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.

Weight regain, body composition, and metabolic responses to weight loss in weight cycling athletes: A systematic review and meta-analyses.

Depending on the nature of their sports, athletes may be engaged in successive weight loss (WL) and regain, conducing to "weight cycling." The aims of this paper were to systematically (and meta-analytically when possible) analyze the post-WL recovery of (i) body weight and (ii) fat mass; fat-free mass; and performance and metabolic responses in weight cycling athletes (18-55 years old, body mass index < 30 kg.m-2 ). MEDLINE, Embase, and SPORTDiscus databases were explored. The quality and risk of bias of the 74 included studies were assessed using the quality assessment tool for quantitative studies. Thirty-two studies were eligible for meta-analyses. Whatever the type of sports or methods used to lose weight, post-WL body weight does not seem affected compared with pre-WL. While similar results are observed for fat-free mass, strength sports athletes (also having longer WL and regain periods) do not seem to fully recover their initial fat mass (ES: -0.39, 95% CI: [-0.77; -0.00], p = 0.048, I2  = 0.0%). Although the methods used by athletes to achieve WL might prevent them from a potential post-WL fat overshooting, further studies are needed to better understand WL episodes consequences on athletes' performance as well as short- and long-term physical, metabolic, and mental health.

Peripheral thyroid hormone deiodination: Entry points to elucidate mechanisms of metabolic adaptation during weight regain.

The concept of dual-adaptive thermogenesis underlying metabolic adaptation to prolonged energy deficit posits that there are two control systems that govern energy sparing: a rapid-reacting system to energy deficit and a slow-reacting system to fat store depletion. The latter control system, referred to as the "adipose-specific" control of thermogenesis, contributes to accelerating fat store replenishment (catch-up fat) during weight regain. The case is put forward here that, whereas adaptive thermogenesis during weight loss results primarily from central suppression of the sympathetic nervous system and hypothalamic-pituitary-thyroid axis, during weight regain it operates primarily through peripheral tissue resistance to the actions of this neurohormonal network. Emerging evidence that altered deiodination of thyroid hormones within the skeletal muscle and liver is a key determinant of such peripheral resistance therefore offers entry points toward elucidating the molecular mechanisms that underlie the adipose-specific control of thermogenesis and unraveling tissue-specific targets to counter obesity recidivism.

Is dieting a risk for higher weight gain in normal-weight individual? A systematic review and meta-analysis.

While there is an increasing prevalence of dieting in the overall population, weight loss (WL) practices could be a risk factor for weight gain (WG) in normal-weight (NW) individuals. The aim of the present work was to systematically review all the studies implicating diet restriction and body weight (BW) evolution in NW people. The literature search was registered in PROSPERO (CRD42021281442) and was performed in three databases from April 2021 to June 2022 for articles involving healthy NW adults. From a total of 1487 records initially identified, eighteen were selected in the systematic review. Of the eight dieting interventional studies, only one found a higher BW after weight recovery, but 75 % of them highlighted metabolic adaptations in response to WL favouring weight regain and persisting during/after BW recovery. Eight of the ten observational studies showed a relationship between dieting and major later WG, while the meta-analysis of observational studies results indicated that 'dieters' have a higher BW than 'non-dieters'. However, considering the high methodological heterogeneity and the publication bias of the studies, this result should be taken with caution. Moreover, the term 'diet' was poorly described, and we observed a large heterogeneity of the methods used to assess dieting status. Present results suggest that dieting could be a major risk factor for WG in the long term in NW individuals. There is, however, a real need for prospective randomised controlled studies, specifically assessing the relationship between WL induced by diet and subsequent weight in this population.

Dynamics of Fat Oxidation from Sitting at Rest to Light Exercise in Inactive Young Humans.

Societal erosion of daily life low-level physical activity has had a great influence on the obesity epidemic. Given that low fat oxidation is also a risk factor for obesity, we investigated, in a repeated measures design, the dynamics of fat oxidation from a resting state to a light-intensity leg cycling exercise (0-50 watts) in inactive, healthy young adults. Using indirect calorimetry, energy expenditure and the respiratory quotient (RQ) were assessed in a sitting posture at rest and during a cycling exercise in 35 subjects (20 women). The rate of perceived exhaustion (RPE) was assessed using the Borg Scale. During graded leg cycling, the mean RPE did not exceed values corresponding to the exercise being perceived as 'light'. However, analysis of individual data at 50 watts revealed two distinct subgroups among the subjects: those having RPE values corresponding to the exercise being perceived as 'very light to light' and showing no increase in RQ relative to resting levels, as opposed to an increase in RQ in those who perceived the exercise as being 'somewhat hard to hard' (p < 0.001). Our study in inactive individuals showing that high fat oxidation was maintained during 'light-perceived' physical activity reinforced the potential importance of light physical activity in the prevention of obesity.

