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Keywords:

  • Obesity;
  • basal metabolic rate;
  • thermogenesis

Background

  1. Top of page
  2. Background
  3. Components of energy expenditure
  4. Is basal metabolic rate abnormally low in obese individuals?
  5. Is diet-induced thermogenesis abnormally low in obese individuals?
  6. Is physical activity abnormally low in obese individuals?
  7. Is adaptive thermogenesis abnormally low in obese individuals?
  8. Could pharmaco-manipulation of metabolic rate offer a viable therapeutic option?
  9. Conflict of Interest Statement
  10. References

In the 1970s and 1980s, much obesity-related research concentrated on the search for ‘energy sparing’ defects that might explain why a small proportion of the population became obese. This research effort was predicated on the belief that obesity developed in metabolically susceptible individuals who apparently consumed the same, or fewer, calories than their lean counterparts. Towards the end of the 1970s, it had become apparent that basal metabolic rate (BMR) was actually higher in obese than in lean people (for example, James et al. (1)), but it was only in the mid-1980s that the development and application of the doubly labelled water (2H218O) method allowed an objective assessment of this basic assumption extrapolated to natural free-living circumstances. It showed it to be false (2). The new method clearly demonstrated that obese people consistently under-report their food intake (3), a finding that has been universally replicated in numerous subsequent studies.

This discovery was a watershed in obesity research and refocused attention on two other factors. First came the understanding that most obesity in the modern world is a natural biological response to a changed environment and that innate body-weight regulatory mechanisms have been overwhelmed by energy-dense diets and sedentary lifestyles (4–6). Second, it became apparent from human genetic studies that all of the monogenic defects leading to obesity so far discovered operate on neuroendocrine pathways involved in the regulation of energy intake rather than energy expenditure, thus suggesting that these pathways are critical (7) (and see contributions by Farooqi and O’Rahilly and Bloom).

Components of energy expenditure

  1. Top of page
  2. Background
  3. Components of energy expenditure
  4. Is basal metabolic rate abnormally low in obese individuals?
  5. Is diet-induced thermogenesis abnormally low in obese individuals?
  6. Is physical activity abnormally low in obese individuals?
  7. Is adaptive thermogenesis abnormally low in obese individuals?
  8. Could pharmaco-manipulation of metabolic rate offer a viable therapeutic option?
  9. Conflict of Interest Statement
  10. References

The human energy budget is usually divided into three major components which, together, constitute the total energy expenditure (TEE): BMR; diet-induced thermogenesis (DIT); and physical activity (PA). A fourth component, adaptive thermogenesis (AT), is sometimes added but its significance in humans is questionable (see below). As the name implies, BMR represents the basal energy costs of keeping the body alive (respiration, cardiac pumping, protein turnover and repair, maintenance of energy-dependent ionic gradients, etc.). DIT is the unavoidable wastage of energy involved in the digestion, absorption, transport, interconversion and storage of the energy within any meal. PA is self-explanatory but can be divided into so-called non-exercise activity thermogenesis (NEAT – see below) and exercise-related expenditure. What follows is a very brief summary of the evidence exploring whether defects in any of these might play a role in the aetiology of obesity.

Is basal metabolic rate abnormally low in obese individuals?

  1. Top of page
  2. Background
  3. Components of energy expenditure
  4. Is basal metabolic rate abnormally low in obese individuals?
  5. Is diet-induced thermogenesis abnormally low in obese individuals?
  6. Is physical activity abnormally low in obese individuals?
  7. Is adaptive thermogenesis abnormally low in obese individuals?
  8. Could pharmaco-manipulation of metabolic rate offer a viable therapeutic option?
  9. Conflict of Interest Statement
  10. References

Basal metabolic rate can represent as much as 65–70% of TEE in sedentary people, so it is an important area to search for possible metabolic differences. After tens of thousands of measurements, it is a universal observation that BMR is raised not suppressed in obese people (2) because of the fact that they have a greater lean body mass (LBM) than their lean counterparts, and because LBM is the major determinant of BMR. The question as to whether a reduced BMR might have been an antecedent to obesity has been much debated. Most observers reject it as a possibility. The most popular experimental approach to this question has been to measure BMR in post-obese subjects. Such studies possibly indicate a very small suppression of BMR (for example, Weinsier et al. (8)), but this is deemed vulnerable to experimental artefact and anyway too small to be of much significance.

