Visceral-to-peripheral adiposity ratio: a critical determinant of sex and ethnic differences in cardiovascular risks among Asian Indians and African Creoles in Mauritius.

BACKGROUND/AIMS: Coronary heart disease morbidity and mortality are higher in people of South Asian origin than in those of African origin. We investigated whether as young adults without diabetes, people in Mauritius of South Asian descent (Indians) would show a more adverse cardiovascular risk profile that those of predominantly African descent (Creoles), and whether this could be explained by ethnic differences in visceral adiposity or other fat distribution patterns. METHODS: The study was conducted in 189 young non-physically active adults, with the following measurements conducted after an overnight fast: anthropometry (weight, height, waist circumference), whole-body and regional body composition by dual-energy x-ray absorptiometry, blood pressure, and blood assays for glycemic (glucose and HbA1c) and lipid profile (triglycerides and cholesterols). RESULTS: The results indicate higher serum triglycerides and lower HDL cholesterol in men than in women, and in Indians than in Creoles (p < 0.001). No significant differences due to sex or ethnicity are observed in body mass index and waist circumference, but indices of visceral adiposity (visceral/android, visceral/subcutaneous) and visceral-to-peripheral adiposity ratio (visceral/gynoid, visceral/limb) were significantly higher in men than in women, and in Indians than in Creoles. The significant effects of sex and ethnicity on blood lipid profile were either completely abolished or reduced to a greater extent after adjusting for the ratio of visceral-to-peripheral adiposity than for visceral adiposity per se. CONCLUSIONS: In young adults in Mauritius, Indians show a more adverse pattern of body fat distribution and blood lipid risk profile than Creoles. Differences in their fat distribution patterns, however, only partially explain their differential atherogenic lipid risk profile, amid a greater impact of visceral-to-peripheral adiposity ratio than that of visceral adiposity per se on sex and ethnic differences in cardiovascular risks; the former possibly reflecting the ratio of hazardous (visceral) adiposity and protective (peripheral) superficial subcutaneous adiposity.

How dieting might make some fatter: modeling weight cycling toward obesity from a perspective of body composition autoregulation.

The notion that dieting makes some people fatter has in the past decade gained considerable interest from both epidemiological predictions and biological plausibility. Several large-scale prospective studies have suggested that dieting to lose weight is associated with future weight gain and obesity, with such predictions being stronger and more consistent among dieters who are in the normal range of body weight rather than in those with obesity. Furthermore, the biological plausibility that dieting predisposes people who are lean (rather than those with overweight or obesity) to regain more body fat than what had been lost (referred to as fat overshooting) has recently gained support from a re-analysis of data on body composition during weight loss and subsequent weight recovery from the classic longitudinal Minnesota Starvation Experiment. These have revealed an inverse exponential relationship between the amount of fat overshot and initial adiposity, and have suggested that a temporal desynchronization in the recoveries of fat and lean tissues, in turn residing in differences in lean-fat partitioning during weight loss vs. during weight recovery (with fat recovery faster than lean tissue recovery) is a cardinal feature of fat overshooting. Within a conceptual framework that integrates the relationship between post-dieting fat overshooting with initial adiposity, the extent of weight loss and the differential lean-fat partitioning during weight loss vs. weight recovery, we describe here a mathematical model of weight cycling to predict the excess fat that could be gained through repeated dieting and multiple weight cycles from a standpoint of body composition autoregulation.

Body composition-derived BMI cut-offs for overweight and obesity in ethnic Indian and Creole urban children of Mauritius.

It is increasingly recognised that the use of BMI cut-off points for diagnosing obesity (OB) and proxy measures for body fatness in a given population needs to take into account the potential impact of ethnicity on the BMI-fat % relationship in order to avoid adiposity status misclassification. This relationship was studied here in 377 Mauritian schoolchildren (200 boys and 177 girls, aged 7-13 years) belonging to the two main ethnic groups: Indian (South Asian descent) and Creole (African/Malagasy descent), with body composition assessed using an isotopic 2H dilution technique as reference. The results indicate that for the same BMI, Indians have more body fat (and less lean mass) than Creoles among both boys and girls: linear regression analysis revealed significantly higher body fat % by 4-5 units (P < 0·001) in Indians than in Creoles across a wide range of BMI (11·6-34·2 kg/m2) and body fat % (5-52 %). By applying Deurenberg's Caucasian-based equation to predict body fat % from WHO-defined BMI thresholds for overweight (OW) and OB, and by recalculating the equivalent BMI values using a Mauritian-specific equation, it is shown that the WHO BMI cut-offs for OB and OW would need to be lowered by 4·6-5·9 units in Indian and 2·0-3·7 units in Creole children in the 7-13-year-old age group. These results have major implications for ethnic-based population research towards improving the early diagnosis of excess adiposity in this multi-ethnic population known to be at high risk for later development of type 2 diabetes and CVD.

