Uncoupling proteins: their roles in adaptive thermogenesis and substrate metabolism reconsidered

During the past few years, there have been two major developments, if not revolutions, in the field of energy balance and weight regulation. The first at the molecular level, which was catalysed by developments in DNA screening technology together with the mapping of the human genome, has been the tremendous advances made in the identification of molecules that play a role in the control of food intake and metabolic rate. The second, at the systemic level, which centered upon the use of modern technologies or more robust analytical techniques for assessing human energy expenditure in response to starvation and overfeeding, has been the publication of several papers providing strong evidence that adaptive thermogenesis plays a much more important role in the regulation of body weight and body composition than previously thought. Within these same few years, several new members of the mitochondrial carrier protein family have been identified in a variety of tissues and organs. All apparently possess uncoupling properties in genetically-modified systems, with two of them (uncoupling protein (UCP) 2 and UCP3) being expressed in adipose tissues and skeletal muscles, which are generally recognised as important sites for variations in thermogenesis and/or in substrate oxidation. Considered as breakthrough discoveries, the cloning of these genes has generated considerable optimism for rapid advances in our molecular understanding of adaptive thermogenesis, and for the identification of new targets for pharmacological management of obesity and cachexia. The present paper traces first, from a historical perspective, the landmark events in the field of thermogenesis that led to the identification of these genes encoding candidate UCP, and then addresses the controversies and on-going debate about their physiological importance in adaptive thermogenesis, in lipid oxidation or in oxidative stress. The general conclusion is that UCP2 and UCP3 may have distinct primary functions, with UCP3 implicated in regulating the flux of lipid substrates across the mitochondria and UCP2 in the control of mitochondrial generation of reactive oxygen species. The distinct functions of these two UCP1 homologues have been incorporated in a conceptual model to illustrate how UCP2 and UCP3 may act in concert in the overall regulation of lipid oxidation concomitant to the prevention of lipid-induced oxidative damag

Pathways from dieting to weight regain, to obesity and to the metabolic syndrome: an overview

Every year, scores of millions of people – as diverse as obese and lean, teenagers and older adults, sedentary and elite athletes, commoners and celebrities – attempt to lose weight on some form of diet. They are often encouraged by their parents, friends, health professionals, training coaches, a media that promotes a slim image and a diet- industry that in Europe and United States alone has an annual turnover in excess of $150 billion. Weight regain is generally the rule, with one-third to two-thirds of the weight lost being regained within 1 year and almost all is regained within 5 years. With studies of the long-term outcomes showing that at least one-third of dieters regain more weight than they lost, together with prospective studies indicating that dieting during childhood and adolescence predicts future weight gain and obesity, there is concern as to whether dieting may paradoxically be promoting exactly the opposite of what it is intended to achieve. Does dieting really make people fatter? How? Does dieting increase the risks for cardiometabolic diseases as many go through repeated cycles of intentional weight loss and unintentional weight regain, i.e. through yo-yo dieting or weight cycling? What's new in adipose tissue biology pertaining to the mechanisms that drive weight regain? Why does exercise not necessarily work in concert with dieting to achieve weight loss and prevent weight regain? What ‘lessons’ are we learning from bariatric surgery about the mechanisms by which long-term weight loss seems achievable? It is these questions, against a background of preoccupation with dieting, that recent advances and controversies relevant to the theme of ‘Pathways from dieting to weight regain, to obesity and to the metabolic syndrome’ are addressed in this overview and the eight review articles in this supplement reporting the proceedings of the 7th Fribourg Obesity Research Conference

Posture allocation revisited: breaking the sedentary threshold of energy expenditure for obesity management

There is increasing recognition that low-intensity physical activities of daily life play an important role in achieving energy balance and that their societal erosion through substitution with sedentary (mostly sitting) behaviours, whether occupational or for leisure, impact importantly on the obesity epidemic. This has generated considerable interest for better monitoring, characterizing and promoting countermeasures to sedentariness through a plethora of low-level physical activities (e.g. active workstations, standing desks, sitting breaks), amid the contention that altering posture allocation (lying, sitting, standing) can modify energy expenditure to impact upon body weight regulation and health. In addressing this contention, this paper first revisits the past and more recent literature on postural energetics, with particular emphasis on potential determinants of the large inter-individual variability in the energy cost of standing and the impact of posture on fat oxidation. It subsequently analyses the available data pertaining to various strategies by which posture allocations, coupled with light physical activity, may increase energy expenditure beyond the sedentary threshold, and their relevance as potential targets for obesity management

Dieting and weight cycling as risk factors for cardiometabolic diseases: who is really at risk?

