypotheses.     

Neutral amino acid transport at the human blood-brain barrier

Transport regulates nutrient availability in the brain, and many pathways of brain amino acid metabolism are influenced by precursor supply. Therefore, amino acid transport through the blood-brain barrier (BBB) plays an important rate-affecting role in brain metabolism. Information on the Km of BBB amino acid transport provides the quantitative basis for understanding the physiological importance of BBB transport competition effects. For example, the uniquely low Km values of BBB amino acid transport as compared to other organs in the rat provides the basis for the selective vulnerability of the rat brain to changes in amino acid supply caused by nutritional factors. The development of amino acid imbalances in the human brain in parallel with amino acid imbalances in blood is likely to occur if the Km of BBB neutral amino acid transport in humans is low, e.g., 25-100 microM, as is the case for the rat. A new model system of the human BBB, the isolated human brain capillary, has been developed. Recent studies with this system indicate that the Km of phenylalanine transport into human brain microvessels is approximately the same as that found during in vivo studies with laboratory rats. These results support the emerging hypothesis that the human brain, like the rat brain, is subject to acute regulation by dietary-related amino acid imbalances, and that the major site of this regulation is the amino acid transport system at the BBB.     

Role of set-point theory in regulation of body weight

In adult individuals body weight is maintained at a relatively stable level for long periods. The set-point theory suggests that body weight is regulated at a predetermined, or preferred, level by a feedback control mechanism. Information from the periphery is carried by an affector to a central controller located in the hypothalamus. The controller integrates and transduces the information into an effector signal that modulates food intake or energy expenditure to correct any deviations in body weight from set-point. Evidence for involvement of various factors and physiological systems in the control of food intake and regulation of body weight and fat are reviewed within the context of a control model. Current working hypotheses include roles for nutrients, dietary composition and organoleptic properties, hormones, neural pathways, various brain nuclei, and many neurotransmitters in the regulation of food intake. It is concluded that regulation of body weight in relation to one specific parameter related to energy balance is unrealistic. It seems appropriate to assume that the level at which body weight and body fat content are maintained represents the equilibria achieved by regulation of many parameters.     

瘦素在糖脂代谢中的调控作用

瘦素（leptin）是OB基因的编码产物,由脂肪细胞分泌,具有广泛的生理学功能.瘦素可通过作用于中枢神经系统与外周组织等途径在糖脂代谢调控、能量代谢、生殖发育及免疫调节过程中起重要作用.不同剂量、不同作用时间,也可导致瘦素产生不同的生理学作用.近年来,随着肥胖及糖尿病在全球范围内成为流行病,瘦素在糖脂代谢中的调控作用引起了人们的广泛关注.现有的研究已发现,瘦素抵抗与胰岛素抵抗之间具有重要的关联性,揭示瘦素功能异常在肥胖诱发的糖脂代谢紊乱过程中起着重要的作用.本文将对瘦素在机体糖脂代谢中的调控作用进行综述和讨论.     

Low Sympathetic Tone and Obese Phenotype in Oxytocin‐deficient Mice

Oxytocin (Oxt) is secreted both peripherally and centrally and is involved in several functions including parturition, milk let‐down reflex, social behavior, and food intake. Recently, it has been shown that mice deficient in Oxt receptor develop late‐onset obesity. In this study, we characterized a murin model deficient in Oxt peptide (Oxt^?/?) to evaluate food intake and body weight, glucose tolerance and insulin tolerance, leptin and adrenaline levels. We found that Oxt^?/? mice develop late‐onset obesity and hyperleptinemia without any alterations in food intake in addition to having a decreased insulin sensitivity and glucose intolerance. The lack of Oxt in our murin model also results in lower adrenalin levels which led us to hypothesize that the metabolic changes observed are associated with a decreased sympathetic nervous tone. It has been shown that Oxt neurons in the paraventricular nucleus (PVN) are a component of a leptin‐sensitive signaling circuit between the hypothalamus and caudal brain stem for the regulation of food intake and energy homeostasis. Nevertheless, the lack of Oxt in these mice does not have a direct impact on feeding behavior whose regulation is probably dependent on the complex interplay of several factors. The lack of hyperphagia evident in the Oxt^?/? mice may, in part, be attributed to the developmental compensation of other satiety factors such as cholecystokinin or bombesin‐related peptides which merits further investigation. These findings identify Oxt as an important central regulator of energy homeostasis.     

Serotonin regulates C. elegans fat and feeding through independent molecular mechanisms

We investigated serotonin signaling in C. elegans as a paradigm for neural regulation of energy balance and found that serotonergic regulation of fat is molecularly distinct from feeding regulation. Serotonergic feeding regulation is mediated by receptors whose functions are not required for fat regulation. Serotonergic fat regulation is dependent on a neurally expressed channel and a G protein-coupled receptor that initiate signaling cascades that ultimately promote lipid breakdown at peripheral sites of fat storage. In turn, intermediates of lipid metabolism generated in the periphery modulate feeding behavior. These findings suggest that, as in mammals, C. elegans feeding behavior is regulated by extrinsic and intrinsic cues. Moreover, obesity and thinness are not solely determined by feeding behavior. Rather, feeding behavior and fat metabolism are coordinated but independent responses of the nervous system to the perception of nutrient availability.     

