John R. Speakman

The physiological costs of reproduction in small mammals

Life-history trade-offs between components of fitness arise because reproduction entails both gains and costs. Costs of reproduction can be divided into ecological and physiological costs. The latter have been rarely studied yet are probably a dominant component of the effect. A deeper understanding of life-history evolution will only come about once these physiological costs are better understood. Physiological costs may be direct or indirect. Direct costs include the energy and nutrient demands of the reproductive event, and the morphological changes that are necessary to facilitate achieving these demands. Indirect costs may be optional ‘compensatory costs’ whereby the animal chooses to reduce investment in some other aspect of its physiology to maximize the input of resource to reproduction. Such costs may be distinguished from consequential costs that are an inescapable consequence of the reproductive event. In small mammals, the direct costs of reproduction involve increased energy, protein and calcium demands during pregnancy, but most particularly during lactation. Organ remodelling is necessary to achieve the high demands of lactation and involves growth of the alimentary tract and associated organs such as the liver and pancreas. Compensatory indirect costs include reductions in thermogenesis, immune function and physical activity. Obligatory consequential costs include hyperthermia, bone loss, disruption of sleep patterns and oxidative stress. This is unlikely to be a complete list. Our knowledge of these physiological costs is currently at best described as rudimentary. For some, we do not even know whether they are compensatory or obligatory. For almost all of them, we have no idea of exact mechanisms or how these costs translate into fitness trade-offs.

Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice

Recent evidence suggests that alterations in insulin/insulin–like growth factor 1 (IGF1) signaling (IIS) can increase mammalian life span. For example, in several mouse mutants, impairment of the growth hormone (GH)/IGF1 axis increases life span and also insulin sensitivity. However, the intracellular signaling route to altered mammalian aging remains unclear. We therefore measured the life span of mice lacking either insulin receptor substrate (IRS) 1 or 2, the major intracellular effectors of the IIS receptors. Our provisional results indicate that female Irs1–/– mice are long–lived. Furthermore, they displayed resistance to a range of age–sensitive markers of aging including skin, bone, immune, and motor dysfunction. These improvements in health were seen despite mild, lifelong insulin resistance. Thus, enhanced insulin sensitivity is not a prerequisite for IIS mutant longevity. Irs1–/– female mice also displayed normal anterior pituitary function, distinguishing them from long–lived somatotrophic axis mutants. In contrast, Irs2–/– mice were short–lived, whereas Irs1–/– and Irs2+/– mice of both sexes showed normal life spans. Our results therefore suggest that IRS1 signaling is an evolutionarily conserved pathway regulating mammalian life span and may be a point of intervention for therapies with the potential to delay age–related processes.—Selman, C., Lingard, S., Choudhury, A. I., Batterham, A. L., Claret, M., Clements, M., Ramadani, F., Okkenhaug, K., Schuster, E., Blanc, E., Piper, M. D., Al‐Qassab, H., Speakman, J. R., Carmignac, D., Robinson, I. C. A., Thornton, J. M., Gems, D., Partridge, L., Withers, D. J. Evidence for lifespan extension and delayed age‐related biomarkers in insulin receptor substrate 1 null mice. FASEB J. 22, 807–818 (2008)

Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer

Two theories of how energy metabolism should be associated with longevity, both mediated via free‐radical production, make completely contrary predictions. The ‘rate of living‐free‐radical theory’ ( Pearl, 1928 ; Harman, 1956 ; Sohal, 2002 ) suggests a negative association, the ‘uncoupling to survive’ hypothesis ( Brand, 2000 ) suggests the correlation should be positive. Existing empirical data on this issue is contradictory and extremely confused ( Rubner, 1908 ; Yan & Sohal, 2000 ; Ragland & Sohal, 1975 ; Daan et al., 1996 ; Wolf & Schmid‐Hempel, 1989 ]. We sought associations between longevity and individual variations in energy metabolism in a cohort of outbred mice. We found a positive association between metabolic intensity (kJ daily food assimilation expressed as g/body mass) and lifespan, but no relationships of lifespan to body mass, fat mass or lean body mass. Mice in the upper quartile of metabolic intensities had greater resting oxygen consumption by 17% and lived 36% longer than mice in the lowest intensity quartile. Mitochondria isolated from the skeletal muscle of mice in the upper quartile had higher proton conductance than mitochondria from mice from the lowest quartile. The higher conductance was caused by higher levels of endogenous activators of proton leak through the adenine nucleotide translocase and uncoupling protein‐3. Individuals with high metabolism were therefore more uncoupled, had greater resting and total daily energy expenditures and survived longest – supporting the ‘uncoupling to survive’ hypothesis.

AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons

Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding to hormones and nutrients in the regulation of energy homeostasis. However, the precise neuronal populations and cellular mechanisms involved are unclear. The effects of long-term manipulation of hypothalamic AMPK on energy balance are also unknown. To directly address such issues, we generated POMC alpha 2KO and AgRP alpha 2KO mice lacking AMPK alpha2 in proopiomelanocortin- (POMC-) and agouti-related protein-expressing (AgRP-expressing) neurons, key regulators of energy homeostasis. POMC alpha 2KO mice developed obesity due to reduced energy expenditure and dysregulated food intake but remained sensitive to leptin. In contrast, AgRP alpha 2KO mice developed an age-dependent lean phenotype with increased sensitivity to a melanocortin agonist. Electrophysiological studies in AMPK alpha2-deficient POMC or AgRP neurons revealed normal leptin or insulin action but absent responses to alterations in extracellular glucose levels, showing that glucose-sensing signaling mechanisms in these neurons are distinct from those pathways utilized by leptin or insulin. Taken together with the divergent phenotypes of POMC alpha 2KO and AgRP alpha 2KO mice, our findings suggest that while AMPK plays a key role in hypothalamic function, it does not act as a general sensor and integrator of energy homeostasis in the mediobasal hypothalamus.