Adaptive Thermogenesis Driving Catch-Up Fat Is Associated With Increased Muscle Type 3 and Decreased Hepatic Type 1 Iodothyronine Deiodinase Activities: A Functional and Proteomic Study.

Refeeding after caloric restriction induces weight regain and a disproportionate recovering of fat mass rather than lean mass (catch-up fat) that, in humans, associates with higher risks to develop chronic dysmetabolism. Studies in a well-established rat model of semistarvation-refeeding have reported that catch-up fat associates with hyperinsulinemia, glucose redistribution from skeletal muscle to white adipose tissue and suppressed adaptive thermogenesis sustaining a high efficiency for fat deposition. The skeletal muscle of catch-up fat animals exhibits reduced insulin-stimulated glucose utilization, mitochondrial dysfunction, delayed in vivo contraction-relaxation kinetics, increased proportion of slow fibers and altered local thyroid hormone metabolism, with suggestions of a role for iodothyronine deiodinases. To obtain novel insights into the skeletal muscle response during catch-up fat in this rat model, the functional proteomes of tibialis anterior and soleus muscles, harvested after 2 weeks of caloric restriction and 1 week of refeeding, were studied. Furthermore, to assess the implication of thyroid hormone metabolism in catch-up fat, circulatory thyroid hormones as well as liver type 1 (D1) and liver and skeletal muscle type 3 (D3) iodothyronine deiodinase activities were evaluated. The proteomic profiling of both skeletal muscles indicated catch-up fat-induced alterations, reflecting metabolic and contractile adjustments in soleus muscle and changes in glucose utilization and oxidative stress in tibialis anterior muscle. In response to caloric restriction, D3 activity increased in both liver and skeletal muscle, and persisted only in skeletal muscle upon refeeding. In parallel, liver D1 activity decreased during caloric restriction, and persisted during catch-up fat at a time-point when circulating levels of T4, T3 and rT3 were all restored to those of controls. Thus, during catch-up fat, a local hypothyroidism may occur in liver and skeletal muscle despite systemic euthyroidism. The resulting reduced tissue thyroid hormone bioavailability, likely D1- and D3-dependent in liver and skeletal muscle, respectively, may be part of the adaptive thermogenesis sustaining catch-up fat. These results open new perspectives in understanding the metabolic processes associated with the high efficiency of body fat recovery after caloric restriction, revealing new implications for iodothyronine deiodinases as putative biological brakes contributing in suppressed thermogenesis driving catch-up fat during weight regain.

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.

Physiology of weight regain: Lessons from the classic Minnesota Starvation Experiment on human body composition regulation.

Since its publication in 1950, the Biology of Human Starvation, which describes the classic longitudinal Minnesota Experiment of semistarvation and refeeding in healthy young men, has been the undisputed source of scientific reference about the impact of long-term food deprivation on human physiology and behavior. It has been a guide in developing famine and refugee relief programs for international agencies, in exploring the effects of food deprivation on the cognitive and social functioning of those with anorexia nervosa and bulimia nervosa, and in gaining insights into metabolic adaptations that undermine obesity therapy and cachexia rehabilitation. In more recent decades, the application of a systems approach to the analysis of its data on longitudinal changes in body composition, basal metabolic rate, and food intake during the 24 weeks of semistarvation and 20 weeks of refeeding has provided rare insights into the multitude of control systems that govern the regulation of body composition during weight regain. These have underscored an internal (autoregulatory) control of lean-fat partitioning (highly sensitive to initial adiposity), which operates during weight loss and weight regain and revealed the existence of feedback loops between changes in body composition and the control of food intake and adaptive thermogenesis for the purpose of accelerating the recovery of fat mass and fat-free mass. This paper highlights the general features and design of this grueling experiment of simulated famine that has allowed the unmasking of fundamental control systems in human body composition autoregulation. The integration of its outcomes constitutes the "famine reactions" that drive the normal physiology of weight regain and obesity relapse and provides a mechanistic "autoregulation-based" explanation of how dieting and weight cycling, transition to sedentarity, or developmental programming may predispose to obesity. It also provides a system physiology framework for research toward elucidating proteinstatic and adipostatic mechanisms that control hunger-appetite and adaptive thermogenesis, with major implications for a better understanding (and management) of cachexia, obesity, and cardiometabolic diseases.

Polyunsaturated fatty acids as modulators of fat mass and lean mass in human body composition regulation and cardiometabolic health.