Despite the poor prognosis of dieting in obesity management, which often results in repeated attempts at weight loss and hence weight cycling, the prevalence of dieting has increased continuously in the past decades in parallel to the steadily increasing prevalence of obesity. However, dieting and weight cycling are not limited to those who are obese or overweight as substantial proportions of the various population groups with normal body weight also attempt to lose weight. These include young and older adults as well as children and adolescents who perceive themselves as too fat (due to media, parental and social pressures), athletes in weight-sensitive competitive sports (i.e. mandatory weight categories, gravitational and aesthetic sports) or among performers for whom a slim image is professionally an advantage. Of particular concern is the emergence of evidence that some of the potentially negative health consequences of repeated dieting and weight cycling are more readily seen in people of normal body weight rather than in those who are overweight or obese. In particular, several metabolic and cardiovascular risk factors associated with weight cycling in normal-weight individuals have been identified from cross-sectional and prospective studies as well as from studies of experimentally induced weight cycling. In addition, findings from studies of experimental weight cycling have reinforced the notion that fluctuations of cardiovascular risk variables (such as blood pressure, heart rate, sympathetic activity, blood glucose, lipids and insulin) with probable repeated overshoots above normal values during periods of weight regain put an additional stress on the cardiovascular system. As the prevalence of diet-induced weight cycling is increasing due to the opposing forces of an ‘obesigenic’ environment and the media pressure for a slim figure (that even targets children), dieting and weight cycling is likely to become an increasingly serious public health issue

How dieting makes some fatter: from a perspective of human body composition autoregulation

Dieting makes you fat – the title of a book published in 1983 – embodies the notion that dieting to control body weight predisposes the individual to acquire even more body fat. While this notion is controversial, its debate underscores the large gap that exists in our understanding of basic physiological laws that govern the regulation of human body composition. A striking example is the key role attributed to adipokines as feedback signals between adipose tissue depletion and compensatory increases in food intake. Yet, the relative importance of fat depletion per se as a determinant of post-dieting hyperphagia is unknown. On the other hand, the question of whether the depletion of lean tissues can provide feedback signals on the hunger–appetite drive is rarely invoked, despite evidence that food intake during growth is dominated by the impetus for lean tissue deposition, amidst proposals for the existence of protein–static mechanisms for the regulation of growth and maintenance of lean body mass. In fact, a feedback loop between fat depletion and food intake cannot explain why human subjects recovering from starvation continue to overeat well after body fat has been restored to pre-starvation values, thereby contributing to ‘fat overshooting’. In addressing the plausibility and mechanistic basis by which dieting may predispose to increased fatness, this paper integrates the results derived from re-analysis of classic longitudinal studies of human starvation and refeeding. These suggest that feedback signals from both fat and lean tissues contribute to recovering body weight through effects on energy intake and thermogenesis, and that a faster rate of fat recovery relative to lean tissue recovery is a central outcome of body composition autoregulation that drives fat overshooting. A main implication of these findings is that the risk of becoming fatter in response to dieting is greater in lean than in obese individuals.</jats:p

How dieting makes some fatter: from a perspective of human body composition autoregulation

Dieting makes you fat - the title of a book published in 1983 - embodies the notion that dieting to control body weight predisposes the individual to acquire even more body fat. While this notion is controversial, its debate underscores the large gap that exists in our understanding of basic physiological laws that govern the regulation of human body composition. A striking example is the key role attributed to adipokines as feedback signals between adipose tissue depletion and compensatory increases in food intake. Yet, the relative importance of fat depletion per se as a determinant of post-dieting hyperphagia is unknown. On the other hand, the question of whether the depletion of lean tissues can provide feedback signals on the hunger-appetite drive is rarely invoked, despite evidence that food intake during growth is dominated by the impetus for lean tissue deposition, amidst proposals for the existence of protein-static mechanisms for the regulation of growth and maintenance of lean body mass. In fact, a feedback loop between fat depletion and food intake cannot explain why human subjects recovering from starvation continue to overeat well after body fat has been restored to pre-starvation values, thereby contributing to ‘fat overshooting'. In addressing the plausibility and mechanistic basis by which dieting may predispose to increased fatness, this paper integrates the results derived from re-analysis of classic longitudinal studies of human starvation and refeeding. These suggest that feedback signals from both fat and lean tissues contribute to recovering body weight through effects on energy intake and thermogenesis, and that a faster rate of fat recovery relative to lean tissue recovery is a central outcome of body composition autoregulation that drives fat overshooting. A main implication of these findings is that the risk of becoming fatter in response to dieting is greater in lean than in obese individual

Postprandial thermogenesis and respiratory quotient in response to galactose: comparison with glucose and fructose in healthy young adults

Circumstantial evidence suggests that substitution of glucose or sucrose by the low- glycaemic index sugar galactose in the diet may lead to greater thermogenesis and/or fat oxidation. Using ventilated hood indirect calorimetry, we investigated, in twelve overnight-fasted adults, the resting energy expenditure (REE) and respiratory quotient (RQ) for 30 min before and 150 min after ingestion of 500 ml of water containing 60 g of glucose, fructose or galactose in a randomised cross-over design. REE increased similarly with all three sugars, reaching peak values after 50–60 min, but its subsequent fall towards baseline values was faster with galactose and glucose than with fructose (P < 0·001). RQ increased with all three sugars, but to a much greater extent with galactose and fructose than with glucose, particularly after 1 h post- ingestion. When ingested as a sugary drink, postprandial thermogenesis and utilisation of fat after galactose are not higher than after glucose or fructose