Physiopathologie de l’insulinorésistance dans le muscle squelettique et implication des fonctions mitochondriales

In modern societies, decreased physical activity, nutritional transition and aging contribute to the increase in the prevalence of obesity and its associated pathologies (as cardiovascular diseases and type 2 diabetes). Obesity is tightly correlated with insulin resistance, which appears in the early stages of type 2 diabetes. As skeletal muscle is quantitatively the main tissue involved in glucose transport in response to insulin, muscle insulin resistance is a key step in the etiology of type 2 diabetes. Several alterations of skeletal muscle insulin signaling in various models of obesity or type 2 diabetes have been evidenced and numerous underlying mechanisms have been hypothesized. Among them, muscle lipotoxicity, obesity-induced adipose tissue inflammation and oxidative stress following excess of energetic substrates could be involved, independently or synergically, in the development of muscle insulin resistance. Moreover, mitochondrial alterations have been reported in the skeletal muscle of obese or diabetic patients and animals. This suggests that mitochondrion, through its capacity of regulating cellular fatty acids flux and redox state, may play a key role in obesity-induced skeletal muscle insulin resistance.     

The danger of weight loss in the elderly

Aging is generally accompanied by weight loss made up of both fat mass and fat-free mass. As more people, including elderly, are overweight or obese, weight loss is recommended to improve health. Health risks are decreased in overweight children and adults by dieting and exercise, but the health benefits of weight loss in elderly, particularly by calorie restriction, are uncertain. Rapid unintentional weight loss in elderly is usually indicative of underlying disease and accelerates the muscle loss which normally occurs with aging. Intentional weight loss, even when excess fat mass is targeted also includes accelerated muscle loss which has been shown in older persons to correlate negatively with functional capacity for independent living. Sarcopenic obesity, the coexistence of diminished lean mass and increased fat mass, characterizes a population particularly at risk for functional impairment since both sarcopenia (relative deficiency of skeletal muscle mass and strength) and obesity have been shown to predict disability. However, indices of overweight and obesity such as body mass index (BMI) do not correlate as strongly with adverse health outcomes such as cardiovascular disease in elderly as compared to younger individuals. Further, weight loss and low BMI in older persons are associated with mortality in some studies. On the other hand, studies have shown improvement in risk factors after weight loss in overweight/obese elderly. The recent focus on pro-inflammatory factors related to adiposity suggest that fat loss could ameliorate some catabolic conditions of aging since some cytokines may directly impact muscle protein synthesis and breakdown. Simply decreasing weight may also ease mechanical burden on weak joints and muscle, thus improving mobility. However, until a strategy is proven whereby further loss of muscle mass can be prevented, weight loss by caloric restriction in individuals with sarcopenic obesity should likely be avoided.     

Sarcopenic obesity predicts instrumental activities of daily living disability in the elderly

OBJECTIVE: To determine the association of sarcopenic obesity with the onset of Instrumental Activities of Daily Living (IADL) disability in a cohort of 451 elderly men and women followed for up to 8 years. RESEARCH METHODS AND PROCEDURES: Sarcopenic obesity was defined at study baseline as appendicular skeletal muscle mass divided by stature squared <7.26 kg/m2 in men and 5.45 kg/m2 in women and percentage body fat greater than the 60th percentile of the study sample (28% body fat in men and 40% in women). Incident disability was defined as a loss of two or more points from baseline score on the IADL. Subjects with disability at baseline (scores < 8) were excluded. Cox proportional hazards analysis was used to determine the association of baseline sarcopenic obesity with onset of IADL disability, controlling for potential confounders. RESULTS: Subjects with sarcopenic obesity at baseline were two to three times more likely to report onset of IADL disability during follow-up than lean sarcopenic or nonsarcopenic obese subjects and those with normal body composition. The relative risk for incident disability in sarcopenic obese subjects was 2.63 (95% confidence interval, 1.19 to 5.85), adjusting for age, sex, physical activity level, length of follow-up, and prevalent morbidity. DISCUSSION: This is the first study, to our knowledge, to indicate that sarcopenic obesity is independently associated with and precedes the onset of IADL disability in the community-dwelling elderly. The etiology of sarcopenic obesity is unknown but may include a combination of decreases in anabolic signals and obesity-associated increases in catabolic signals in old age.     

Que devient le tissu adipeux dans l’obésité ?

