Disruption of the class IIa HDAC corepressor complex increases energy expenditure and lipid oxidation

Drugs that recapitulate aspects of the exercise adaptive response have the potential to provide better treatment for diseases associated with physical inactivity. We previously observed reduced skeletal muscle class IIa HDAC (histone deacetylase) transcriptional repressive activity during exercise. Here, we find that exercise-like adaptations are induced by skeletal muscle expression of class IIa HDAC mutants that cannot form a corepressor complex. Adaptations include increased metabolic gene expression, mitochondrial capacity, and lipid oxidation. An existing HDAC inhibitor, Scriptaid, had similar phenotypic effects through disruption of the class IIa HDAC corepressor complex. Acute Scriptaid administration to mice increased the expression of metabolic genes, which required an intact class IIa HDAC corepressor complex. Chronic Scriptaid administration increased exercise capacity, whole-body energy expenditure and lipid oxidation, and reduced fasting blood lipids and glucose. Therefore, compounds that disrupt class IIa HDAC function could be used to enhance metabolic health in chronic diseases driven by physical inactivity.

Flipper strokes can predict energy expenditure and locomotion costs in free-ranging northern and Antarctic fur seals

Flipper strokes have been proposed as proxies to estimate the energy expended by marine vertebrates while foraging at sea, but this has never been validated on free-ranging otariids (fur seals and sea lions). Our goal was to investigate how well flipper strokes correlate with energy expenditure in 33 foraging northern and Antarctic fur seals equipped with accelerometers, GPS, and time-depth recorders. We concomitantly measured field metabolic rates with the doubly-labelled water method and derived activity-specific energy expenditures using fine-scale time-activity budgets for each seal. Flipper strokes were detected while diving or surface transiting using dynamic acceleration. Despite some inter-species differences in flipper stroke dynamics or frequencies, both species of fur seals spent 3.79 ± 0.39 J/kg per stroke and had a cost of transport of ~1.6-1.9 J/kg/m while diving. Also, flipper stroke counts were good predictors of energy spent while diving (R(2) = 0.76) and to a lesser extent while transiting (R(2) = 0.63). However, flipper stroke count was a poor predictor overall of total energy spent during a full foraging trip (R(2) = 0.50). Amplitude of flipper strokes (i.e., acceleration amplitude × number of strokes) predicted total energy expenditure (R(2) = 0.63) better than flipper stroke counts, but was not as accurate as other acceleration-based proxies, i.e. Overall Dynamic Body Acceleration.

The metabolic and cognitive energy costs of stabilising a high-energy interlimb coordination task

Kinematic (relative phase error), metabolic (oxygen consumption, heart rate) and attentional (baseline and cycling reaction times) variables were measured while participants practised a high energy-demanding, intrinsically unstable 90° relative phase coordination pattern on independent bicycle ergometers. The variables were found to be strongly inter-correlated, suggesting a link between emerging performance stability with practice and minimal metabolic and attentional cost. The effects of practice of 90° relative phase coordination on the performance of in-phase (0°-phase) and antiphase (180°-phase) coordination were investigated by measuring the relative phase attractor layouts and recording the metabolic and attentional cost of the three coordination patterns before and after practice. The attentional variables did not differ significantly between coordination patterns and did not change with practice. Before practice, the coordination performance was most accurate and stable for in-phase cycling, with antiphase next and 90°-phase the poorest. However, metabolic cost was lower for antiphase than either in-phase or 90°-phase cycling, and the pre-practice attractor layout deviated from that predicted on the basis of dynamic stability as an attractor state, revealing an attraction to antiphase cycling. After practice of 90°-phase cycling, in-phase cycling remained the most accurate and stable, with 90°-phase next and antiphase the poorest, but antiphase retained the lowest metabolic energy cost. The attractor layout had changed, with new attractors formed at the practised 90°-phase pattern and its symmetrical partner of 270°-phase. Considering both the pre- and post-practice results, attractors were formed at either a low metabolic energy cost but less stable (antiphase) pattern or at a more stable but higher metabolic energy cost (90°-phase) pattern, but in neither case at the most stable and accurate (in-phase) pattern. The results suggest that energetic factors affect coordination dynamics and that coordination modes lower in metabolic energy expenditure may compete with dynamically stable modes.