Is diet-induced thermogenesis abnormally low in obese individuals?

  1. Top of page
  2. Background
  3. Components of energy expenditure
  4. Is basal metabolic rate abnormally low in obese individuals?
  5. Is diet-induced thermogenesis abnormally low in obese individuals?
  6. Is physical activity abnormally low in obese individuals?
  7. Is adaptive thermogenesis abnormally low in obese individuals?
  8. Could pharmaco-manipulation of metabolic rate offer a viable therapeutic option?
  9. Conflict of Interest Statement
  10. References

Diet-induced thermogenesis represents only 5–10% of TEE. Nonetheless, there have been numerous highly detailed experimental studies that have examined whether differences in this small component could explain an obese person’s susceptibility to weight gain. Numerous studies did indeed claim evidence of such a difference (for example, Jequier and Schutz (9)), but the differences were again susceptible to experimental artefact (mostly related to the problem of defining the equivalent energy load in the tests’ meals given to subjects of very different body weights) and were again very small (10). Few people would now credit this as having great significance to the causation of obesity.

Is physical activity abnormally low in obese individuals?

  1. Top of page
  2. Background
  3. Components of energy expenditure
  4. Is basal metabolic rate abnormally low in obese individuals?
  5. Is diet-induced thermogenesis abnormally low in obese individuals?
  6. Is physical activity abnormally low in obese individuals?
  7. Is adaptive thermogenesis abnormally low in obese individuals?
  8. Could pharmaco-manipulation of metabolic rate offer a viable therapeutic option?
  9. Conflict of Interest Statement
  10. References

Here, it is critical to make a distinction between the secular trends towards a societal reduction in PA, which are strongly believed to be a partial cause of the population-wide trends towards weight gain (4,6) and the issue of whether individuals who are especially obesity-prone have a lower than expected level of PA compared with their peers. The energy cost of PA can best be approximated as TEE minus BMR, where TEE is assessed by the doubly labelled water (2H218O) method. A major compilation of such data showed that, as is the case for BMR, obese people generally have a much higher, not lower, energy expenditure on PA (11). This is largely because they have a much greater body weight that requires considerably more energy to move, especially in weight-bearing activities. Precisely, the best way of adjusting for differences in body weight in order to compare the underlying propensity for PA in lean and obese subjects is a complex issue with no perfect resolution. One approach is simply to examine the physical activity level (PAL = TEE/BMR), because this incorporates an automatic adjustment for body size and LBM, as these determine BMR. On this basis, it appears that obese subjects have very similar levels of PA except when they become morbidly obese, at which stage it is assumed that their obesity is physically incapacitating them (11). Contrary to this evidence is a series of epidemiological studies, which show that low levels of participation in active pursuits and high levels of sedentary behaviours such as TV viewing are significant predictors of weight gain (12,13). This topic is covered in more detail elsewhere in this report (see contribution by Fox and Hillson).

Some studies have assessed possible differences in what has been termed non-exercise activity thermogenesis (NEAT), which has been defined as ‘the energy expended for everything that is not sleeping, eating, or sports-like exercise’. It includes the energy expended walking to work, typing, performing yard work, undertaking agricultural tasks and fidgeting (14). Although claims have been made that low levels of NEAT may contribute to an individual’s susceptibility (15), the case is not strong and, as with some similar claims for reduced levels of BMR (for example, Ravussin and Gautier (10) and Ravussin (16)), needs to be interpreted against the background of an overall adipogenic environment. Under such circumstances, people at the lower end of the energy expenditure spectrum will be at greater risk of gaining weight more rapidly, but this does not mean that it is the overall driver of their obesity.