Low 24-hour core body temperature as a thrifty metabolic trait driving catch-up fat during weight regain after caloric restriction.

The recovery of body weight after substantial weight loss or growth retardation is often characterized by a disproportionately higher rate of fat mass vs. lean mass recovery, with this phenomenon of "preferential catch-up fat" being contributed by energy conservation (thrifty) metabolism. To test the hypothesis that a low core body temperature (Tc) constitutes a thrifty metabolic trait underlying the high metabolic efficiency driving catch-up fat, the Anipill system, with telemetry capsules implanted in the peritoneal cavity, was used for continuous monitoring of Tc for several weeks in a validated rat model of semistarvation-refeeding in which catch-up fat is driven solely by suppressed thermogenesis. In animals housed at 22°C, 24-h Tc was reduced in response to semistarvation (-0.77°C, P < 0.001) and remained significantly lower than in control animals during the catch-up fat phase of refeeding (-0.27°C on average, P < 0.001), the lower Tc during refeeding being more pronounced during the light phase than during the dark phase of the 24-h cycle (-0.30°C vs. -0.23°C, P < 0.01) and with no between-group differences in locomotor activity. A lower 24-h Tc in animals showing catch-up fat was also observed when the housing temperature was raised to 29°C (i.e., at thermoneutrality). The reduced energy cost of homeothermy in response to caloric restriction persists during weight recovery and constitutes a thrifty metabolic trait that contributes to the high metabolic efficiency that underlies the rapid restoration of the body's fat stores during weight regain, with implications for obesity relapse after therapeutic slimming and the pathophysiology of catch-up growth.

Arginase-II negatively regulates renal aquaporin-2 and water reabsorption.

Type-II l-arginine:ureahydrolase, arginase-II (Arg-II), is abundantly expressed in the kidney. The physiologic role played by Arg-II in the kidney remains unknown. Herein, we report that in mice that are deficient in Arg-II (Arg-II-/-), total and membrane-associated aquaporin-2 (AQP2) protein levels were significantly higher compared with wild-type (WT) controls. Water deprivation enhanced Arg-II expression, AQP2 levels, and membrane association in collecting ducts. Effects of water deprivation on AQP2 were stronger in Arg-II-/- mice than in WT mice. Accordingly, a decrease in urine volume and an increase in urine osmolality under water deprivation were more pronounced in Arg-II-/- mice than in WT mice, which correlated with a weaker increase in plasma osmolality in Arg-II-/- mice. There was no difference in vasopressin release under water deprivation conditions between either genotype of mice. Although total AQP2 and phosphorylated AQP2-S256 levels (mediated by PKA) in kidneys under water deprivation conditions were significantly higher in Arg-II-/- mice compared with WT animals, there is no difference in the ratio of AQP2-S256:AQP2. In cultured mouse collecting duct principal mCCDcl1 cells, expression of both Arg-II and AQP2 were enhanced by the vasopressin type 2 receptor agonist, desamino- d-arginine vasopressin (dDAVP). Silencing Arg-II enhanced the expression and membrane association of AQP2 by dDAVP without influencing cAMP levels. In conclusion, in vivo and in vitro experiments demonstrate that Arg-II negatively regulates AQP2 and the urine-concentrating capability in kidneys via a mechanism that is not associated with the modulation of the cAMP pathway.-Huang, J., Montani, J.-P., Verrey, F., Feraille, E., Ming, X.-F., Yang, Z. Arginase-II negatively regulates renal aquaporin-2 and water reabsorption.

Cardiovascular responses to sugary drinks in humans: galactose presents milder cardiac effects than glucose or fructose.