Adipose tissue exerts multiples functions related to glucose and lipid homeostasis. The adipose tissue is a site of low-grade inflammation in obese subjects, evidenced by immune cells accumulation, mainly macrophages. Pro-inflammatory factors produced by macrophages alter adipocytes biology and may contribute to the severity of metabolic complications, including insulin resistance and hepatic diseases. However, macrophages might also be beneficial to tissue homeostasis through the elimination of deficient adipocytes or pro-angiogenic effects. The cellular and molecular mechanisms of macrophage infiltration are related, at least in part, to a dialogue among hypertrophied adipocytes, macrophages and other cell-types, including lymphocytes, pre-adipocytes and endothelial cells within adipose tissue. A newly discovered consequence of adipose tissue inflammation is fibrosis that is organized both in bundles and around adipocytes. These cellular and structural alterations are only partly reversible after weight loss and reflect the pathology of adipose tissue that may contribute to the chronicity of obesity. In this context, identification of pharmacological means to maintain adipose tissue integrity remains a major challenge in the field.     

L’obésité du sujet âgé

Our population is ageing, and obesity is increasing in the elderly. BMI value associated with the lowest relative mortality is slightly higher in older than in younger (between 25 and 32 kg/m²). Nevertheless, the combined effect of aging and obesity increases the risk of comorbidities, including type 2 diabetes mellitus, cardiovascular risk, respiratory insufficiency, obstructive sleep apneas, cancer, urinary incontinence and dementia. The medical consequences of obesity are alleviated by modest, achievable weight loss (5–10 kg) with an evidence-based maintenance strategy. A combination of exercise and modest calorie restriction appears to be the optimal method of reducing fat mass and preserving muscle mass. The clinical outcomes have been evaluated in diabetes mellitus and in cardiovascular diseases, showing favorable effects on the morbidity and probably on the mortality. Very-low-energy diets have to be avoided for elderly patients. The risk of muscle loss increases with the level of diet restriction. In older people, the risks of laparoscopic bariatric surgery are not higher than in younger but the benefits have not been evaluated. The sarcopenic obesity (excess in body fat and loss of muscle mass and function) burdens the functional consequences of obesity in older people. Since sarcopenia is frequent in the elderly, a screening should be done in obese patients for whom a restrictive diet is not recommended. In renal or cardiac insufficiency, only physical activity can be recommended. In elderly people, weight management interventions using moderate calorie restriction and physical activity exercise are recommended. Daily protein intake must be maintained. Health benefits and risks from long-term weight management in obese elderly have to be studied in randomized controlled studies.     

Obésité : que nous dit l’épidémiologie ?

In most developed and developing countries, a regular increase of the prevalence of obesity has been documented during the last decade(s) of the xxth century. The last figure from the USA is for the first time discordant with this general trend by showing a clear slowing down since year 2000. In children likewise, a rapid increase in the prevalence of obesity took place in the second half of the xxth century but recent publications from France, Switzerland, UK, USA also report a stabilization of childhood overweight and obesity prevalences. The experience of developing countries clearly shows the impact of socioeconomic status improvement and urbanization on the prevalence of obesity. In developed countries like France, a striking element was the diffuse nature of the adult obesity epidemic observed from the 1990s. The general improvement of living conditions after the Second World War probably explains the diffuse nature of the epidemics. Specifically, the changes in the nutritional status of children that happened at that time have long lasting consequences for adult obesity epidemics. Indeed, a new current in epidemiology, lifecourse epidemiology, has prompted over the past decade a new approach of the pathophysiology of chronic diseases, including obesity. Lifecourse epidemiology considers factors affecting the susceptibility to diseases over the whole life with critical periods during developmental phases. Critical periods for the susceptibility to obesity have been documented in prenatal life, during the first 6 months of postnatal life and from 3 years on starting at the time of the adiposity rebound. Parental obesity is involved at each of the critical periods. The transgenerational transmission of obesity is explained by genetic factors, shared lifestyle but also epigenetics especially during the early developmental periods. The slowing down of the childhood obesity epidemics observed in several developed countries may signal that factors affecting the early susceptibility to obesity have recently changed.     

Associations between Sarcopenic Obesity and Cognitive Impairment in Elderly Chinese Community-Dwelling Individuals

Introduction

This study aimed to estimate the prevalence of sarcopenic obesity (SO) and the association between cognitive impairment and SO in a cohort of elderly Chinese community-dwelling individuals.

Methods

A total of 948 elderly Chinese community-dwelling individuals aged 60–92 years were recruited. The participants were categorized into the following four groups according to their sarcopenia and obesity status: sarcopenic obese, sarcopenic, obese and non-sarcopenic, and non-obese group. Sarcopenia was defined as appendicular skeletal muscle index of <7.0 kg/m² in men and <5.7 kg/m² in women; obesity was defined as values greater than the upper two quintiles for body fat percentage stratified by gender of the study population; cognitive impairment was measured using the Mini-Mental State Examination and defined as a score of <24.