Is adaptive thermogenesis abnormally low in obese individuals?

  1. Top of page
  2. Background
  3. Components of energy expenditure
  4. Is basal metabolic rate abnormally low in obese individuals?
  5. Is diet-induced thermogenesis abnormally low in obese individuals?
  6. Is physical activity abnormally low in obese individuals?
  7. Is adaptive thermogenesis abnormally low in obese individuals?
  8. Could pharmaco-manipulation of metabolic rate offer a viable therapeutic option?
  9. Conflict of Interest Statement
  10. References

The concept of AT was first mooted over a century ago in an attempt to explain why some individuals apparently gain less weight than would be predicted when they are experimentally overfed. Numerous studies claimed to substantiate this thesis, but all were based on indirect calculations comparing the theoretical and predicted rates of weight gain in overfeeding studies. Very few studies have actually made direct measurements to test for the existence of AT. The most comprehensive of these used whole-body indirect calorimetry and the doubly labelled water method to measure changes in all components of the energy budget and detailed body-composition techniques to assess tissue gained (17). It was concluded that the changes induced by overfeeding were similar in lean and overweight subjects and were in line with theoretical predictions without any need to invoke an adaptive component of energy expenditure to balance the budget. Numerous other studies that have attempted to measure AT (rather than to merely compute it) have reached similar conclusions (for example, Ravussin et al. (18)). It should be acknowledged, however, that shorter-term measurements of thermogenesis have suggested that there could be a difference between lean and obese people, especially in response to over-eating protein (for example, Stock (19)).

Could pharmaco-manipulation of metabolic rate offer a viable therapeutic option?

  1. Top of page
  2. Background
  3. Components of energy expenditure
  4. Is basal metabolic rate abnormally low in obese individuals?
  5. Is diet-induced thermogenesis abnormally low in obese individuals?
  6. Is physical activity abnormally low in obese individuals?
  7. Is adaptive thermogenesis abnormally low in obese individuals?
  8. Could pharmaco-manipulation of metabolic rate offer a viable therapeutic option?
  9. Conflict of Interest Statement
  10. References

The uncoupling proteins (UCP1, 2 and 3) can dissipate a proportion of metabolic energy through uncoupled metabolism that creates heat rather than generating adenosine triphosphate. Consequently, these have been the topic of extensive research as possible pharmacological or even gene-therapy targets (20,21). The favoured route has been to develop specific β3-adrenergic compounds that might stimulate UCP1 without the undesirable β1 and β2 effects on pulse rate and blood pressure (22). These have tended to be effective in small animal studies and then fail the transition to humans, most likely because adult humans have only vestigial amounts of UCP1, which is only expressed in brown adipose tissue (23).

Any pharmacological agent that significantly increases energy expenditure must, by definition, also raise heart rate, as the body requires extra oxygen. This sine quo non generates its own Catch-22 insofar as regulatory bodies are wary of any compound that affects pulse rate and pressure, and the more effectively an agent raises metabolism, the less likely it is to pass through the regulatory hurdles. On these grounds, pharmacological suppression of appetite seems a much more viable therapeutic route.

One possible future option might be gene therapy that over-expresses uncoupling proteins (although this would be similarly vulnerable to the Catch-22 above). Mice that were genetically modified to over-express UCP3 were shown to be resistant to diet-induced obesity, but the genetic modification was extreme, resulting in a 50-fold increase in muscle UCP3 (24). Such options seem highly remote for human interventions.

References

  1. Top of page
  2. Background
  3. Components of energy expenditure
  4. Is basal metabolic rate abnormally low in obese individuals?
  5. Is diet-induced thermogenesis abnormally low in obese individuals?
  6. Is physical activity abnormally low in obese individuals?
  7. Is adaptive thermogenesis abnormally low in obese individuals?
  8. Could pharmaco-manipulation of metabolic rate offer a viable therapeutic option?
  9. Conflict of Interest Statement
  10. References