Learning to minimize energy costs and maximize mechanical work in a bimanual coordination task

The authors addressed the hypothesis that economy in motor coordination is a learning phenomenon realized by both reduced energy cost for a given workload and more external work at the same prepractice metabolic and attentional energy expenditure. "Self-optimization" of movement parameters has been proposed to reflect learned motor adaptations that minimize energy costs. Twelve men aged 22.3 [+ or -] 3.9 years practiced a 90[degrees] relative phase, upper limb, independent ergometer cycling task at 60 rpm, followed by a transfer test of unpracticed (45 and 75 rpm) and self-paced cadences. Performance in all conditions was initially unstable, inaccurate, and relatively high in both metabolic and attentional energy costs. With practice, coordinative stability increased, more work was performed for the same metabolic and attentional costs, and the same work was done at a reduced energy cost. Self-paced cycling was initially below the metabolically optimal, but following practice at 60 rpm was closer to optimal cadence. Given the many behavioral options of the motor system in meeting a variety of everyday movement task goals, optimal metabolic and attentional energy criteria may provide a solution to the problem of selecting the most adaptive coordination and control parameters.

Estimating the effects of energy imbalance on changes in body weight in children

BACKGROUND: Estimating changes in weight from changes in energy balance is important for predicting the effect of obesity prevention interventions. OBJECTIVE: The objective was to develop and validate an equation for predicting the mean weight of a population of children in response to a change in total energy intake (TEI) or total energy expenditure (TEE). DESIGN: In 963 children with a mean (+/-SD) age of 8.1 +/- 2.8 y (range: 4-18 y) and weight of 31.5 +/- 17.6 kg, TEE was measured by using doubly labeled water. Log weight (dependent variable) and log TEE (independent variable) were analyzed in a linear regression model with height, age, and sex as covariates. It was assumed that points of dynamic balance, called "settling points," occur for populations wherein energy is in balance (TEE = TEI), weight is stable (ignoring growth), and energy flux (EnFlux) equals TEE. RESULTS: TEE (or EnFlux) explained 74% of the variance in weight. The unstandardized regression coefficient was 0.45 (95% CI: 0.38, 0.51; R(2) = 0.86) after including covariates. Conversion into proportional changes (time(1) to time(2)) gave the equation (weight(2)/weight(1)) = (EnFlux(2)/EnFlux(1))(0.45). In 3 longitudinal studies (n = 212; mean follow-up of 3.4 y), the equation predicted the mean follow-up measured weight to within 0.5%. CONCLUSIONS: The relation of EnFlux with weight was positive, which implied that a high TEI (rather than low physical activity and low TEE) was the main determinant of high body weight. Two populations of children with a 10% difference in mean EnFlux would have a 4.5% difference in mean weight.

Energy system interaction and relative contribution during maximal exercise

There are 3 distinct yet closely integrated processes that operate together to satisfy the energy requirements of muscle. The anaerobic energy system is divided into alactic and lactic components, referring to the processes  involved in the splitting of the stored phosphagens, ATP and  phosphocreatine (PCr), and the nonaerobic breakdown of carbohydrate to lactic acid through glycolysis. The aerobic energy system refers to the combustion of carbohydrates and fats in the presence of oxygen. The anaerobic pathways are capable of regenerating ATP at high rates yet are limited by the amount of energy that can be released in a single bout of intense exercise. In contrast, the aerobic system has an enormous capacity yet is somewhat hampered in its ability to delivery energy quickly. The focus of this review is on the interaction and relative contribution of the energy systems during single bouts of maximal exercise. A particular emphasis has been placed on the role of the aerobic energy system during high intensity exercise.

Attempts to depict the interaction and relative contribution of the energy systems during maximal exercise first appeared in the 1960s and 1970s. While insightful at the time, these representations were based on calculations of anaerobic energy release that now appear questionable. Given repeated reproduction over the years, these early attempts have lead to 2 common misconceptions in the exercise science and coaching professions. First, that the energy systems respond to the demands of intense exercise in an almost sequential manner, and secondly, that the aerobic system responds slowly to these energy demands, thereby playing little role in determining performance over short durations. More recent research suggests that energy is derived from each of the energy-producing pathways during almost all exercise activities. The duration of maximal exercise at which equal contributions are derived from the anaerobic and aerobic energy systems appears to occur between 1 to 2 minutes and most probably around 75 seconds, a time that is considerably earlier than has traditionally been suggested.