PURPOSE: There is increasing interest into the potentially beneficial effects of galactose for obesity and type 2 diabetes management as it is a low-glycemic sugar reported to increase satiety and fat mobilization. However, fructose is also a low-glycemic sugar but with greater blood pressure elevation effects than after glucose ingestion. Therefore, we investigated here the extent to which the ingestion of galactose, compared to glucose and fructose, impacts upon haemodynamics and blood pressure. METHODS: In a randomized cross-over study design, 9 overnight-fasted young men attended 3 separate morning sessions during which continuous cardiovascular monitoring was performed at rest for at least 30 min before and 120 min after ingestion of 500 mL of water containing 60 g of either glucose, fructose or galactose. These measurements included beat-to-beat systolic and diastolic blood pressure, heart rate deduced by electrocardiography, and stroke volume derived by impedance cardiography; these measurements were used to calculate cardiac output and total peripheral resistance. RESULTS: Ingestion of galactose, like glucose, led to significantly lesser increases in systolic, diastolic and mean blood pressure than fructose ingestion (p < 0.05). Furthermore, the increase in cardiac output and reduction in total peripheral resistance observed after ingestion of glucose were markedly lower after galactose ingestion (p < 0.01). CONCLUSIONS: Galactose thus presents the interesting characteristics of a low-glycemic sugar with mild cardiovascular effects. Further studies are warranted to confirm the clinical relevance of the milder cardiovascular effects of galactose than other sugars for insulin resistant obese and/or diabetic patients with cardiac insufficiency.

Standing economy: does the heterogeneity in the energy cost of posture maintenance reside in differential patterns of spontaneous weight-shifting?

PURPOSE: Due to sedentarity-associated disease risks, there is much interest in methods to increase low-intensity physical activity. In this context, it is widely assumed that altering posture allocation can modify energy expenditure (EE) to impact body-weight regulation and health. However, we have recently shown the existence of two distinct phenotypes pertaining to the energy cost of standing-with most individuals having no sustained increase in EE during steady-state standing relative to sitting comfortably. Here, we investigated whether these distinct phenotypes are related to the presence/absence of spontaneous "weight-shifting", i.e. the redistribution of body-weight from one foot to the other. METHODS: Using indirect calorimetry to measure EE in young adults during sitting and 10 min of steady-state standing, we examined: (i) heterogeneity in EE during standing (n = 36); (ii) EE and spontaneous weight-shifting patterns (n = 18); (iii) EE during spontaneous weight-shifting versus experimentally induced weight-shifting (n = 7), and; (iv) EE during spontaneous weight-shifting versus intermittent leg/body displacement (n = 6). RESULTS: Despite heterogeneity in EE response to steady-state standing, no differences were found in the amount or pattern of spontaneous weight-shifting between the two phenotypes. Whilst experimentally induced weight-shifting resulted in a mean EE increase of only 11% (range: 0-25%), intermittent leg/body displacement increased EE to >1.5 METs in all participants. CONCLUSIONS: Although the variability in spontaneous weight-shifting signatures between individuals does not appear to underlie heterogeneity in the energy cost of standing posture maintenance, these studies underscore the fact that leg/body displacement, rather than standing posture alone, is needed to increase EE above the currently defined sedentary threshold.

Effect of chronic renal failure on the hepatic, intestinal, and renal expression of bile acid transporters.

Although the kidney is believed to play a minor role in bile acid (BA) excretion, chronic renal failure (CRF) has been reported to be associated with increased serum bile acid levels and alterations in BA homeostasis. The mechanisms for elevated BA levels are poorly understood in both clinical and experimental studies. This study was designed to examine the effects of naturally progressing CRF of longer duration on the hepatic and renal mRNA and protein levels of the BA-synthesizing enzyme Cyp7a1 and the BA transporters Ntcp, Bsep, Mrp3, Ost-α, and Ost-ß. Sprague-Dawley rats were randomized to the CRF group (⅚ nephrectomy) or to the sham-operated control group and were analyzed 8 wk after surgery. Results obtained in the CRF rats were compared with those obtained in rats that had undergone uninephrectomy (UNX). The CRF group exhibited significantly increased plasma cholesterol and BA concentrations. Hepatic Cyp7a1 mRNA and protein levels were almost identical in the two groups. Hepatic Mrp3, Ost-α, and Ost-ß expression was increased, suggesting increased basolateral efflux of bile acids into the blood. However, no such changes in BA transporter expression were observed in the remnant kidney. In UNX rats, similar changes in plasma BA levels and in the expression of BA transporters were found. We hypothesize that the increase in plasma BA is an early event in the progression of CRF and is caused by increased efflux across the basolateral hepatocyte membrane.

p38 mitogen-activated protein kinase is involved in arginase-II-mediated eNOS-uncoupling in obesity.