It is now recognized that the amount and type of dietary fat consumed play an important role in metabolic health. In humans, high intake of polyunsaturated fatty acids (PUFAs) has been associated with reductions in cardiovascular disease risk, improvements in glucose homeostasis, and changes in body composition that involve reductions in central adiposity and, more recently, increases in lean body mass. There is also emerging evidence, which suggests that high intakes of the plant-based essential fatty acids (ePUFAs)-n-6 linoleic acid (LA) and n-3 α-linolenic acid (ALA)-have a greater impact on body composition (fat mass and lean mass) and on glucose homeostasis than the marine-derived long-chain n-3 PUFA-eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In addition, high intake of both ePUFAs (LA and ALA) may also have anti-inflammatory effects in humans. The purpose of this review is to highlight the emerging evidence, from both epidemiological prospective studies and clinical intervention trials, of a role for PUFA, in particular ePUFA, in the long-term regulation of body weight and body composition, and their impact on cardiometabolic health. It also discusses current notions about the mechanisms by which PUFAs modulate fat mass and lean mass through altered control of energy intake, thermogenesis, or lean-fat partitioning.

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.

Countering impaired glucose homeostasis during catch-up growth with essential polyunsaturated fatty acids: is there a major role for improved insulin sensitivity?

BACKGROUND/OBJECTIVES: Catch-up growth, an important risk factor for later obesity and type 2 diabetes, is often characterized by a high rate of fat deposition associated with hyperinsulinemia and glucose intolerance. We tested here the hypothesis that refeeding on a high-fat diet rich in essential polyunsaturated fatty acids (ePUFA) improves glucose homeostasis primarily by enhancing insulin sensitivity in skeletal muscles and adipose tissues. METHODS: Rats were caloric restricted for 2 weeks followed by 1-2 weeks of isocaloric refeeding on either a low-fat (LF) diet, a high-fat (HF) diet based on animal fat and high in saturated and monounsaturated fatty acids (HF SMFA diet), or a HF diet based on vegetable oils (1:1 mixture of safflower and linseed oils) and rich in the essential fatty acids linoleic and α-linolenic acids (HF ePUFA diet). In addition to measuring body composition and a test of glucose tolerance, insulin sensitivity was assessed during hyperinsulinemic-euglycemic clamps at the whole-body level and in individual skeletal muscles and adipose tissue depots. RESULTS: Compared to animals refed the LF diet, those refed the HF-SMFA diet showed a higher rate of fat deposition, higher plasma insulin and glucose responses during the test of glucose tolerance, and markedly lower insulin-stimulated glucose utilization at the whole body level (by a-third to a-half) and in adipose tissue depots (by 2-5 folds) during insulin clamps. While refeeding on the ePUFA diet prevented the increases in fat mass and in plasma insulin and glucose, the results of insulin clamps revealed that insulin-stimulated glucose utilization was not increased in skeletal muscles and only marginally higher in adipose tissues and at the whole-body level. CONCLUSIONS: These results suggest only a minor role for enhanced insulin sensitivity in the mechanisms by which diets high in ePUFA improves glucose homeostasis during catch-up growth.

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.

Total energy expenditure assessed by doubly labeled water technique and estimates of physical activity in Mauritian children: analysis by gender and ethnicity.

BACKGROUND/OBJECTIVES: In the tropical island of Mauritius, the rise in obesity has accelerated in the past decades, and could be contributed by low physical activity and increased sedentary behavior. The study objectives were to generate the first dataset of total energy expenditure (TEE), to estimate physical activity in Mauritian children, and to explore differences due to gender and ethnicity. SUBJECTS/METHODS: The doubly labeled water (DLW) technique was used to evaluate TEE over 14 days in 56 Mauritian school children (aged 7-11 years) belonging to the two main ethnic groups: Indian (South Asian descent) and Creole (African/Malagasy descent). Physical activity level (PAL) was calculated as the ratio of TEE and resting energy expenditure (using Schofield equations), and daily step counts were measured by accelerometry. Anthropometry and body composition were also assessed. RESULTS: TEE measured by DLW was lower in Mauritian children (by ~155 kcal/d) than that predicted using FAO/WHO/UNU equations for children of the same sex, age, and body size. Furthermore, TEE, as well as PAL and step counts, also differed according to gender (lower in girls than in boys) and to ethnicity (lower in Indians than in Creoles) even after adjusting for differences in body weight and body composition. CONCLUSION: These results in Mauritian children provide the first dataset of objectively measured TEE, from which physical activity is estimated as PAL, and complemented by step counts measurements. They suggest potential gender and ethnic differences in TEE and physical activity that need consideration in developing strategies to counter sedentary behavior and obesity.

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.

Assessment of the Dose-Response Relationship between Meal Protein Content and Postprandial Thermogenesis: Effect of Sex and the Oral Contraceptive Pill.