Estimating the changes in energy flux that characterize the rise in obesity prevalence

Background: The daily energy imbalance gap associated with the current population weight gain in the obesity epidemic is relatively small. However, the substantially higher body weights of populations that have accumulated over several years are associated with a substantially higher total energy expenditure (TEE) and total energy intake (TEI), or energy flux (EnFlux = TEE = TEI).
Objective: The objective was to develop an equation relating EnFlux to body weight in adults for estimating the rise in EnFlux associated with the obesity epidemic.
Design: Multicenter, cross-sectional data for TEE from doubly labeled water studies in 1399 adults aged 5.9 ± 18.8 y (mean ± SD) were analyzed in linear regression models with natural log (ln) weight as the dependent variable and ln EnFlux as the independent variable, adjusted for height, age, and sex. These equations were compared with those for children and applied to population trends in weight gain.
Results: ln EnFlux was positively related to ln weight (β = 0.71; 95% CI: 0.66, 0.76; R2 = 0.52), adjusted for height, age, and sex. This slope was significantly steeper than that previously described for children (β = 0.45; 95% CI: 0.38, 0.51).
Conclusions: This relation suggests that substantial increases in TEI have driven the increases in body weight over the past 3 decades. Adults have a higher proportional weight gain than children for the same proportional increase in energy intake, mostly because of a higher fat content of the weight being gained. The obesity epidemic will not be reversed without large reductions in energy intake, increases in physical activity, or both.

Energy metabolism and animal personality

In this paper we show how animal personality could explain some of the large inter-individual variation in resting metabolic rate (MR) and explore methodological and functional linkages between personality and energetics. Personality will introduce variability in resting MR measures because individuals consistently differ in their stress response, exploration or activity levels, all of which influence MR measurements made with respirometry and the doubly-labelled water technique. Physiologists try to exclude these behavioural influences from resting MR measurements, but animal personality research indicates that these attempts are unlikely to be successful. For example, because reactive animals “freeze” when submitted to a stress, their MR could be classified as “resting” because of immobility when in fact they are highly stressed with an elevated MR. More importantly, recent research demonstrating that behavioural responses to novel and highly artificial stimuli are correlated with both behaviour and fitness under more natural circumstances calls into question the wisdom of excluding these behavioural influences on MR measurements. The reason that intra-specific variation in resting MR are so weakly correlated with daily energy expenditure (DEE) and fitness, may be that the latter two measures fully incorporate personality while the former partially excludes its influence. Because activity, exploration, boldness and aggressiveness are energetically costly, personality and metabolism should be correlated and physiological constraints may underlie behavioural syndromes. We show how physiological ecologists can better examine behavioural linkages between personality and metabolism, as required to better understand the physiological correlates of personality and the evolutionary consequences of metabolic variability.

Acceleration data reveal the energy management strategy of a marine ectotherm during reproduction

1. Maintaining a high and stable body temperature is often critical for female ectotherms during reproduction. Yet this strategy may be energetically costly, and therefore challenging, during this period of already high-energy demand. 2. Here, the 6-week deployment of tri-axial accelerometers (n = 6) on a marine ectotherm, the loggerhead turtle (Caretta caretta), reproducing at the northern limit of the species’ breeding range (i.e. in a thermally dynamic environment) revealed the behavioural mechanisms underlying its energy management strategy during the breeding season. 3. The estimated activity levels of female loggerheads using overall dynamic body acceleration (ODBA) were high during the breeding season, suggesting that marine turtles may not be able to remain inactive for long periods in the same manner as terrestrial ectotherms, because of the thermally dynamic nature of their environment. 4. However, activity levels were not constant throughout the season, being impacted by both ambient water temperature and female reproductive status. In cold water at the beginning of the nesting season, high levels of activity suggested that females behaviourally thermoregulated by seeking out warm water patches along the shoreline. Interactions with male turtles (courtship and/or avoidance) may also explain this high level of activity. As sea temperatures warmed up and the amount of energy devoted to reproduction probably increased, the turtles spent more time resting during long sequential flat-bottomed dives, and reduced any unnecessary locomotory activity. 5. Turtles may therefore adjust their activity patterns in response to seasonal variations in abiotic (i.e. ambient temperature) and biotic (i.e. reproductive status) factors. This may help minimize activity-linked metabolic rate and maximize reproductive output over a season while breeding in thermally dynamic environments. 6. A mechanistic model gave support to these empirical results. The model revealed that actively maintaining high and stable body temperature is of clear benefit to female turtles at temperate breeding sites. While energetically costly, such active thermoregulatory behaviour may speed up egg maturation, allowing turtles to initiate nesting earlier in the season, and hence maximize reproductive output.