BACKGROUND: Endothelial nitric oxide synthase (eNOS)-uncoupling links obesity-associated insulin resistance and type-II diabetes to the increased incidence of cardiovascular disease. Studies have indicated that increased arginase is involved in eNOS-uncoupling through competing with the substrate L-arginine. Given that arginase-II (Arg-II) exerts some of its biological functions through crosstalk with signal transduction pathways, and that p38 mitogen-activated protein kinase (p38mapk) is involved in eNOS-uncoupling, we investigated here whether p38mapk is involved in Arg-II-mediated eNOS-uncoupling in a high fat diet (HFD)-induced obesity mouse model. METHODS: Obesity was induced in wild type (WT) and Arg-II-deficient (Arg-II(-/-)) mice on C57BL/6 J background by high-fat diet (HFD, 55% fat) for 14 weeks starting from age of 7 weeks. The entire aortas were isolated and subjected to 1) immunoblotting analysis of the protein level of eNOS, Arg-II and p38mapk activation; 2) arginase activity assay; 3) endothelium-dependent and independent vasomotor responses; 4) en face staining of superoxide anion and NO production with Dihydroethidium and 4,5-Diaminofluorescein Diacetate, respectively, to assess eNOS-uncoupling. To evaluate the role of p38mapk, isolated aortas were treated with p38mapk inhibitor SB203580 (10 µmol/L, 1 h) prior to the analysis. In addition, the role of p38mapk in Arg-II-induced eNOS-uncoupling was investigated in cultured human endothelial cells overexpressing Arg-II in the absence or presence of shRNA against p38mapk. RESULTS: HFD enhanced Arg-II expression/activity and p38mapk activity, which was associated with eNOS-uncoupling as revealed by decreased NO and enhanced L-NAME-inhibitable superoxide in aortas of WT obese mice. In accordance, WT obese mice revealed decreased endothelium-dependent relaxations to acetylcholine despite of higher eNOS protein level, whereas Arg-II(-/-) obese mice were protected from HFD-induced eNOS-uncoupling and endothelial dysfunction, which was associated with reduced p38mapk activation in aortas of the Arg-II(-/-) obese mice. Moreover, overexpression of Arg-II in human endothelial cells caused eNOS-uncoupling and augmented p38mapk activation. The Arg-II-induced eNOS-uncoupling was prevented by silencing p38mapk. Furthermore, pharmacological inhibition of p38mapk recouples eNOS in isolated aortas from WT obese mice. CONCLUSIONS: Taking together, we demonstrate here for the first time that Arg-II causes eNOS-uncoupling through activation of p38 mapk in HFD-induced obesity.

Cardiovascular responses to the ingestion of sugary drinks using a randomised cross-over study design: Does glucose attenuate the blood pressure-elevating effect of fructose?

Overconsumption of sugar-sweetened beverages has been implicated in the pathogenesis of CVD. The objective of the present study was to elucidate acute haemodynamic and microcirculatory responses to the ingestion of sugary drinks made from sucrose, glucose or fructose at concentrations similar to those often found in commercial soft drinks. In a randomised cross-over study design, twelve young healthy human subjects (seven men) ingested 500 ml tap water in which was dissolved 60 g of either sucrose, glucose or fructose, or an amount of fructose equivalent to that present in sucrose (i.e. 30 g fructose). Continuous cardiovascular monitoring was performed for 30 min before and at 60 min after ingestion of sugary drinks, and measurements included beat-to-beat blood pressure (BP) and impedance cardiography. Additionally, microvascular endothelial function testing was performed after iontophoresis of acetylcholine and sodium nitroprusside using laser Doppler flowmetry. Ingestion of fructose (60 or 30 g) increased diastolic and mean BP to a greater extent than the ingestion of 60 g of either glucose or sucrose (P< 0.05). Ingestion of sucrose and glucose increased cardiac output (CO; P< 0.05), index of contractility (P< 0.05) and stroke volume (P< 0.05), but reduced total peripheral resistance (TPR; P< 0.05), which contrasts with the tendency of fructose (60 and 30 g) to increase resistance. Microvascular endothelial function did not differ in response to the ingestion of various sugary drinks. In conclusion, ingestion of fructose, but not sucrose, increases BP in healthy human subjects. Although sucrose comprises glucose and fructose, its changes in TPR and CO are more related to glucose than to fructose.