Implementation of efficacious dietary interventions to regulate energy balance requires understanding of the determinants of individual response. To date, information regarding individual variability in response to elevated meal protein content is lacking. This study investigates whether sex and/or oral contraceptive pill (OCP) use play a role in the response to elevated meal protein in 21 healthy young adults (seven men, seven women not taking OCP, and seven women who were OCP users). Participants consumed each of three standardized isocaloric (590 kcal) meals of differing protein content (11, 23, 31% kcal protein). Resting energy expenditure (EE), respiratory quotient (RQ), hunger and satiety were measured at baseline (fasting) and during 180 min postprandial. Whilst significant dose-response increases in EE were observed in men, meal protein-induced EE in women without OCP reached a maximum at <23% protein. Women taking OCP reported lower postprandial fullness than women without OCP, despite similar body size, but also, most notably, no significant difference in EE response between any of the meals. Whilst the mechanisms underpinning this thermogenic inflexibility in response across a wide-range (three-fold) of protein meal content require further investigation, this highlights the need for careful consideration of factors that may influence an individual's metabolic response to dietary interventions aimed at optimising postprandial thermogenesis for body weight regulation.

Reduced Skeletal Muscle Protein Turnover and Thyroid Hormone Metabolism in Adaptive Thermogenesis That Facilitates Body Fat Recovery During Weight Regain.

Objective: The recovery of body composition after weight loss is characterized by an accelerated rate of fat recovery (preferential catch-up fat) resulting partly from an adaptive suppression of thermogenesis. Although the skeletal muscle has been implicated as an effector site for such thrifty (energy conservation) metabolism driving catch-up fat, the underlying mechanisms remain to be elucidated. We test here the hypothesis that this thrifty metabolism driving catch-up fat could reside in a reduced rate of protein turnover (an energetically costly "futile" cycle) and in altered local thyroid hormone metabolism in skeletal muscle. Methods: Using a validated rat model of semistarvation-refeeding in which catch-up fat is driven solely by suppressed thermogenesis, we measured after 1 week of refeeding in refed and control animals the following: (i) in-vivo rates of protein synthesis in hindlimb skeletal muscles using the flooding dose technique of 13C-labeled valine incorporation in muscle protein, (ii) ex-vivo muscle assay of net formation of thyroid hormone tri-iodothyronine (T3) from precursor hormone thyroxine (T4), and (iii) protein expression of skeletal muscle deiodinases (type 1, 2, and 3). Results: We show that after 1 week of calorie-controlled refeeding, the fractional protein synthesis rate was lower in skeletal muscles of refed animals than in controls (by 30-35%, p < 0.01) despite no between-group differences in the rate of skeletal muscle growth or whole-body protein deposition-thereby underscoring concomitant reductions in both protein synthesis and protein degradation rates in skeletal muscles of refed animals compared to controls. These differences in skeletal muscle protein turnover during catch-up fat were found to be independent of muscle type and fiber composition, and were associated with a slower net formation of muscle T3 from precursor hormone T4, together with increases in muscle protein expression of deiodinases which convert T4 and T3 to inactive forms. Conclusions: These results suggest that diminished skeletal muscle protein turnover, together with altered local muscle metabolism of thyroid hormones leading to diminished intracellular T3 availability, are features of the thrifty metabolism that drives the rapid restoration of the fat reserves during weight regain after caloric restriction.

The case of GWAS of obesity: does body weight control play by the rules?

As yet, genome-wide association studies (GWAS) have not added much to our understanding of the mechanisms of body weight control and of the etiology of obesity. This shortcoming is widely attributed to the complexity of the issues. The appeal of this explanation notwithstanding, we surmise that (i) an oversimplification of the phenotype (namely by the use of crude anthropometric traits) and (ii) a lack of sound concepts of body weight control and, thus, a lack of a clear research focus have impeded better insights most. The idea of searching for polygenetic mechanisms underlying common forms of obesity was born out of the impressive findings made for monogenetic forms of extreme obesity. In the case of common obesity, however, observational studies on normal weight and overweight subjects never provided any strong evidence for a tight internal control of body weight. In addition, empirical studies of weight changes in normal weight and overweight subjects revealed an intra-individual variance that was similar to inter-individual variance suggesting the absence of tight control of body weight. Not least, this lack of coerciveness is reflected by the present obesity epidemic. Finally, data on detailed body composition highlight that body weight is too heterogeneous a phenotype to be controlled as a single entity. In summary GWAS of obesity using crude anthropometric traits have likely been misled by popular heritability estimates that may have been inflated in the first place. To facilitate more robust and useful insights into the mechanisms of internal control of human body weight and, consequently, the genetic basis of obesity, we argue in favor of a broad discussion between scientists from the areas of integrative physiologic and of genomics. This discussion should aim at better conceived studies employing biologically more meaningful phenotypes based on in depth body composition analysis. To advance the scientific community-including the editors of our top journals-needs a re-launch of future GWAS of obesity.