A guide to analysis of mouse energy metabolism

We present a consolidated view of the complexity and challenges of designing studies for measurement of energy metabolism in mouse models, including a practical guide to the assessment of energy expenditure, energy intake and body composition and statistical analysis thereof. We hope this guide will facilitate comparisons across studies and minimize spurious interpretations of data. We recommend that division of energy expenditure data by either body weight or lean body weight and that presentation of group effects as histograms should be replaced by plotting individual data and analyzing both group and body-composition effects using analysis of covariance (ANCOVA).

Energy balance and its components: implications for body weight regulation 1-3

A fundamental principle of nutrition and metabolism is that body weight change is associated with an imbalance between the energy content of food eaten and energy expended by the body to maintain life and to perform physical work. Such an energy balance framework is a potentially powerful tool for investigating the regulation of body weight. However, we need a better understanding of the components of energy balance and their interactions over various time scales to explain the natural history of conditions such as obesity and to estimate the magnitude and potential success of therapeutic interventions. Therefore, the ASN and the International Life Sciences Institute convened a panel composed of members with expertise in weight management, energy metabolism, physical activity, and behavior to review the published scientific literature and to hear presentations from other experts in these fields. The Consensus Panel met 9–12 May 2011 in Chicago, IL, and was charged to provide answers to the following 5 questions: Explain energy balance and imbalance in terms of a biological system in which energy intake and energy expenditure change over time in response to the environment. What are the interactions between the components of energy balance and how are they regulated? What is the veracity of some of the popular beliefs related to energy balance? What limitations do we face in the study of energy balance and its components? What research would better inform our knowledge of energy balance and its components?

The Cost of Living: Field Metabolic Rates of Small Mammals

Publisher Summary The chapter begins with an overview of cost of living based on field metabolic rates of small mammals. The chapter then goes on to discuss the importance of energy in living systems, limitations on animal energy expenditure, the extrinsic limitation hypothesis, the intrinsic limitation hypothesis, experimental studies of the limitation hypotheses, the central limitation hypothesis and links between field metabolic rate (FMR) and resting metabolic rate (RMR), interspecific reviews of the link between daily energy expenditure (DEE) and RMR, and also gives summary and aims of the chapter. Methods section proposes to review the methods available for measurement of energy expenditure by mammals, in particular, the method of indirect calorimetry and the field techniques of time and energy budgeting and doubly labelled water, and also direct measurements of free-living energy expenditure. It also gives summary and data inclusion criteria for the present review. The chapter has also discussed results and provided an overview of database studied and has described factors influencing daily energy expenditure in mammals. The chapter closes with discussion about links between FMR and RMR and sustainable metabolic scope.

Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure.

The FTO gene has significant polymorphic variation associated with obesity, but its function is unknown. We screened a population of 150 whites (103F/47M) resident in NE Scotland, United Kingdom, for variants of the FTO gene and linked these to phenotypic variation in their energy expenditure (basal metabolic rate (BMR) and maximal oxygen consumption VO2max) and energy intake. There was no significant association between the FTO genotype and BMR or VO2max. The FTO genotype was significantly associated (P = 0.024) with variation in energy intake, with average daily intake being 9.0 MJ for the wild‐type TT genotype and 10.2 and 9.5 MJ for the “at risk” AT and AA genotypes, respectively. Adjusting intake for BMR did not remove the significance (P = 0.043). FTO genotype probably affects obesity via effects on food intake rather than energy expenditure.

Energy balance measurement: when something is not better than nothing

Energy intake (EI) and physical activity energy expenditure (PAEE) are key modifiable determinants of energy balance, traditionally assessed by self-report despite its repeated demonstration of considerable inaccuracies. We argue here that it is time to move from the common view that self-reports of EI and PAEE are imperfect, but nevertheless deserving of use, to a view commensurate with the evidence that self-reports of EI and PAEE are so poor that they are wholly unacceptable for scientific research on EI and PAEE. While new strategies for objectively determining energy balance are in their infancy, it is unacceptable to use decidedly inaccurate instruments, which may misguide health-care policies, future research and clinical judgment. The scientific and medical communities should discontinue reliance on self-reported EI and PAEE. Researchers and sponsors should develop objective measures of energy balance.

Climate-mediated energetic constraints on the distribution of hibernating mammals

To predict the consequences of human-induced global climate change, we need to understand how climate is linked to biogeography. Energetic constraints are commonly invoked to explain animal distributions, and physiological parameters are known to vary along distributional gradients. But the causal nature of the links between climate and animal biogeography remain largely obscure. Here we develop a bioenergetic model that predicts the feasibility of mammalian hibernation under different climatic conditions. As an example, we use the well-quantified hibernation energetics of the little brown bat (Myotis lucifugus) to parameterize the model. Our model predicts pronounced effects of ambient temperature on total winter energy requirements, and a relatively narrow combination of hibernaculum temperatures and winter lengths permitting successful hibernation. Microhabitat and northern distribution limits of M. lucifugus are consistent with model predictions, suggesting that the thermal dependence of hibernation energetics constrains the biogeography of this species. Integrating projections of climate change into our model predicts a pronounced northward range expansion of hibernating bats within the next 80 years. Bioenergetics can provide the simple link between climate and biogeography needed to predict the consequences of climate change.