Human metabolic adaptations and prolonged expensive neurodevelopment: A review

1.	After weaning, human hunter-gatherer juveniles receive substantial (≈3.5-7 MJ day^-1^), extended (≈15 years) and reliable (kin and nonkin food pooling) energy provision.
2.	The childhood (pediatric) and the adult human brain takes a very high share of both basal metabolic rate (BMR) (child: 50-70%; adult: ≈20%) and total energy expenditure (TEE) (child: 30-50%; adult: ≈10%).
3.	The pediatric brain for an extended period (≈4-9 years-of-age) consumes roughly 50% more energy than the adult one, and after this, continues during adolescence, at a high but declining rate. Within the brain, childhood cerebral gray matter has an even higher 1.9 to 2.2-fold increased energy consumption. 
4.	This metabolic expensiveness is due to (i) the high cost of synapse activation (74% of brain energy expenditure in humans), combined with (ii), a prolonged period of exuberance in synapse numbers (up to double the number present in adults). Cognitive development during this period associates with volumetric changes in gray matter (expansion and contraction due to metabolic related size alterations in glial cells and capillary vascularization), and in white matter (expansion due to myelination). 
5.	Amongst mammals, anatomically modern humans show an unique pattern in which very slow musculoskeletal body growth is followed by a marked adolescent size/stature spurt. This pattern of growth contrasts with nonhuman primates that have a sustained fast juvenile growth with only a minor period of puberty acceleration. The existence of slow childhood growth in humans has been shown to date back to 160,000 BP. 
6.	Human children physiologically have a limited capacity to protect the brain from plasma glucose fluctuations and other metabolic disruptions. These can arise in adults, during prolonged strenuous exercise when skeletal muscle depletes plasma glucose, and produces other metabolic disruptions upon the brain (hypoxia, hyperthermia, dehydration and hyperammonemia). These are proportional to muscle mass.
7.	Children show specific adaptations to minimize such metabolic disturbances. (i) Due to slow body growth and resulting small body size, they have limited skeletal muscle mass. (ii) They show other adaptations such as an exercise specific preference for free fatty acid metabolism. (iii) While children are generally more active than adolescents and adults, they avoid physically prolonged intense exertion. 
8.	Childhood has a close relationship to high levels of energy provision and metabolic adaptations that support prolonged synaptic neurodevelopment. 
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Human neuromaturation, juvenile extreme energy liability, and adult cognition/cooperation

Human childhood and adolescence is the period in which adult cognitive competences (including those that create the unique cooperativeness of humans) are acquired. It is also a period when neural development puts a juvenile’s survival at risk due to the high vulnerability of their brain to energy shortage. The brain of a 4 year-old human uses ≈50% of its total energy expenditure (TEE) (cf. adult ≈12%). This brain expensiveness is due to (1) the brain making up ≈6% of a 4 year-old body compared to 2% in an adult, and (2) increased energy metabolism that is ≈100% greater in the gray matter of a child than in an adult (a result of the extra costs of synaptic neuromaturation). The high absolute number of neurons in the human brain requires as part of learning a prolonged neurodevelopment. This refines inter- and intraarea neural networks so they become structured with economical “small world” connectivity attributes (such as hub organization and high cross-brain differentiation/integration). Once acquired, this connectivity enables highly complex adult cognitive capacities. Humans evolved as hunter-gatherers. Contemporary hunter-gatherers (and it is also likely Middle Paleolithic ones) pool high energy foods in an egalitarian manner that reliably supported mothers and juveniles with high energy intake. This type of sharing unique to humans protects against energy shortage happening to the immature brain. This cooperation that protects neuromaturation arises from adults having the capacity to communicate and evaluate social reputation, cognitive skills that exist as a result of extended neuromaturation. Human biology is therefore characterized by a presently overlooked bioenergetic-cognition loop (called here the “HEBE ring”) by which extended neuromaturation creates the cooperative abilities in adults that support juveniles through the potentially vulnerable period of the neurodevelopment needed to become such adults

Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice

Insulin resistance and impaired glucose homoeostasis are important indicators of Type 2 diabetes and are early risk factors of AD (Alzheimer's disease). An essential feature of AD pathology is the presence of BACE1 (β-site amyloid precursor protein-cleaving enzyme 1), which regulates production of toxic amyloid peptides. However, whether BACE1 also plays a role in glucose homoeostasis is presently unknown. We have used transgenic mice to analyse the effects of loss of BACE1 on body weight, and lipid and glucose homoeostasis. BACE1−/− mice are lean, with decreased adiposity, higher energy expenditure, and improved glucose disposal and peripheral insulin sensitivity than wild-type littermates. BACE1−/− mice are also protected from diet-induced obesity. BACE1-deficient skeletal muscle and liver exhibit improved insulin sensitivity. In a skeletal muscle cell line, BACE1 inhibition increased glucose uptake and enhanced insulin sensitivity. The loss of BACE1 is associated with increased levels of UCP1 (uncoupling protein 1) in BAT (brown adipose tissue) and UCP2 and UCP3 mRNA in skeletal muscle, indicative of increased uncoupled respiration and metabolic inefficiency. Thus BACE1 levels may play a critical role in glucose and lipid homoeostasis in conditions of chronic nutrient excess. Therefore strategies that ameliorate BACE1 activity may be important novel approaches for the treatment of diabetes