A role for beta-melanocyte-stimulating hormone in human body-weight regulation

Pro-opiomelanocortin (POMC) expressing neurons mediate the regulation of orexigenic drive by peripheral hormones such as leptin, cholecystokinin, ghrelin, and insulin. Most research effort has focused on alpha-melanocyte-stimulating hormone (alpha-MSH) as the predominant POMC-derived neuropeptide in the central regulation of human energy balance and body weight. Here we report a missense mutation within the coding region of the POMC-derived peptide beta-MSH (Y5C-beta-MSH) and its association with early-onset human obesity. In vitro and in vivo data as well as postmortem human brain studies indicate that the POMC-derived neuropeptide beta-MSH plays a critical role in the hypothalamic control of body weight in humans.     

Responses to nutrients in farm animals: implications for production and quality

It is well known that any quantitative (energy and protein levels) and qualitative (nature of the diet, nutrient dynamic) changes in the feeding of animals affect metabolism. Energy expenditure and feed efficiency at the whole-body level, nutrient partitioning between and within tissues and organs and, ultimately, tissue and organ characteristics are the major regulated traits with consequences on the quality of the meat and milk produced. Recent progress in biology has brought to light important biological mechanisms which explain these observations: for instance, regulation by the nutrients of gene expression or of key metabolic enzyme activity, interaction and sometimes cross-regulation or competition between nutrients to provide free energy (ATP) to living cells, indirect action of nutrients through a complex hormonal action, and, particularly in herbivores, interactions between trans-fatty acids produced in the rumen and tissue metabolism. One of the main targets of this nutritional regulation is a modification of tissue insulin sensitivity and hence of insulin action. In addition, the nutritional control of mitochondrial activity (and hence of nutrient catabolism) is another major mechanism by which nutrients may affect body composition and tissue characteristics. These regulations are of great importance in the most metabolically active tissues (the digestive tract and the liver) and may have undesirable (i.e. diabetes and obesity in humans) or desirable consequences (such as the production of fatty liver by ducks and geese, and the production of fatty and hence tasty meat or milk with an adapted fatty acid profile).     

Orexins and adipoinsular axis function in the rat

Orexin A and B are recently identified as peptides that are derived from the same precursor and their expression is highly specifically localized in neurons located in the lateral hypothalamic area, a region implicated in the feeding behaviour. These peptides appear to be a part of a complex circuit that integrates the aspects of energy metabolism, cardiovascular function, hormone homeostasis and sleep/wake behaviours. The functional linking of orexins with leptin and insulin suggests the possibility of its involvement in the regulation of the adipoinsular axis, and the present investigation was designed to examine the potential role of orexins in this axis regulation. In all the tested doses (8, 16 and 40 nmol/kg body weight (b.w.)), subcutaneous (s.c.) injections of orexin A caused the significant increase in insulin and leptin blood levels. These elevations were observed 60 and 120 min after peptide administration. On the other hand, after the orexin B administration, elevated insulin and leptin blood concentrations were found only at 60 min of the experiment, and in that time point, the increases were comparable to that evoked by orexin A. In comparison with the control animals, the administration of orexins for 7 days resulted in a significant gain in body weight. Prolonged administration of either orexin A or orexin B significantly elevated insulin and leptin blood concentrations. Under these conditions, the orexin A effect on the leptin secretion was more marked than on the insulin secretion, and this difference is reflected by the lowered insulin/leptin molar ratio. These results suggest that orexins play an important role in the adipoinsular axis function and may be a significant regulator of both insulin and leptin secretion. In this regard, we suggest the updated functional model of Kieffer and Habener [Am. J. Physiol.: Endocrinol. Metab. 27 (2000) E1] that proposed the adipoinsular axis. Our model is extended by the probable humoral links between orexins and leptin and orexins and insulin and points on the dependence of the effects evoked by orexins, leptin and insulin on the blood glucose levels.     