Cardio- and cerebrovascular responses to the energy drink Red Bull in young adults: a randomized cross-over study.

PURPOSE: Energy drinks are beverages containing vasoactive metabolites, usually a combination of caffeine, taurine, glucuronolactone and sugars. There are concerns about the safety of energy drinks with some countries banning their sales. We determined the acute effects of a popular energy drink, Red Bull, on cardiovascular and hemodynamic variables, cerebrovascular parameters and microvascular endothelial function. METHODS: Twenty-five young non-obese and healthy subjects attended two experimental sessions on separate days according to a randomized crossover study design. During each session, primary measurements included beat-to-beat blood pressure measurements, impedance cardiography and transcranial Doppler measurements for at least 20 min baseline and for 2 h following the ingestion of either 355 mL of the energy drink or 355 mL of tap water; the endothelial function test was performed before and two hours after either drink. RESULTS: Unlike the water control load, Red Bull consumption led to increases in both systolic and diastolic blood pressure (p < 0.005), associated with increased heart rate and cardiac output (p < 0.05), with no significant changes in total peripheral resistance and without diminished endothelial response to acetylcholine; consequently, double product (reflecting myocardial load) was increased (p < 0.005). Red Bull consumption also led to increases in cerebrovascular resistance and breathing frequency (p < 0.005), as well as to decreases in cerebral blood flow velocity (p < 0.005) and end-tidal carbon dioxide (p < 0.005). CONCLUSION: Our results show an overall negative hemodynamic profile in response to ingestion of the energy drink Red Bull, in particular an elevated blood pressure and double product and a lower cerebral blood flow velocity.

PI3Kγ within a nonhematopoietic cell type negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance.

Obesity is associated with a chronic low-grade inflammation, and specific antiinflammatory interventions may be beneficial for the treatment of type 2 diabetes and other obesity-related diseases. The lipid kinase PI3Kγ is a central proinflammatory signal transducer that plays a major role in leukocyte chemotaxis, mast cell degranulation, and endothelial cell activation. It was also reported that PI3Kγ activity within hematopoietic cells plays an important role in obesity-induced inflammation and insulin resistance. Here, we show that protection from insulin resistance, metabolic inflammation, and fatty liver in mice lacking functional PI3Kγ is largely consequent to their leaner phenotype. We also show that this phenotype is largely based on decreased fat gain, despite normal caloric intake, consequent to increased energy expenditure. Furthermore, our data show that PI3Kγ action on diet-induced obesity depends on PI3Kγ activity within a nonhematopoietic compartment, where it promotes energetic efficiency for fat mass gain. We also show that metabolic modulation by PI3Kγ depends on its lipid kinase activity and might involve kinase-independent signaling. Thus, PI3Kγ is an unexpected but promising drug target for the treatment of obesity and its complications.

Space physiology IV: mathematical modeling of the cardiovascular system in space exploration.

Mathematical modeling represents an important tool for analyzing cardiovascular function during spaceflight. This review describes how modeling of the cardiovascular system can contribute to space life science research and illustrates this process via modeling efforts to study postflight orthostatic intolerance (POI), a key issue for spaceflight. Examining this application also provides a context for considering broader applications of modeling techniques to the challenges of bioastronautics. POI, which affects a large fraction of astronauts in stand tests upon return to Earth, presents as dizziness, fainting and other symptoms, which can diminish crew performance and cause safety hazards. POI on the Moon or Mars could be more critical. In the field of bioastronautics, POI has been the dominant application of cardiovascular modeling for more than a decade, and a number of mechanisms for POI have been investigated. Modeling approaches include computational models with a range of incorporated factors and hemodynamic sophistication, and also physical models tested in parabolic and orbital flight. Mathematical methods such as parameter sensitivity analysis can help identify key system mechanisms. In the case of POI, this could lead to more effective countermeasures. Validation is a persistent issue in modeling efforts, and key considerations and needs for experimental data to synergistically improve understanding of cardiovascular responses are outlined. Future directions in cardiovascular modeling include subject-specific assessment of system status, as well as research on integrated physiological responses, leading, for instance, to assessment of subject-specific susceptibility to POI or effects of cardiovascular alterations on muscular, vision and cognitive function.

