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Increasing lifestyle energy expenditure has long been advocated in the prevention and treatment of obesity, as embodied in the ancient prescription of Hippocrates (the 'father of modern medicine') that people with obesity should eat less and exercise more. However, the long-term outcome of exercise alone or in combination with dieting in obesity management is poor. To understand the reasons underlying these failures and to develop novel strategies that target lifestyle energy expenditure in both prevention and treatment of obesity, research over the past decades has focused on (i) the interactions between physical activity and body weight (and its composition) throughout the lifespan; (ii) the influence of biology and potential compensatory changes in energy expenditure, food intake and food assimilation in response to energy deficits; and (iii) the impact of the built environment (outdoor and indoor) and smart technology on physical activity behaviours, thermoregulatory thermogenesis and metabolic health. It is against this background that recent advances relevant to the theme of 'Targeting Lifestyle Energy Expenditure in the Management of Obesity and Health: From Biology to Built Environment' are addressed in this overview and the nine review articles in this supplement, reporting the proceedings of the 9th Fribourg Obesity Research Conference.

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.

Recent body composition studies on the island of Mauritius in young adults belonging to the two main ethnicities—Indians (South Asian descent) and Creoles (African/Malagasy descent)—have shown gender-specific ethnic differences in their body mass index (BMI)–Fat% relationships. We investigated here whether potential gender and ethnic differences in blood leptin would persist beyond that explained by differences in body composition. In healthy young adult Mauritian Indians and Creoles (79 men and 80 women; BMI range: 15–41 kg m−2), we investigated the relationships between fasted serum leptin with BMI, waist circumference (WC), total fat% assessed by deuterium oxide dilution technique and central adiposity (trunk fat%) assessed by abdominal bioimpedance analysis. The results indicate that the greater elevations in leptin-BMI and leptin-WC regression lines in women compared with men, as well as in Indian men compared with Creole men, are abolished when BMI and WC are replaced by total body fat% and trunk fat%, respectively. In women, no significant between-ethnic difference is observed in total body fat%, trunk fat% and serum leptin. Thus, in young adult Mauritians, a population at high risk for later cardiometabolic diseases, the differences in body fat% entirely accounted for the observed gender and ethnic differences in serum leptin.

Isometric thermogenesis as applied to human energy expenditure refers to heat production resulting from increased muscle tension. While most physical activities consist of both dynamic and static (isometric) muscle actions, the isometric component is very often essential for the optimal performance of dynamic work given its role in coordinating posture during standing, walking and most physical activities of everyday life. Over the past 75 years, there has been sporadic interest into the relevance of isometric work to thermoregulatory thermogenesis and to adaptive thermogenesis pertaining to body-weight regulation. This has been in relation to (i) a role for skeletal muscle minor tremor or microvibration - nowadays referred to as 'resting muscle mechanical activity' - in maintaining body temperature in response to mild cooling; (ii) a role for slowed skeletal muscle isometric contraction-relaxation cycle as a mechanism for energy conservation in response to caloric restriction and weight loss and (iii) a role for spontaneous physical activity (which is contributed importantly by isometric work for posture maintenance and fidgeting behaviours) in adaptive thermogenesis pertaining to weight regulation. This paper reviews the evidence underlying these proposed roles for isometric work in adaptive thermogenesis and highlights the contention that variability in this neglected component of energy expenditure could contribute to human predisposition to obesity.

