International Journal of Obesity (1999) 23, 1105±1117 ß 1999 Stockton Press All rights reserved 0307±0565/99 $15.00 http://www.stockton-press.co.uk/ijo Review Gluttony and thermogenesis revisited{ Michael J Stock1 1Department of Physiology, St George's Hospital Medical School, University of London, London SW17 0RE, UK The evolutionary and biological signi®cance of adaptive, homeostatic forms of heat production (thermogenesis) is reviewed. After summarizing the role and selective value of thermogenesis in body temperature regulation (shivering and non-shivering thermogenesis) and the febrile response to infection (fever), the review concentrates on diet- induced thermogenesis (DIT). Animal studies indicate that DIT evolved mainly to deal with nutrient-de®cient or unbalanced diets, and re-analysis of twelve overfeeding studies carried out between 1967 and 1999 suggests the same may be so for humans, particularly when dietary protein concentration is varied. This implies that the role of DIT in the regulation of energy balance is secondary to its function in regulating the metabolic supply of essential nutrients. However, individual differences in DIT are much more marked when high- or low-protein diets are overfed, and this could provide a very sensitive method for discriminating between those who are, in metabolic terms, resistant and those who are susceptible to obesity. Keywords: diet-induced thermogenesis; non-shivering thermogenesis; energy balance; overfeeding; brown adipose tissue; protein; evolution Introduction Cafeteria feeding, DIT and obesity The title of this review echoes that of two papers The relevance of any study of BAT thermogenesis to (Gluttony 1 and Gluttony 2)1,2 published in 1967 that the regulation of energy balance and obesity depends described the effects of overfeeding humans low- and crucially on being able to demonstrate that thermo- high-protein diets. The second of these, dealing with genesis makes an important quantitative contribution the effects of overfeeding on thermogenesis, was my to the regulation of energy balance, and that defective ®rst scienti®c paper and the start of an interest in thermogenesis results in obesity. Until the early thermogenesis that still remains, more than 30 years 1980s, there was very little interest in DIT. Thermo- later. A personal high point in the past 30 years was genesis rarely, if ever, appeared in textbooks, reviews the 1979 Nature paper with Nancy Rothwell3 that or conferences on energy balance regulation and identi®ed brown adipose tissue (BAT) as the likely obesity. Only a few research groups were actively source of diet-induced thermogenesis (DIT). It would investigating the topic, and even these were mainly seem that this paper, and others linking impaired BAT interested in non-shivering thermogenesis (NST) and thermogenesis with obesity,4,5 had a major effect in thermoregulation. Thus, the use of the cafeteria diet in stimulating scienti®c interest in BAT. As shown in the 1979 Nature paper to induce voluntary hyperpha- Figure 1, the number of BAT papers being published gia and stimulate DIT in rats represented an important rose rapidly from approximate 50 per year prior to advance and provided the raison d'eÃtre for invoking 1979 to 150 ± 200 per year thereafter, with our Nature BAT as the effector of this form of thermogenesis. paper accumulating over 1000 citations. While one Table 1 shows the energy balance results from a cannot deny feeling pleased by having helped spark typical cafeteria-feeding experiment, and illustrates this upsurge of interest in brown fat research, I have the remarkable capacity for DIT in young adult rats. always felt that the fascination with BAT de¯ected It can be seen that in spite of a 73% increase in attention away from our important demonstration that voluntary energy intake in the cafeteria-fed rats, this DIT could exert a greater impact on the regulation of had very little effect on the rate of body energy gain energy balance than had hitherto been suspected. because there was an almost equivalent increase in energy expenditure, with 90% of the excess dietary energy being dissipated as heat. These, and many similar experiments, provided unequivocal quantita- tive evidence of the importance of DIT in the regula- { Review based on the EASO Wasserman Prize Lecture delivered tion of energy balance. at the 9th European Congress of Obesity, Milan, June 1999. It still seems remarkable that simply feeding a Correspondence: Professor MJ Stock, Department of Physiology, St George's Hospital Medical School, Tooting, varied and palatable cafeteria diet to induce voluntary London, SW17 0RE, UK. E-mail: [email protected] hyperphagia can produce more than a 50% increase in Gluttony and thermogenesis revisited MJ Stock 1106 pressing a lever which dispenses food for