Abstract
Many compounds and genetic manipulations are claimed to confer resistance to obesity in rodents by raising energy expenditure. Examples taken from recent and older literature, demonstrate that such claims are often based on measurements of energy expenditure after body composition has changed, and depend on comparisons of energy expenditure divided by body weight. This is misleading because white adipose tissue has less influence than lean tissue on energy expenditure. Application of this approach to human data would suggest that human obesity is usually due to a low metabolic rate, which is not an accepted view. Increased energy expenditure per animal is a surer way of demonstrating thermogenesis, but even then it is important to know whether this is due to altered body composition (repartitioning), or increased locomotor activity rather than thermogenesis per se. Regression analysis offers other approaches. The thermogenic response to some compounds has a rapid onset and so cannot be due to altered body composition. These compounds usually mimic or activate the sympathetic nervous system. Thermogenesis occurs in, but may not be confined to, brown adipose tissue. It should not be assumed that weight loss in response to these treatments is due to thermogenesis unless there is a sustained increase in 24-h energy expenditure. Thyroid hormones and fibroblast growth factor 21 also raise energy expenditure before they affect body composition. Some treatments and genetic modifications alter the diurnal rhythm of energy expenditure. It is important to establish whether this is due to altered locomotor activity or efficiency of locomotion. There are no good examples of compounds that do not affect short-term energy expenditure but have a delayed effect. How and under what conditions a genetic modification or compound increases energy expenditure influences the decision on whether to seek drugs for the target or take a candidate drug into clinical studies.
Highlights
Despite the continuing rise in the worldwide prevalence of obesity and the vast sales that a safe and effective drug for this disorder might achieve, many pharmaceutical companies have been disinclined to invest in research and development in this field in recent years because the task seemed near impossible
Better evidence is that the thermogenic effect on days 2–6 of subcutaneously infused leptin was reduced by about 50% in mice that lack all three β-adrenoceptors (Asensio et al, 2008)
Thyroid hormones and possibly fibroblast growth factor 21 (FGF21) are examples of treatments that bridge the gap between sympathomimetic compounds, which elicit rapid increases in energy expenditure, and some of the compounds and genetic modifications that are described in section Detection of NonAcute Thermogenesis
Summary
Despite the continuing rise in the worldwide prevalence of obesity and the vast sales that a safe and effective drug for this disorder might achieve, many pharmaceutical companies have been disinclined to invest in research and development in this field in recent years because the task seemed near impossible. Apart from orlistat, the primary mechanism of which is to reduce energy absorption rather than intake, these drugs have all been perceived as anorectic agents It is important to understand how evidence that compounds are thermogenic in rodents has been obtained and whether this evidence translates to humans, because the question “Is it anorectic or thermogenic?” will continue to be asked of new drugs, drug candidates and drug targets.
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