At present there is a range of commercial high-fat diets available that have been demonstrated to make small rodents obese. However, some of these diets contain levels of dietary fat that are much ...higher than the levels that humans routinely consume. The question has been raised as to whether experimental use of these diets with very high levels of fat adequately models the situation of human obesity.
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.
Bigger animals live longer. The scaling exponent for the relationship between lifespan and body mass is between 0.15 and 0.3. Bigger animals also expend more energy, and the scaling exponent for the ...relationship of resting metabolic rate (RMR) to body mass lies somewhere between 0.66 and 0.8. Mass-specific RMR therefore scales with a corresponding exponent between -0.2 and -0.33. Because the exponents for mass-specific RMR are close to the exponents for lifespan, but have opposite signs, their product (the mass-specific expenditure of energy per lifespan) is independent of body mass (exponent between -0.08 and 0.08). This means that across species a gram of tissue on average expends about the same amount of energy before it dies regardless of whether that tissue is located in a shrew, a cow, an elephant or a whale. This fact led to the notion that ageing and lifespan are processes regulated by energy metabolism rates and that elevating metabolism will be associated with premature mortality--the rate of living theory. The free-radical theory of ageing provides a potential mechanism that links metabolism to ageing phenomena, since oxygen free radicals are formed as a by-product of oxidative phosphorylation. Despite this potential synergy in these theoretical approaches, the free-radical theory has grown in stature while the rate of living theory has fallen into disrepute. This is primarily because comparisons made across classes (for example, between birds and mammals) do not conform to the expectations, and even within classes there is substantial interspecific variability in the mass-specific expenditure of energy per lifespan. Using interspecific data to test the rate of living hypothesis is, however, confused by several major problems. For example, appeals that the resultant lifetime expenditure of energy per gram of tissue is 'too variable' depend on the biological significance rather than the statistical significance of the variation observed. Moreover, maximum lifespan is not a good marker of ageing and RMR is not a good measure of total energy metabolism. Analysis of residual lifespan against residual RMR reveals no significant relationship. However, this is still based on RMR. A novel comparison using daily energy expenditure (DEE), rather than BMR, suggests that lifetime expenditure of energy per gram of tissue is NOT independent of body mass, and that tissue in smaller animals expends more energy before expiring than tissue in larger animals. Some of the residual variation in this relationship in mammals is explained by ambient temperature. In addition there is a significant negative relationship between residual lifespan and residual daily energy expenditure in mammals. A potentially much better model to explore the links of body size, metabolism and ageing is to examine the intraspecific links. These studies have generated some data that support the original rate of living theory and other data that conflict. In particular several studies have shown that manipulating animals to expend more or less energy generate the expected effects on lifespan (particularly when the subjects are ectotherms). However, smaller individuals with higher rates of metabolism live longer than their slower, larger conspecifics. An addition to these confused observations has been the recent suggestion that under some circumstances we might expect mitochondria to produce fewer free radicals when metabolism is higher--particularly when they are uncoupled. These new ideas concerning the manner in which mitochondria generate free radicals as a function of metabolism shed some light on the complexity of observations linking body size, metabolism and lifespan.
The idea that oxidative stress may underpin life history trade‐offs has become extremely popular. However, experimental support for the concept has proved equivocal. It has recently been suggested ...that this might be because of flaws in the design of existing studies. Here, we explore the background to the oxidative stress hypothesis and highlight some of the complexities in testing it. We conclude that the approach recently suggested to be least useful in this context (comparing reproducing to non‐reproducing animals) may in fact be the most powerful. Moreover, suggested alternative approaches of limiting food supply or manipulating litter sizes have many complexities and problems. We suggest some useful alternative approaches that have not been previously advocated, particularly the study of individuals reproducing at greater parity later in life. Finally, the measures of oxidative stress and tissues that are analysed influence the experimental outcome. This suggests our conceptual model of the trade‐off is currently too simplistic, and that studies based on single or limited numbers of assays, or restricted to single tissues, whether they support or refute the theory, should be interpreted with great caution.
Recent evidence suggests reproduction, possibly mediated via reproductive hormones, in combination with uncoupling, and energy supply results in different levels of free‐radical production in different tissues. Consequent damage to Protein, DNA and Fat depends on selective allocation of protection. Survival may be a consequence of effects across all tissues or a single crucially important impact.
The mouse is one of the most important model organisms for understanding human genetic function and disease. This includes characterization of the factors that influence energy expenditure and ...dysregulation of energy balance leading to obesity and its sequelae. Measuring energy metabolism in the mouse presents a challenge because the animals are small, and in this respect it presents similar challenges to measuring energy demands in many other species of small mammal. This paper considers some theoretical, practical, and analytical considerations to be considered when measuring energy expenditure in mice. Theoretically total daily energy expenditure is comprised of several different components: basal or resting expenditure, physical activity, thermoregulation, and the thermic effect of food. Energy expenditure in mice is normally measured using open flow indirect calorimetry apparatus. Two types of system are available - one of which involves a single small Spartan chamber linked to a single analyzer, which is ideal for measuring the individual components of energy demand. The other type of system involves a large chamber which mimics the home cage environment and is generally configured with several chambers/analyzer. These latter systems are ideal for measuring total daily energy expenditure but at present do not allow accurate decomposition of the total expenditure into its components. The greatest analytical challenge for mouse expenditure data is how to account for body size differences between individuals. This has been a matter of some discussion for at least 120 years. The statistically most appropriate approach is to use analysis of covariance with individual aspects of body composition as independent predictors.