itself and for its obese partner in an adjacent cage.9 A much more convincing demonstration of reduced DIT contributing to obesity comes more or less by chance from a study by Trayhurn et al in cafeteria-fed lean and genetically-obese (ob=ob) mice.10 Energy balance data from this study are shown in Table 2, where the effects of cafeteria feeding on voluntary hyperphagia and energetic ef®ciency in the lean mice are seen to be very similar to those shown for rats in Table 1 Ð i.e. hyperphagia stimulates energy expen- diture rather than increasing body energy stores, and there is a signi®cant decrease in energetic ef®ciency. This contrasts with the response to cafeteria feeding in Figure 1 Number of papers dealing with brown adipose tissue the ob=ob mice where there is only a modest increase appearing each year since 1966, as revealed by a Medline in energy expenditure, a large increase in energy search. deposition and an increase, rather than a decrease, in energetic ef®ciency. This effect of genotype on the response to voluntary Table 1 Energy balance and thermogenesis in rats hyperphagia is quite remarkable and was the main Chow diet Cafeteria diet focus of that paper, but what is equally remarkable is Intake (kJ=d) 208 360*** the comparison of the cafeteria-fed lean mice with the Body gain (kJ=d) 33 50 chow-fed ob=ob mice. These two columns have been Expenditure (kJ=d) 175 310*** highlighted in Table 2 since they show that Trayhurn Net ef®ciency (%) 34 20*** 10 % Excess intake expended 89 et al had, perhaps without realizing it, conducted a pair-feeding experiment in which the lean mice had *** P < 0.01 vs Chow. voluntarily consumed the same amount of energy as Adapted from Rothwell and Stock.6 the obese mice Ð that is, this was pair-feeding that was free of experimental artifacts resulting from metabolic rate, and perhaps even more remarkable restriction of energy intake and disruption of normal that the phenomenon had gone undetected, ignored or meal patterns. This comparison shows that despite the discounted for so long. Likewise, the impact of same energy intake, the obese mice stored nearly three defective DIT in the aetiology of rodent obesity had times more body energy than the lean mice and also been ignored, even though there had been several illustrates the enormous impact that increased meta- pair-feeding studies on both genetic7 and experimen- bolic ef®ciency (that is decreased DIT) can have by tal8 models to show that obesity could develop in the itself on the development of obesity. This emphasizes absence of the hyperphagia Ð i.e. as a result of the fact that hyperphagia is not necessary for obesity reduced DIT and the consequent increase in energetic to develop in the ob=ob mice, and that the primary ef®ciency. However, one criticism of these sorts of lesion is not in the control of intake, but in the control experiments is that controlling the hyperphagia of the of energy expenditure. Since this is due entirely to the obese animal by restricting its intake to the level of absence of leptin in the ob=ob mutant, it should the normal, lean control can by itself increase ener- reinforce the concept of leptin as a thermogenic getic ef®ciency, due to the restricted animal eating a hormone. One suspects that the predilection of most smaller number of larger meals. However, this experi- workers to label leptin as a satiety hormone is mainly mental artefact can be avoided by performing yoke- due to the fact that it is very easy to measure food feeding experiments, where the amount and frequency intake, whereas it is quite dif®cult and demanding to of food eaten is determined by the control animal measure metabolic ef®ciency. Table 2 Cafeteria feeding in genetically lean and obese (ob=ob) mice Lean Obese Chow Cafeteria Chow Cafeteria Intake (kJ=d) 65 109*** 104 154* Gain (kJ=d) 9 11 31 58*** Expenditure (kJ=d) 56 98*** 73 96** Net ef®ciency (%) 24 13*** 44 50* * P < 0.05, **P < 0.01, ***P < 0.001 vs chow. Adapted from Trayhurn et al.10 Gluttony and thermogenesis revisited MJ Stock 1107 The ease or dif®culty with which one can mea- Evolution of thermogenesis sure things can often in¯uence the development of scienti®c ideas. In the same way that most of the research on the role of leptin in body-weight reg- One has to step back from DIT and obesity and ulation has concentrated on food intake (even mole- consider thermogenesis in a much broader biological cular biologists can measure food intake), so did the perspective to assess its evolutionary signi®cance and study of thermogenesis and obesity tend to concen- value in natural selection. To begin with, it should be trate on measuring BAT function. Following the noted that thermogenesis has very primitive origins, identi®cation of the BAT mitochondrial proton con- and is not restricted to homeotherms.