Role of Insulin Signaling in Maintaining Energy Homeostasis

ObjectiveTo examine the role that insulin signaling plays in modulating metabolic functions involving both peripheral and hypothalamic systems.MethodsWe review the literature regarding insulin signaling as it relates to energy homeostasis.ResultsInsulin signaling in the periphery is known to affect hepatic glucose production and glucose uptake in muscle and adipose tissue. In the brain, insulin is involved in a variety of signaling pathways that control positive and negative aspects of food intake and energy metabolism. Disruption of insulin signaling can affect key cellular pathways that serve to maintain energy balance and glucose homeostasis, which can then lead to insulin resistance and progression toward various metabolic disorders, including cardiovascular disease, obesity, and type 2 diabetes. The use of exogenous insulin as therapy for patients with type 2 diabetes is traditionally associated with increases in weight.ConclusionAn enhanced understanding of how these insulin signaling pathways function may provide answers about how to control weight gain associated with exogenous insulin use. Pharmacologic agents, such as the long-acting insulin analogues and particularly insulin detemir, that may reduce these weight effects hold considerable advantage. (Endocr Pract. 2008;14:373-380)     

High body weight associated with impaired nonshivering thermogenesis but improved glucose tolerance in Mongolian gerbils (Meriones unguiculatus)

Overweight and obesity correspond with metabolic syndromes, such as glucose intolerance and type 2 diabetes. The objective of this study was to determine whether decreased thermogenesis mass and glucose intolerance are directly related to changes in body mass in Mongolian gerbils. High body weight gerbils displayed increase in total body fat mass especially epididymal fat pad, and decrease in nonshivering thermogenesis, as indicated by depressed mitochondrial protein content and uncoupling protein-1 content in brown adipose tissue. No variations of sirtuin 1 and subunit IV of cytochrome oxidase expression were found in brown adipose tissue and skeletal muscle between the two groups. High body weight gerbils showed increased serum leptin and insulin concentrations but surprisingly increased glucose tolerance, suggesting a difference from other obese species in the regulation of glucose metabolism. Serum leptin levels were negatively correlated with UCP1 content in BAT and positively correlated with energy intake and insulin concentration. Our data suggest that leptin may be involved in thermogenesis regulation, insulin secretion and glucose metabolism in HBW gerbils.     

Repeating of emotional stress prevents development of melanocortin obesity and type 2 diabetes in the mice with the Agouti yellow mutation

Brain melanocortin system (MC-system) participates in regulation of energy homeostasis. Dominant mutation yellow of the Agouti gene leads to the hyperphagia, obesity and type 2 diabetes. Stress is known to inhibit food intake and body weight. The aim of the work was to study effects of repeating emotional stress on food intake and lipid-carbohydrate metabolism in Ay-mice. Male mice of C57B1/6J strain predisposed to the obesity (Ay/a-genotype) and normal (a/a-genotype) were used. In control group food intake, body weight and blood levels of insulin and leptin were increased in Ay/a-mice as compared to a/a-mice. Repeating emotional stress (30 min restraint 3 times a week for 5 weeks) did not alter food intake and indices of lipid-carbohydrate metabolism in a/a-mice and decreased food intake, body weight and blood levels of insulin and leptin in Ay/a-mice. Insulin and leptin blood levels were the same in Ay/a- and a/a-mice on 5 week of treatment. The stress increased basal and stress-induced concentrations of corticosterone to an equal degree in Ay/a- and a/a-mice. Thus, light repeating emotional stress hampered development of obesity and 2 type diabetes in the mice with the Agouti yellow mutation.     

脑能量代谢与线粒体功能关系的研究进展

线粒体是人体内的能量代谢工厂,而脑是人体内能量代谢最活跃的部位。神经元和胶质细胞是脑内主要的细胞。本文对线粒体在能量产生的作用进行综述,同时比较神经元和星形胶质细胞能量代谢的异同及密切联系,并对神经退行性变中能量代谢障碍与线粒体可塑性改变进行了回顾。以三种神经退行性疾病帕金森、阿尔兹海默和脊髓侧索硬化症为例说明线粒体在神经系统疾病和脑能量代谢之间的重要作用。从而进一步系统的认识,脑内的线粒体在生理和病理状态下对能量代谢的影响。深入了解其机制,为研究神经系统退行性疾病提供新的治疗策略。     

A model to estimate insulin sensitivity in dairy cows

Impairment of the insulin regulation of energy metabolism is considered to be an etiologic key component for metabolic disturbances. Methods for studies of insulin sensitivity thus are highly topical. There are clear indications that reduced insulin sensitivity contributes to the metabolic disturbances that occurs especially among obese lactating cows. Direct measurements of insulin sensitivity are laborious and not suitable for epidemiological studies. We have therefore adopted an indirect method originally developed for humans to estimate insulin sensitivity in dairy cows. The method, "Revised Quantitative Insulin Sensitivity Check Index" (RQUICKI) is based on plasma concentrations of glucose, insulin and free fatty acids (FFA) and it generates good and linear correlations with different estimates of insulin sensitivity in human populations. We hypothesized that the RQUICKI method could be used as an index of insulin function in lactating dairy cows. We calculated RQUICKI in 237 apparently healthy dairy cows from 20 commercial herds. All cows included were in their first 15 weeks of lactation. RQUICKI was not affected by the homeorhetic adaptations in energy metabolism that occurred during the first 15 weeks of lactation. In a cohort of 24 experimental cows fed in order to obtain different body condition at parturition RQUICKI was lower in early lactation in cows with a high body condition score suggesting disturbed insulin function in obese cows. The results indicate that RQUICKI might be used to identify lactating cows with disturbed insulin function.