Habitat switching by Bewick's swans: Maximization of average long-term energy gain?

1. In a system where depletion drives a habitat shift, the hypothesis was tested that animals switch habitat as soon as the average daily net energy intake (or gain) drops below that attainable in the alternative habitat.

2. The study was performed in the Lauwersmeer area. Upon arrival during the autumn migration, Bewick's swans first feed on below-ground tubers of fennel pondweed on the lake, but subsequently switched to feeding on harvest remains in sugar beet fields.

3. The daily energy intake was estimated by multiplying the average time spent foraging per day with the instantaneous energy intake rate while foraging. In the case of pondweed feeding, the latter was estimated from the functional response and the depletion of tuber biomass. In the case of beet feeding, it was estimated from dropping production rate. Gross energy intake was converted to metabolizable energy intake using the assimilation as determined in digestion trials. The daily energy expenditure was estimated by the time-energy budget method. Energetic costs were determined using heart rate.

4. The daily gain of pondweed feeding at the median date of the habitat switch (i.e. when 50% of the swans had switched) was compared with that of beet feeding. The daily gain of beet feeding was calculated for two strategies depending on the night activity on the lake: additional pondweed feeding (mixed feeding) or sleeping (pure beet feeding).

5. The majority of the swans switched when the daily gain they could achieve by staying on the pondweed bed fell just below the average daily gain of pure beet feeders. However, mixed feeders would attain an average daily gain considerably above that of pondweed feeders. A sensitivity analysis showed that this result was robust.

6. We therefore reject the hypothesis that the habitat switch by swans can be explained by simple long-term energy rate maximization. State-dependency, predation risk, and protein requirements are put forward as explanations for the delay in habitat switch.

A mobile phone based method to assess energy and food intake in young children: a validation study against the doubly labelled water method and 24 h dietary recalls

Mobile phones are becoming important instruments for assessing diet and energy intake. We developed the Tool for Energy Balance in Children (TECH), which uses a mobile phone to assess energy and food intake in pre-school children. The aims of this study were: (a) to compare energy intake (EI) using TECH with total energy expenditure (TEE) measured via doubly labelled water (DLW); and (b) to compare intakes of fruits, vegetables, fruit juice, sweetened beverages, candy, ice cream, and bakery products using TECH with intakes acquired by 24 h dietary recalls. Participants were 39 healthy, Swedish children (5.5 ± 0.5 years) within the ongoing Mobile-based Intervention Intended to Stop Obesity in Preschoolers (MINISTOP) obesity prevention trial. Energy and food intakes were assessed during four days using TECH and 24 h telephone dietary recalls. Mean EI (TECH) was not statistically different from TEE (DLW) (5820 ± 820 kJ/24 h and 6040 ± 680 kJ/24 h, respectively). No significant differences in the average food intakes using TECH and 24 h dietary recalls were found. All food intakes were correlated between TECH and the 24 h dietary recalls (ρ = 0.665-0.896, p < 0.001). In conclusion, TECH accurately estimated the average intakes of energy and selected foods and thus has the potential to be a useful tool for dietary studies in pre-school children, for example obesity prevention trials.

A new method for resolving uncertainty of energy requirements in large water breathers: The 'mega-flume' seagoing swim-tunnel respirometer

Body size is a key determinant of metabolic rate, but logistical constraints have led to a paucity of energetics measurements from large water-breathing animals. As a result, estimating energy requirements of large fish generally relies on extrapolation of metabolic rate from individuals of lower body mass using allometric relationships that are notoriously variable. Swim-tunnel respirometry is the 'gold standard' for measuring active metabolic rates in water-breathing animals, yet previous data are entirely derived from body masses <10 kg - at least one order of magnitude lower than the body masses of many top-order marine predators. Here, we describe the design and testing of a new method for measuring metabolic rates of large water-breathing animals: a c. 26 000 L seagoing 'mega-flume' swim-tunnel respirometer. We measured the swimming metabolic rate of a 2·1-m, 36-kg zebra shark Stegostoma fasciatum within this new mega-flume and compared the results to data we collected from other S. fasciatum (3·8-47·7 kg body mass) swimming in static respirometers and previously published measurements of active metabolic rate measurements from other shark species. The mega-flume performed well during initial tests, with intra- and interspecific comparisons suggesting accurate metabolic rate measurements can be obtained with this new tool. Inclusion of our data showed that the scaling exponent of active metabolic rate with mass for sharks ranging from 0·13 to 47·7 kg was 0·79; a similar value to previous estimates for resting metabolic rates in smaller fishes. We describe the operation and usefulness of this new method in the context of our current uncertainties surrounding energy requirements of large water-breathing animals. We also highlight the sensitivity of mass-extrapolated energetic estimates in large aquatic animals and discuss the consequences for predicting ecosystem impacts such as trophic cascades.