Non-signalling energy use in the brain.

Energy use limits the information processing power of the brain. However, apart from the ATP used to power electrical signalling, a significant fraction of the brain's energy consumption is not directly related to information processing. The brain spends just under half of its energy on non-signalling processes, but it remains poorly understood which tasks are so energetically costly for the brain. We review existing experimental data on subcellular processes that may contribute to this non-signalling energy use, and provide modelling estimates, to try to assess the magnitude of their ATP consumption and consider how their changes in pathology may compromise neuronal function. As a main result, surprisingly little consensus exists on the energetic cost of actin treadmilling, with estimates ranging from < 1% of the brain's global energy budget up to one-half of neuronal energy use. Microtubule treadmilling and protein synthesis have been estimated to account for very small fractions of the brain's energy budget, whereas there is stronger evidence that lipid synthesis and mitochondrial proton leak are energetically expensive. Substantial further research is necessary to close these gaps in knowledge about the brain's energy-expensive non-signalling tasks

Neuronal human BACE1 knock-in induces systemic diabetes in mice

Acknowledgements The authors thank S. Tammireddy (Diabetes and Cardiovascular Science, University of the Highlands and Islands, Inverness, UK) for technical support with the lipidomics component. Funding We would like to thank R. Simcox, Romex Oilfield Chemicals, for financial support for KP, and acknowledge additional contributions from the Scottish Alzheimer’s Research UK network for the lipidomics work. The College of Life Science and Medicine, University of Aberdeen, sponsored the imaging study. MD was funded by British Heart Foundation and Diabetes UK; NM was funded by a British Heart Foundation Intermediate Fellowship; KS was funded by a European Foundation for the Study of Diabetes/Lilly programme grant; and RD was funded by an Institute of Medical Sciences PhD studentship.Peer reviewedPublisher PDFPublisher PD

Human metabolic adaptations and prolonged expensive neurodevelopment: A review

1.&#x9;After weaning, human hunter-gatherer juveniles receive substantial (&#x2248;3.5-7 MJ day^-1^), extended (&#x2248;15 years) and reliable (kin and nonkin food pooling) energy provision.&#xd;&#xa;2.&#x9;The childhood (pediatric) and the adult human brain takes a very high share of both basal metabolic rate (BMR) (child: 50-70%; adult: &#x2248;20%) and total energy expenditure (TEE) (child: 30-50%; adult: &#x2248;10%).&#xd;&#xa;3.&#x9;The pediatric brain for an extended period (&#x2248;4-9 years-of-age) consumes roughly 50% more energy than the adult one, and after this, continues during adolescence, at a high but declining rate. Within the brain, childhood cerebral gray matter has an even higher 1.9 to 2.2-fold increased energy consumption. &#xd;&#xa;4.&#x9;This metabolic expensiveness is due to (i) the high cost of synapse activation (74% of brain energy expenditure in humans), combined with (ii), a prolonged period of exuberance in synapse numbers (up to double the number present in adults). Cognitive development during this period associates with volumetric changes in gray matter (expansion and contraction due to metabolic related size alterations in glial cells and capillary vascularization), and in white matter (expansion due to myelination). &#xd;&#xa;5.&#x9;Amongst mammals, anatomically modern humans show an unique pattern in which very slow musculoskeletal body growth is followed by a marked adolescent size/stature spurt. This pattern of growth contrasts with nonhuman primates that have a sustained fast juvenile growth with only a minor period of puberty acceleration. The existence of slow childhood growth in humans has been shown to date back to 160,000 BP. &#xd;&#xa;6.&#x9;Human children physiologically have a limited capacity to protect the brain from plasma glucose fluctuations and other metabolic disruptions. These can arise in adults, during prolonged strenuous exercise when skeletal muscle depletes plasma glucose, and produces other metabolic disruptions upon the brain (hypoxia, hyperthermia, dehydration and hyperammonemia). These are proportional to muscle mass.&#xd;&#xa;7.&#x9;Children show specific adaptations to minimize such metabolic disturbances. (i) Due to slow body growth and resulting small body size, they have limited skeletal muscle mass. (ii) They show other adaptations such as an exercise specific preference for free fatty acid metabolism. (iii) While children are generally more active than adolescents and adults, they avoid physically prolonged intense exertion. &#xd;&#xa;8.&#x9;Childhood has a close relationship to high levels of energy provision and metabolic adaptations that support prolonged synaptic neurodevelopment. &#xd;&#xa