Whether dieting makes people fatter has been a subject of considerable controversy over the past 30 years. More recent analysis of several prospective studies suggest, however, that it is dieting to lose weight in people who are in the healthy normal range of body weight, rather than in those who are overweight or obese, that most strongly and consistently predict future weight gain. This paper analyses the ongoing arguments in the debate about whether repeated dieting to lose weight in normal-weight people represents unsuccessful attempts to counter genetic and familial predispositions to obesity, a psychosocial reaction to the fear of fatness or that dieting per se confers risks for fatness and hence a contributing factor to the obesity epidemic. In addressing the biological plausibility that dieting predisposes the lean (rather than the overweight or obese) to regaining more body fat than what had been lost (i.e. fat overshooting), it integrates the results derived from the re-analysis of body composition data on fat mass and fat-free mass (FFM) losses and recoveries from human studies of experimental energy restriction and refeeding. These suggest that feedback signals from the depletion of both fat mass (i.e. adipostats) and FFM (i.e. proteinstats) contribute to weight regain through the modulation of energy intake and adaptive thermogenesis, and that a faster rate of fat recovery relative to FFM recovery (i.e. preferential catch-up fat) is a central outcome of body composition autoregulation in lean individuals. Such a temporal desynchronization in the restoration of the body's fat vs. FFM results in a state of hyperphagia that persists beyond complete recovery of fat mass and interestingly until FFM is fully recovered. However, as this completion of FFM recovery is also accompanied by fat deposition, excess fat accumulates. In other words, fat overshooting is a prerequisite to allow complete recovery of FFM. This confers biological plausibility for post-dieting fat overshooting - which through repeated dieting and weight cycling would increase the risks for trajectories from leanness to fatness. Given the increasing prevalence of dieting in normal-weight female and male among young adults, adolescents and even children who perceive themselves as too fat (due to media, family and societal pressures), together with the high prevalence of dieting for optimizing performance among athletes in weight-sensitive sports, the notion that dieting and weight cycling may be predisposing a substantial proportion of the population to weight gain and obesity deserves greater scientific scrutiny.

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.

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.

The publication of this 4th Fribourg Obesity Research Conference on the theme of ‘dysfunctional foods’ coincides with a recent proposal of the European Union to spend 90 million euros yearly to provide free fruits and vegetables to schools across the continent in a drive to curb childhood obesity. Whether this European Union proposal, if implemented, will prove to be a turning point in genuine political will to curtail the dramatic escalation of childhood obesity in European Union countries is far from certain. It nonetheless embodies an urgent need for reversing the increasing trend of children to consume—at the expense of fruits and vegetables—unhealthy foods and snacks that are too fatty, too salty and too sugary.

We investigated, in skeletal muscle mitochondria isolated from semistarved and refed rats, the relation between the protein expression of uncoupling protein 3 (UCP3) and mitochondrial oxidative capacity, assessed as state 4 and state 3 respiration rates in presence of substrates that are either non-lipids (glutamate, succinate) or lipids (palmitoyl CoA, palmitoylcarnitine). During semistarvation, when whole-body thermogenesis is diminished, state 3 respiration was lower than in fed controls by about 30% independently of substrate types, while state 4 respiration was lower by 20% only during succinate oxidation, but UCP3 was unaltered. After 5 days of refeeding, when thermogenesis is still diminished, neither state 4, state 3 nor UCP3 were lower than in controls. Refeeding on a high-fat diet, which exacerbates the suppression of thermogenesis, resulted in a two-fold elevation in UCP3 but no change in state 4 or state 3 respiration. These results during semistarvation and refeeding, in line with those previously reported for fasting, are not in support of the hypothesis that UCP3 is a mediator of adaptive thermogenesis pertaining to weight regulation, and underscore the need for caution in interpreting parallel changes in UCP3 and mitochondrial oxidative capacity as the reflection of mitochondrial uncoupling by UCP3.

To test the hypothesis that continuous measurement of cardiac output 24 h a day would provide a better day-by-day reproducibility of the daily average cardiac output than acute measurements, we developed a computer-assisted method to monitor cardiac output continuously using an electromagnetic flow transducer. Because the diastolic aortic flow, which is used as a zero-flow reference, can drift significantly with electromagnetic flow probes, automatic tracking of the diastolic flow baseline was considered essential for long-term measurements. To accomplish this, the analog pulsatile flow signal was digitally converted and processed by an IBM PC to correct for signal drift on a beat-per-beat basis. Using this computerized system in 19 chronically instrumented dogs, we compared the values of cardiac output during 5 consecutive control days, measured either for 20 h each day (allowed 4 h for special care) or for 30 min in the morning when the trained dogs were required to lie quietly in their cages. The results show that the coefficient of variation of the five daily averages in cardiac output for each individual dog was three times smaller when cardiac output was measured 20 h each day (2.9 +/- 0.3 vs. 9.7 +/- 1.0%). Whole-day coefficients of variation were also smaller for mean arterial pressure, heart rate, stroke volume, and total peripheral resistance. Because of this greater day-by-day reproducibility, continuous monitoring of cardiac output is likely to be more sensitive to small changes in cardiac output induced by experimental protocols.