Sucrose dampens caffeine-induced blood pressure elevations - A randomized crossover pilot study in healthy, non-obese men.

Purpose: Sales for sugar-sweetened and caffeinated beverages are still rising globally and their consumption has been linked to the development of cardiovascular diseases. However, direct evidence from human interventional studies in response to such beverages is still scarce. Methods: Seven young, non-obese men participated in a randomized crossover study where four test drinks [60 g sucrose + 50 mg caffeine, 60 g sucrose + caffeine-placebo, 50 mg caffeine, and caffeine-placebo] were investigated. Each drink was brought to a total volume of 500 mL with water. Continuous and beat-to-beat hemodynamic monitoring was conducted for 30 min baseline and continued for 90 min after the ingestion of each drink. Measurements included blood pressure, heart rate, stroke volume, cardiac output, total peripheral resistance, index of contractility, and double product. Results: Two-factor ANOVA analysis revealed significant treatment-by-time effects for diastolic blood pressure, heart rate, stroke volume, cardiac output, total peripheral resistance, index of contractility, and double product (all p < 0.01). Diastolic blood pressure and total peripheral resistance increased significantly to caffeine-only (all p < 0.05), while sucrose + caffeine-placebo and sucrose + caffeine both decreased resistance responses (all p < 0.05). Cardiac output increased significantly to sucrose + caffeine-placebo and sucrose + caffeine (all p < 0.05), and on trend for heart rate, stroke volume, and index of contractility (all p between 0.05 and 0.09). Conclusion: In young, non-obese men, a caffeinated and sucrose-sweetened beverage at concentrations similar to classical commercial Cola products exhibited distinct hemodynamic actions where the presence of sucrose dampened caffeine-induced blood pressure elevations, but at the expense of a tendency to increase cardiac work.

Dietary modulation of body composition and insulin sensitivity during catch-up growth in rats: effects of oils rich in n-6 or n-3 PUFA.

The present study investigates whether excessive fat accumulation and hyperinsulinaemia during catch-up growth on high-fat diets are altered by n-6 and n-3 PUFA derived from oils rich in either linoleic acid (LA), α-linolenic acid (ALA), arachidonic acid (AA) or DHA. It has been shown that, compared with food-restricted rats refed a high-fat (lard) diet low in PUFA, those refed isoenergetically on diets enriched in LA or ALA, independently of the n-6:n-3 ratio, show improved insulin sensitivity, lower fat mass and higher lean mass, the magnitude of which is related to the proportion of total PUFA precursors (LA+ALA) consumed. These relationships are best fitted by quadratic regression models (r2>0·8, P < 0·001), with threshold values for an impact on body composition corresponding to PUFA precursors contributing 25-30 % of energy intake. Isoenergetic refeeding on high-fat diets enriched in AA or DHA also led to improved body composition, with increases in lean mass as predicted by the quadratic model for PUFA precursors, but decreases in fat mass, which are disproportionately greater than predicted values; insulin sensitivity, however, was not improved. These findings pertaining to the impact of dietary intake of PUFA precursors (LA and ALA) and their elongated-desaturated products (AA and DHA), on body composition and insulin sensitivity, provide important insights into the search for diets aimed at counteracting the pathophysiological consequences of catch-up growth. In particular, diets enriched in essential fatty acids (LA and/or ALA) markedly improve insulin sensitivity and composition of weight regained, independently of the n-6:n-3 fatty acid ratio.

Ancel Keys: The legacy of a giant in physiology, nutrition, and public health.