Calpain 3 gene expression in skeletal muscle is associated with body fat content and measures of insulin resistance

OBJECTIVE: To investigate whether skeletal muscle gene expression of calpain 3 is related to obesity and insulin resistance.

DESIGN: Cross-sectional studies in 27 non-diabetic human subjects and in Psammomys obesus, a polygenic animal model of obesity and type 2 diabetes.

MEASUREMENTS: Expression of CAPN3 in skeletal muscle was measured using Taqman fluorogenic PCR. In the human subjects, body composition was assessed by DEXA and insulin sensitivity was measured by euglycemic-hyperinsulinemic clamp. In Psammomys obesus, body composition was determined by carcass analysis, and substrate oxidation rates, physical activity and energy expenditure were measured by whole-body indirect calorimetry.

RESULTS: In human subjects, calpain 3 gene expression was negatively correlated with total (P=0.022) and central abdominal fat mass (P=0.034), and with blood glucose concentration in non-obese subjects (P=0.017). In Psammomys obesus, calpain 3 gene expression was negatively correlated with circulating glucose (P=0.013) and insulin (P=0.034), and with body fat mass (P=0.049). Indirect calorimetry revealed associations between calpain 3 gene expression and carbohydrate oxidation (P=0.009) and energy expenditure (P=0.013).

CONCLUSION/INTERPRETATION: Lower levels of expression of calpain 3 in skeletal muscle were associated with reduced carbohydrate oxidation and elevated circulating glucose and insulin concentrations, and also with increased body fat and in particular abdominal fat. Therefore, reduced expression of calpain 3 in both humans and Psammomys obesus was associated with phenotypes related to obesity and insulin resistance.

Preventive strategies against weight gain and obesity

A well-resourced, comprehensive, population-based set of strategies is needed to
attenuate and eventually reverse the current trends of increasing obesity prevalence
now apparent in most countries. The Epidemiological Triad (host, vector,
environment) has proven to be a robust model for other epidemics and is applied
to obesity. Host-based strategies are primarily educational and these tend to
be most effective among people with higher incomes and higher educational
attainment. The main vectors for a high-energy intake are energy-dense foods and
drinks and large portion sizes and, for low energy expenditure, machines that
promote physical inactivity. Vector-based strategies that alter food formulation
can have a significant impact, particularly through influencing common, highvolume
foods. The increasingly ‘obesogenic’ environments are probably the main
driving forces for the obesity epidemic. There are many environmental strategies
that can influence the physical, economic, policy or socio-cultural environments,
but the evidence base for these potentially powerful interventions is small.
Children should be the priority population for interventions, and improving the
general socio-economic conditions for disadvantaged, marginalized or poor population
sectors is also a central strategy for obesity prevention. The key settings
for interventions are schools, homes, neighbourhoods, primary health care services
and communities. The key macroenvironments for interventions are the
transport and infrastructure sector, the media and the food sector.

Dusting off the epidemiological triad: could it work with obesity

The search for effective ways of dealing with obesity has centred on biological research and clinical management. However, obesity needs to be conceptualized more broadly if the modern pandemic is to be arrested. The epidemiological triad (hosts, agent/vectors and environments) has served us well in dealing with epidemics in the past, and may be worth re-evaluating to this end. Education, behaviour change and clinical practices deal predominantly with the host, although multidisciplinary practices such as shared-care might also be expected to impact on other corners of the triad. Technology deals best with the agent of obesity (energy imbalance) and it's vectors (excessive energy intake and/or inadequate energy expenditure), and policy and social change are needed to cope with the environment. The value of a broad model like this, rather than specific isolated approaches, is that the key players such as legislators, health professionals, governments and industry can see their roles in attenuating and eventually reversing the epidemic. It also highlights the need to intervene at all levels in obesity control and reduces the relevance of arguments about nature vs. nurture.


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