According to Lavoisier, 'Life is combustion'. But to what extent humans adapt to changes in food intake through adaptive thermogenesis--by turning down the rate of heat production during energy deficit (so as to conserve energy) or turning it up during overnutrition (so as to dissipate excess calories)--has been one of the most controversial issues in nutritional sciences over the past 100 years. The debate nowadays is not whether adaptive thermogenesis exists or not, but rather about its quantitative importance in weight homoeostasis and its clinical relevance to the pathogenesis and management of obesity. Such uncertainties are likely to persist in the foreseeable future primarily because of limitations to unobtrusively measure changes in energy expenditure and body composition with high enough accuracy and precision, particularly when even small inter-individual variations in thermogenesis can, in dynamic systems and over the long term, be important in the determining weight maintenance in some and obesity and weight regain in others. This paper reviews the considerable body of evidence, albeit fragmentary, suggesting the existence of quantitatively important adaptive thermogenesis in several compartments of energy expenditure in response to altered food intake. It then discusses the various limitations that lead to over- or underestimations in its assessment, including definitional and semantics, technical and methodological, analytical and statistical. While the role of adaptive thermogenesis in human weight regulation is likely to remain more a concept than a strictly 'quantifiable' entity in the foreseeable future, the evolution of this concept continues to fuel exciting hypothesis-driven mechanistic research which contributes to advance knowledge in human metabolism and which is bound to result in improved strategies for the management of a healthy body weight.

We developed a stereological method for quantitating length density (Lv; vessel length per unit reference volume) of the arterial system. Accurate estimation of Lv for a sparse system of blood vessels in a three-dimensional specimen requires information on individual vessel orientation. The method we present extracts the necessary information on vessel orientation from profile geometry. Major and minor diameters of elliptical profiles of sectioned tubular structures are used to calculate Lv. The method does not require special sectioning alignment and does not assume a prior distribution of blood vessels; however, the method does assume that arteries are cylindrical. A physical model consisting of boiled spaghetti mixed with agar in a cylinder was used to test the stereological method. Measurements of over 1,000 elliptical profiles in 5 separate trials have demonstrated that the method can accurately estimate Lv with < 5% error even when tortuosity is high, i.e., when anisotrophy coefficient is 1.55. This method may facilitate a better understanding of the mechanisms of artery growth by making it possible to quantify linear growth of the arterial system.

We studied the effects of hypoxia and hyperoxia on the angiogenesis process in the chick embryo chorioallantoic membrane (CAM) using four different morphometric measurements of vascularity. Chick eggs were incubated in various oxygen atmospheres (12, 16, 21, 45, or 70% oxygen) beginning on the 7th day of development, and vascularity was measured on the 14th day. Measurements of vascularity included vessel endpoint density (VED), length density, fractional image area, and a vascular density index. All measurements were made on blood vessels in randomly selected areas of CAM using a computerized image analysis system. An opaque colloidal carbon-albumin perfusate was used as a vascular marker. All four measurements showed that vascularity of CAM was inversely related to the oxygen tension to which the embryos were subjected. The VED, an estimate of total number of pre- and postcapillary vessels, exhibited the greatest degree of change, but overall changes in vascularity were modest. Prolonged exposure to a 12% oxygen atmosphere increased VED by approximately 16%, whereas 70% oxygen decreased VED by approximately 19% compared with room air control groups. We also studied the normal growth of CAM vasculature from days 8 to 18 of development. In these studies, the values of VED increased progressively throughout the entire period of development, whereas the other measurements of vascularity reached maximum values by the 14th day. We conclude that hypoxia stimulates angiogenesis in the CAM in a dose-related manner, hyperoxia inhibits CAM angiogenesis in a dose-related manner, and VED provides a sensitive estimate of vascularity in chick CAM throughout its development.