The prevalence of obesity in modern societies has two major contributory factors-an environmental change that has happened in historical times and a genetic predisposition that has its origins in our ...evolutionary history. Understanding both aspects is complex. From an evolutionary perspective, three different types of explanation have been proposed. The first is that obesity was once adaptive and enabled us to survive (or sustain fecundity) through periods of famine. People carrying so-called thrifty genes that enabled the efficient storage of energy as fat between famines would be at a selective advantage. In the modern world, however, people who have inherited these genes deposit fat in preparation for a famine that never comes, and the result is widespread obesity. The key problem with this, and any other adaptive scenario, is to understand why, if obesity was historically so advantageous, many people did not inherit these thrifty genes and in modern society are able to remain slim, despite the environmental change favoring fat storage. The second type of explanation is that obesity is not adaptive and may never even have existed in our evolutionary past, but it is favored today as a maladaptive by-product of positive selection on some other trait. An example of this type of explanation is the suggestion that obesity results from variation in brown adipose tissue thermogenesis. Finally, a third class of explanation is that most mutations in the genes that predispose us to obesity are neutral and have been drifting over evolutionary time--so-called drifty genes, leading some individuals to be obesity prone and others obesity resistant. In this article, I review the current evidence for and against these three different scenarios and conclude that the thrifty gene hypothesis is untenable but the other two ideas may provide a cogent explanation of the modern obesity phenomenon.
Most people are aware of the health benefits of being physically active. The question arises then why people so easily fall into sedentary habits. The idea developed here is that sedentary behavior ...is part of a suite of behaviors to reduce levels of physical activity that were strongly selected in the evolutionary past, likely because high levels of physical activity had direct negative consequences for survival. However, hunter‐gatherer populations could not reduce activity indefinitely because of the need to be active to hunt for, and gather food. Hence they never experienced low levels of activity that are damaging to health, and no corresponding mechanism avoiding low activity evolved. Consequently, gene variants promoting efficiency of activity and increased sedentariness were never selected against. Modern society facilitates reduced activity by providing many options to become less active and divorcing food intake from the need to be active. Choosing the less active option is hard wired in the genes; this explains why being sedentary is so common, and why reversing it is so difficult. Incentivizing activity may be enabled using modern technology, but ultimately may only end up replacing one set of health issues with others. Also see the video here https://youtu.be/ekHbUwPw-v4.
In the past, being active was associated with increased mortality risks, leading to selection for inactivity. However, there was no counterbalancing selection against being sedentary because individuals had to be active to find food. In modern society, the need to feed is disconnected from being physically active. Hence, individuals are driven to be highly sedentary, with negative impacts on health.
Recent work on a small European cave salamander (Proteus anguinus) has revealed that it has exceptional longevity, yet it appears to have unexceptional defences against oxidative damage. This paper ...comes at the end of a string of other studies that are calling into question the free-radical damage theory of ageing. This theory rose to prominence in the 1990s as the dominant theory for why we age and die. Despite substantial correlative evidence to support it, studies in the last five years have raised doubts over its importance. In particular, these include studies of mice with the major antioxidant genes knocked out (both singly and in combination), which show the expected elevation in oxidative damage but no impact on lifespan. Combined, these findings raise fundamental questions over whether the free-radical damage theory remains useful for understanding the ageing process, and variation in lifespan and life histories.
A cluster of single nucleotide polymorphisms (SNPs) in the first intron of the fat mass and obesity related (
FTO
) gene were the first common variants discovered to be associated with body mass ...index and body fatness. This review summarises what has been later discovered about the biology of
FTO
drawing together information from both human and animal studies. Subsequent work showed that the ‘at risk’ alleles of these SNPs are associated with greater food intake and increased hunger/lowered satiety, but are not associated with altered resting energy expenditure or low physical activity in humans.
FTO
is an FE (II) and 2-oxoglutarate dependent DNA/RNA methylase. Contrasting the impact of the SNPs on energy balance in humans, knocking out or reducing activity of the
Fto
gene in the mouse resulted in lowered adiposity, elevated energy expenditure with no impact on food intake (but the impact on expenditure is disputed). In contrast, overexpression of the gene in mice led to elevated food intake and adiposity, with no impact on expenditure. In rodents, the
Fto
gene is widely expressed in the brain including hypothalamic nuclei linked to food intake regulation. Since its activity is 2-oxoglutarate dependent it could potentially act as a sensor of citrate acid cycle flux, but this function has been dismissed, and instead it has been suggested to be much more likely to act as an amino acid sensor, linking circulating AAs to the mammalian target of rapamycin complex 1. This may be fundamental to its role in development but the link to obesity is less clear. It has been recently suggested that although the obesity related SNPs reside in the first intron of
FTO
, they may not only impact
FTO
but mediate their obesity effects via nearby genes (notably
RPGRIP1L
and
IRX3
).
Rather, as we pointed out, although the reverse causality idea originated in the CIM, our paper primarily concerned the impact of high levels of dietary fat. ...reverse causality in our context might ...reflect a "similar process" to the CIM but not the actual CIM. ...we stated in the first paragraph of the Discussion the fact that we did not find evidence to support the reverse causality idea in our experiment: "... does not mean that reverse causality is unimportant in other contexts such as obesity driven by excess carbohydrate consumption in other species like humans, as has been claimed elsewhere 14,15,16" 1. ...work will be needed to establish whether there is some minor undetected change in fat stores and fuel partitioning that underpins the increase in food intake that accompanies the change in diet from low to high fat.
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