Dielectric properties measurements of brown and white adipose tissue in rats from 0.5 to 10 GHz

Brown adipose tissue (BAT) plays an important role in whole body metabolism and with appropriate stimulus could potentially mediate weight gain and insulin sensitivity. Although imaging techniques are available to detect subsurface BAT, there are currently no viable methods for continuous acquisition of BAT energy expenditure. Microwave (MW) radiometry is an emerging technology that allows the quantification of tissue temperature variations at depths of several centimeters. Such temperature differentials may be correlated with variations in metabolic rate, thus providing a quantitative approach to monitor BAT metabolism. In order to optimize MW radiometry, numerical and experimental phantoms with accurate dielectric properties are required to develop and calibrate radiometric sensors. Thus, we present for the first time, the characterization of relative permittivity and electrical conductivity of brown (BAT) and white (WAT) adipose tissues in rats across the MW range 0.5-10GHz. Measurements were carried out in situ and post mortem in six female rats of approximately 200g. A Cole-Cole model was used to fit the experimental data into a parametric model that describes the variation of dielectric properties as a function of frequency. Measurements confirm that the dielectric properties of BAT (εr = 14.0-19.4, σ = 0.3-3.3S/m) are significantly higher than those of WAT (εr = 9.1-11.9, σ = 0.1-1.9S/m), in accordance with the higher water content of BAT

Repeatability of brown adipose tissue measurements on FDG PET/CT following a simple cooling procedure for BAT activation

Brown Adipose Tissue (BAT) is present in a significant number of adult humans and can be activated by exposure to cold. Measurement of active BAT presence, activity, and volume are desirable for determining the efficacy of potential treatments intended to activate BAT. The repeatability of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) measurements of BAT presence, activity, and volume under controlled conditions has not been extensively studied. Eleven female volunteers underwent double baseline FDG PET imaging performed following a simple, regional cold intervention intended to activate brown fat. The cold intervention involved the lightly-clothed participants intermittently placing their feet on a block of ice while sitting in a cooled room. A repeat study was performed under the same conditions within a target of two weeks. FDG scans were obtained and maximum standardized uptake value adjusted for lean body mass (SULmax), CT Hounsfield units (HU), BAT metabolic volume (BMV), and total BAT glycolysis (TBG) were determined according to the Brown Adipose Reporting Criteria in Imaging STudies (BARCIST) 1.0. A Lin's concordance correlation (CCC) of 0.80 was found for BMV between test and retest imaging. Intersession BAT SULmax was significantly correlated (r = 0.54; p < 0.05). The session #1 mean SULmax of 4.92 ± 4.49 g/mL was not significantly different from that of session #2 with a mean SULmax of 7.19 ± 7.34 g/mL (p = 0.16). BAT SULmax was highly correlated with BMV in test and retest studies (r ≥ 0.96, p < 0.001). Using a simplified ice-block cooling method, BAT was activated in the majority (9/11) of a group of young, lean female participants. Quantitative assessments of BAT SUL and BMV were not substantially different between test and retest imaging, but individual BMV could vary considerably. Intrasession BMV and SULmax were strongly correlated. The variability in estimates of BAT activity and volume on test-retest with FDG should inform sample size choice in studies quantifying BAT physiology and support the dynamic metabolic characteristics of this tissue. A more sophisticated cooling method potentially may reduce variations in test-retest BAT studies

Impact of Sleep and Circadian Disruption on Energy Balance and Diabetes: A Summary of Workshop Discussions

A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact of sleep/circadian disruption in humans to move beyond measurements of insulin and glucose and conduct more in-depth phenotyping. There is also a need for the assessments of sleep and circadian rhythms as well as assessments for sleep-disordered breathing to be incorporated into all ongoing cohort studies related to diabetes risk. Studies in humans need to complement the elegant short-term laboratory-based human studies of simulated short sleep and shift work etc. with studies in subjects in the general population with these disorders. It is conceivable that chronic adaptations occur, and if so, the mechanisms by which they occur needs to be identified and understood. Particular areas of opportunity that are ready for translation are studies to address whether CPAP treatment of patients with pre-diabetes and obstructive sleep apnea (OSA) prevents or delays the onset of diabetes and whether temporal restricted feeding has the same impact on obesity rates in humans as it does in mice