The epidemiology of salt-induced hypertension has been explored in detail in animal studies, in some cases involving exposures to excess dietary salt for much of the animal's lifespan. The results of these studies demonstrate the presence of two distinct time courses of the blood pressure response to a high salt intake: an acute (rapid) blood pressure response occurring over days to weeks, and a slow and progressive blood pressure response that develops over extremely long periods of time, amounting to a significant fraction of the lifespan in normal individuals. The acute form of salt sensitivity is well known in humans, having often been demonstrated as a fall in blood pressure during the period of salt restriction. The slow and progressive form of salt sensitivity has been demonstrated directly in rats and chimpanzees and is also evident in analyses of human cross-population data as a salt dependency of age-associated changes of blood pressure. This slow and progressive component of salt-induced hypertension may be attributable, at least in part, to a progressive rise in the acute salt sensitivity of blood pressure during sustained exposure to high salt. However, a progressively irreversible or 'self sustaining' component of salt-induced hypertension has also been demonstrated in rat studies. This irreversible component has not been completely characterized, but its presence raises the possibility that blood pressure responses to salt restriction may not fully reveal the contribution of salt to blood pressure or the epidemiology of hypertension. These various components of salt sensitivity (acute vs slow, reversible vs irreversible) should be considered in any comprehensive explanation of the effects of salt on blood pressure and especially in experimental studies of the genetic and physiological mechanisms underlying salt-induced hypertension.

Background/Objectives: Drinking large amounts of water is often recommended for weight control. Whether water intake stimulates energy and fat metabolism is, however, controversial with some studies reporting that drinking half a litre or more of water increases resting energy expenditure (REE) by 10–30% and decreases respiratory quotient (RQ), whereas others report no significant changes in REE or RQ. The aim here was to reassess the concept of water-induced thermogenesis and fat oxidation in humans, with particular focus on interindividual variability in REE and RQ responses, comparison with a time-control Sham drink, and on the potential impact of gender, body composition and abdominal adiposity. Subjects/Methods: REE and RQ were measured in healthy young adults (n=27; body mass index range: 18.5–33.9 kg m−2), by ventilated hood indirect calorimetry for at least 30 min before and 130 min after ingesting 500 ml of purified (distilled) water at 21–22 °C or after Sham drinking, in a randomized cross-over design. Body composition and abdominal fat were assessed by bioimpedance techniques. Results: Drinking 500 ml of distilled water led to marginal increases in REE ( Conclusions: This study conducted in young men and women varying widely in adiposity, comparing the ingestion of distilled water to Sham drinking, suggests that ingestion of purified water per se does not result in the stimulation of thermogenesis or fat oxidation.

Ectopic fat stores: housekeepers that can overspill into weapons of lean body mass destruction

Obesity and arterial hypertension are important public health problems. Both overweight and hypertension predispose to cardiovascular diseases, such as myocardial infarction, stroke and renal failure. Moreover, overweight clearly predisposes to hypertension, and thus to an increased prevalence of cardiovascular diseases. This in turn favors inactivity and further weight gain, leading to an exacerbation of cardiovascular disorders. Obesity, hypertension and cardiovascular diseases thus contribute to three corners of a vicious triangle. It is within this conceptual framework that this paper reviews the pathogenesis of obesity-related hypertension, which is highly complex. Many factors act together to promote vasoconstriction and sodium retention. Leptin, free fatty acids and insulin, whose levels are increased in obesity, may act synergistically to stimulate sympathetic activity and vasoconstriction. In addition, obesity-induced insulin resistance and endothelial dysfunction may operate as amplifiers of the vasoconstrictor response. Finally, increased renal tubular reabsorption of sodium may also occur, caused by an increased renal sympathetic nerve activity, the direct effect of insulin, hyperactivity of the renin-angiotensin system and possibly by an alteration of intrarenal physical forces. All together, these factors will lead to sustained hypertension. Because the prevalence of obesity was steadily increasing in the last decades, leading to an increased prevalence of hypertension and cardiovascular disorders, obesity and hypertension will most likely become the health challenges of the twenty-first century.