Ancel Keys, whose life spanned over 100 years (1904-2004), made a wealth of seminal scientific and public health contributions. As a physiologist, nutritionist, and public health scientist, he has left his mark on the 20th century by exploring different areas of physiology and nutrition, as well as by contributing to the understanding of basic public health issues. Among his major achievements one can mention in chronological order: studying adaptation to very high altitude, developing the K ration to enable the US military to survive with light but dense food, dissecting the physiology of starvation and nutritional rehabilitation to optimize recovery of functions, uncovering the link between serum cholesterol and heart disease, coordinating the first multi-country epidemiological longitudinal study in nutrition and health, coining the word "body mass index" (BMI), which he showed to be the best body weight index to predict body fat, and promoting the Mediterranean diet for a healthy life style. This review examines the historical events and scientific intrigues that have surrounded Ancel Keys's major classical studies that have ensured him a central place in the history of medical science.

Low-carbohydrate ketogenic diets in body weight control: A recurrent plaguing issue of fad diets?

The most appropriate type of diets to maintain or lose body weight over the medium to long term has been a matter of controversy and debates for more than half a century. Both voluntarily and coercive food restriction, resulting in negative energy and macronutrient balance and hence weight loss, have not been designed to be maintained for the long term. By contrast, when a classical and traditional type of alimentation is consumed in ad lib conditions (e.g., the Mediterranean "diet"), it generally provides an appropriate nutritional density of essential macronutrients and micronutrients; it is hence appropriate for long-term use, and it provides several benefits for health if the compliance of the individuals is maintained over time. In this short review, we focus on four specific aspects: first, the need to agree on a clear definition of what is "low" versus "high" in terms of total carbohydrate intake and total fat intakes, both generally inversely related, in a representative individual with a certain lifestyle and a certain body morphology; second, the importance of discussing the duration over which it could be prescribed, that is, acute versus chronic conditions, focusing on the comparison between the fashion and often ephemeral low-carbohydrate diet (acute) with the well-recognized traditional Mediterranean type of alimentation (chronic), which includes lifestyle changes; third, the particular metabolic characteristics induced by the low-carbohydrate (high fat) diet, namely, the scramble up of ketone bodies production. The recent debate on ketogenic diets concern whether or not, in iso-energetic conditions, low-carbohydrate diets would significantly enhance energy expenditure. This is an issue that is more "academic" than practical, on the ground that the putative difference of 100-150 kcal/day or so (in the recent studies) is not negligible but within the inherent error of the methodology used to track total energy expenditure in free living conditions by the doubly labeled water technique. Fourth, the potential medical risks and shortcomings of ingesting (over the long term) low-carbohydrate ketogenic diets could exacerbate underlying renal dysfunction, consecutive to the joint combination of high-fat, high-protein diets, particularly in individuals with obesity. This particular diet promotes metabolic acidosis and renal hyperfiltration, which ultimately may contribute to a significant reduction in life expectancy in middle-age people.

Pathogenesis of obesity and cardiometabolic diseases: From the legacy of Ancel Keys to current concepts.

Several areas of research into the prevention and treatment of obesity today can be traced to one or more of the scientific works pioneered by Ancel Keys between the 1930s to 1970s in fields that cut across the physiology of extremes and public health nutrition. These range from his classical studies into how body and mind respond to chronic exposure to hypoxia in "The Physiology of Life at High Altitudes" or to simulated famine under controlled laboratory conditions in "The Biology of Human Starvation", the impact of diet and lifestyle on cardiovascular morbidity and mortality in "The Seven Countries Study," to the "Indices of Relative Weight and Obesity" in which he identified what has since been the most widely utilized diagnostic tool to monitor obesity across populations worldwide and which he coined as the body mass index. The contribution of Ancel Keys to medical sciences through his observations, analytical approaches, and research output of his classic studies, and how these have (and continue) to impact on a plethora of current concepts in obesity research today, are embodied in the eight review articles that constitute this supplement reporting the proceedings of the 10th Fribourg Obesity Research Conference. The aim of this introductory paper is to put into perspective the legacy of Ancel Keys to current concepts that are encapsulated in these review articles that cover research areas that include (i) the diagnosis of obesity for health risks; (ii) the role of dietary fat types in the pathogenesis of obesity and cardiometabolic diseases; (iii) the rationale, efficacy and safety of low carbohydrate ketogenic diets, or the therapeutic potential of hypoxic conditioning, in weight management programs; (iv) the psychological and physiological basis of the "famine reaction" that counters therapeutic dieting and facilitates weight regain; and (v) the potential impact of weight cycling and yoyo dieting on risks for later obesity and cardiometabolic diseases.