We investigated cardiac morphometry 6 wk after sinoaortic baroreceptor denervation (SAD) in Long-Evans rats. SAD (n = 19) was associated with an 11% increase in the weight of the left ventricle (LV) plus septum (P < 0.001) and a 39% increase in that of the right ventricular (RV) free wall (P < 0.001), relative to sham-operated rats (n = 18). RV wall thickness was significantly increased in SAD animals, but there was no difference in the LV wall thickness and volumes of the RV and LV between groups. Constrictor responses to methoxamine and dilation responses to acetylcholine were assessed in an in vitro perfused mesenteric circulation preparation, but neither response was affected by SAD. Baroreceptor denervation was associated with marked and significant increases in the variability (2.8-fold) and daily peak (39 mmHg) levels of telemetered mean arterial pressure (MAP) and small (5%) but significant increases in the daily mean MAP level. Our results are consistent with an effect of increased MAP variability on ventricular weight but cannot rule out possible contributions from other mechanisms.

We investigated why resting heart rate is elevated in dogs fed a high saturated fat diet for 12.7 +/- 1.8 wk. Obese dogs exhibited elevated body weight (59%), blood pressure (14%), and heart rate (25%). Differences in resting heart rate (control, 58 +/- 5 beats/min; obese, 83 +/- 7 beats/min) were abolished after hexamethonium, indicating an autonomic mechanism. Hexamethonium also reduced blood pressure in obese (20 +/- 4 mmHg) but not control (9 +/- 6 mmHg) animals. Propranolol did not affect heart rate in either group, excluding a beta-adrenergic mechanism. Subsequent administration of atropine increased heart rate more in control than in obese dogs (110 +/- 9 vs. 57 +/- 11 beats/min). The sensitivity of the cardiac limb of the baroreflex (Oxford method) was reduced by 46% in the obese group, confirming impairment of the parasympathetic control of heart rate. The standard deviation of blood pressure measurements was normal when expressed as a percentage of the mean arterial blood pressure (control, 11.2 +/- 0.4%; obese, 11.2 +/- 0.5%). Our results indicate that the development of obesity in dogs fed a high saturated fat diet is accompanied by an attenuated resting and reflex parasympathetic control of heart rate.

Prolonged imbalances between the perfusion capabilities of the blood vessels and the metabolic requirements of the tissue cells often lead to modification of the vasculature to satisfy the tissue needs. This homeostatic response appears to be bidirectional, since the vascularity of a tissue can increase or decrease in parallel with primary changes in metabolic rate. The factors that mediate the responses are not well understood, but oxygen has been implicated as a major control element, since vessel growth increases during hypoxic conditions and decreases during hyperoxic conditions. The following feedback control hypothesis may apply to many different physiological situations. Decreased oxygenation causes the tissues to become hypoxic, and this initiates a variety of signals that lead to the growth of blood vessels. The increase in vascularity promotes oxygen delivery to the tissue cells by decreasing diffusion distances, increasing capillary surface area, and increasing the maximum rate of blood flow. When the tissues receive adequate amounts of oxygen even during periods of peak activity, the intermediate effectors return to normal levels, and this negative signal, in turn, stops the further development of the vasculature. Although the effector mechanisms of the hypoxic stimulus are still being investigated, adenosine, which is produced in hypoxic tissues, appears to mediate hypoxia-induced increases in vascularity in some instances. Roles for fibroblast growth factor as well as mechanical factors associated with vasodilation and increased blood flow are postulated. Although blood vessel growth is a multifactorial process, a major influence in its regulation appears to be metabolic need. If this view is correct, it may be found that many of the quantitatively significant factors that control growth in a given vasculature are themselves modulated or controlled by metabolic signals reflecting the nutritional status of the tissues which that vasculature supplies.

Previous studies suggest that the renal vasoconstrictor effect of angiotensin II (ANG II) is confined primarily to efferent arterioles, with little direct action on preglomerular vessels. The present study examined the role of prostaglandins (PG) in protecting preglomerular vessels from ANG II constriction. In dogs in which ANG II formation was blocked with captopril and renal artery pressure was servo-controlled, i.v. ANG II infusion (20 ng/kg per min) decreased renal blood flow (RBF) by about 50% while causing no significant change in glomerular filtration rate (GFR) and increasing filtration fraction (FF). After PG blockade, ANG II infusion decreased GFR by more than 30% and RBF by more than 50%, while causing much greater increases in calculated preglomerular resistance (RA) than in dogs without PG blockade. To prevent secondary changes in renal resistances via tubuloglomerular feedback (TGF), glomerular filtration was stopped by occluding the ureter during mannitol diuresis. After inhibition of TGF, ANG II decreased RBF markedly and increased glomerular hydrostatic pressure by 8-10 mmHg due to large increases in postglomerular resistance (RE) with no change in RA. After PG blockade and inhibition of TGF, ANG II decreased RBF by about the same amount as in control dogs but did not change glomerular hydrostatic pressure due to marked increases in both RA and RE. These data suggest that PGs selectively protect preglomerular vessels from ANG II constriction but do not interfere with the effect of ANG II on efferent arterioles.

This paper summarizes the role of the renal pressure natriuresis and diuresis mechanisms in maintaining sodium and water balance in hypertension. In all forms of chronic hypertension studied to date, the renal pressure natriuresis and diuresis mechanisms are abnormal, since increased arterial pressure is required to maintain normal excretion of sodium and water, and therefore fluid balance. When renal perfusion pressure is prevented from increasing in various forms of experimental hypertension, caused by infusion of mineralocorticoids, angiotensin II, vasopressin, or norepinephrine and adrenocorticotrophic hormone (ACTH), sodium and water retention continues until ascites, pulmonary oedema and circulatory collapse occur within a few days. Thus, chronic hypertension appears to be an essential homeostatic response that permits sodium and water balance to be maintained despite various abnormalities which tend to decrease renal excretory capability. The intrarenal mechanisms by which increased renal perfusion pressure maintains sodium and water balance in hypertension have not been fully elucidated, but appear to involve small changes in glomerular filtration rate (GFR) and reductions in fractional sodium reabsorption, due either to the direct hydraulic effects of pressure or to various indirect effects, such as changes in angiotensin II formation.

The renal-body fluid mechanism for arterial pressure control is almost certainly the most primitive of all the pressure-regulating mechanisms in animals. Through the stages of evolution, the system has been greatly improved. Nervous controls provide rapid pressure-control mechanisms that function almost instantaneously, many hours or days before the renal-body fluid mechanism can act fully. The renin-angiotensin-aldosterone system plays another important role: this system ensures that very large changes in salt intake, from as little as one-tenth normal up to as high as 10 times normal, have very little effect on the regulated level of the arterial pressure. Finally, the long-term autoregulatory mechanism helps to dissociate the long-term control of cardiac output from long-term control of arterial pressure; it also makes it possible for extremely slight increases in body fluid volume to cause chronic volume-loading hypertension.

Catch-up growth is a risk factor for later obesity, type 2 diabetes, and cardiovascular diseases. We show here that after growth arrest by semistarvation, rats refed the same amount of a low-fat diet as controls show 1) lower energy expenditure due to diminished thermogenesis that favors accelerated fat deposition or catch-up fat and 2) normal glucose tolerance but higher plasma insulin after a glucose load at a time point when their body fat and plasma free fatty acids (FFAs) have not exceeded those of controls. Isocaloric refeeding on a high-fat diet resulted in even lower energy expenditure and thermogenesis and increased fat deposition and led to even higher plasma insulin and elevated plasma glucose after a glucose load. Stepwise regression analysis showed that plasma insulin and insulin-to-glucose ratio after the glucose load are predicted by variations in efficiency of energy use (i.e., in thermogenesis) rather than by the absolute amount of body fat or plasma FFAs. These studies suggest that suppression of thermogenesis per se may have a primary role in the development of hyperinsulinemia and insulin resistance during catch-up growth and underscore a role for suppressed thermogenesis directed specifically at catch-up fat in the link between catch-up growth and chronic metabolic diseases.