Results

A total of 945 participants were included in the statistical analyses with a mean age of 68.76 ± 6.50 years. The prevalence of SO was 6.0% (7.3% in men and 4.8% in women). The sarcopenic obese (odds ratio [OR]: 2.550, 95% confidence interval [CI], 1.196-5.435) and obese (ORs: 2.141, 95% CI, 1.230-3.728) groups had significantly increased risk for cognitive impairment in fully adjusted model, respectively.

Conclusion

The SO prevalence in elderly Chinese community-dwelling individuals was relatively low (6.0%). The present study suggested SO was independently associated with cognitive impairment.

     

Prise en charge nutritionnelle périopératoire du patient obèse

Recommendations for perioperative nutrition in obese subjects require considering the following evidences. Obesity has long been falsely considered a risk factor for poor outcomes from a variety of surgical procedures, yet recent studies of critically and chronically ill patients suggest that overweight and obese patients may paradoxically have better outcomes than normal weight patients. Preoperative weight loss should be considered as a risk factor of postoperative complications in obese subjects as in normal weight patients. Obese patients could be malnourished because of vitamin deficiencies and of sarcopenia. The prevalence of vitamin deficiencies in the morbidly obese population prior to surgery is high, especially for vitamins B1, B12, B9, A, C, D and E. Standard of care should include perioperative thiamine replacement, especially in case of prolonged vomiting. Vitamin B12 deficiency could appear fast after gastric or ileal surgery, and iron deficiency is more frequent. Low caloric diet is not recommended in obese subjects before surgery, especially for the elderly, because of the frequent sarcopenia in this population. Energy and protein recommendations are not easy to be determined in obese subjects. Recommended allowance for protein should be defined according of the fat free mass, which is not easy to evaluate in clinical practice. So it is recommended to use a normalized weigh for a theoretic BMI between 25 and 30 kg/m². The loss of muscle mass can be very fast in the postoperative period in these subjects. The nutritional objective of care is to preserve skeletal muscle mass and to enhance the protein balance.     

Prise en charge de l’obésité : quel est le niveau de formation des médecins généralistes du département de la Haute-Vienne et comment perçoivent-ils leur pratique ?

Introduction

Obesity is a public health problem affecting in France at least one person in seven over 15 years. General practitioners (GPs) play a major role in the management of this chronic disease, but little is known about their level of education and their modalities of care in front of obese patients. The main objectives of the study were to assess knowledge and practices on obesity of the GPs in a French department.

Methods

An anonymous declarative questionnaire was sent to a sample of 200 GPs of the Haute-Vienne department. The questionnaire noted epidemiological data on GPs, asked their level of education and knowledge on obesity, assessed their modalities of care, their difficulties facing this disease and their proposals for improvement.

Results

Exactly 40.5% of GPs gave answers. 19.5% of their patients were obese. 23.5% of GPs have been educated on nutrition. A percentage of 76.6 of GPs detected obesity with BMI at a threshold ≥ 30 kg/m². A percentage of 96.3% were involved in the care of their obese patients, and 70.0% in partnership with a specialist. Only 12.8% of GPs proposed an association between the three modalities of treatment: dietary intervention, higher physical activity and psychobehavioral care. Precisely, 27.7% of practitioners used medicaments and 21.0% protein diets. Bariatric surgery had already been used by 60.8% of GPs. Several difficulties noted were already known, but they particularly pointed out the lack of reimbursement for dietetic visit. The main suggestions were to improve networking, to promote a better education of patients and their families, to obtain a special coding for obesity visits and better psychobehavioral care.

Conclusions

The management of obese patients is an important part of GPs’ activity. Their care habits are broadly consistent with recommendations for the diagnosis of obesity and weight loss goals. However, few practitioners are trained in nutrition, resulting in a high use of specialists and a low proportion of GPs managing their patients in a full-recommended manner. One of the main suggestions of GPs is to work on obesity with a better-structured environment.     

Sarcopenic-obesity and cardiovascular disease risk in the elderly

Objectives  To determine: 1) whether sarcopenic-obesity is a stronger predictor of cardiovascular disease (CVD) than either sarcopenia or obesity alone in the elderly, and 2) whether muscle mass or muscular strength is a stronger marker of CVD risk. Design  Prospective cohort study. Participants  Participants included 3366 community-dwelling older (65 years) men and women who were free of CVD at baseline. Measurements  Waist circumference (WC), bioimpedance analysis, and grip strength were used to measure abdominal obesity, whole-body muscle mass, and muscular strength, respectively. Subjects were classified as normal, sarcopenic, obese, or sarcopenic-obese based on measures of WC and either muscle mass or strength. Participants were followed for 8 years for CVD development and proportional hazard regression models were used to compare risk estimates for CVD in the four groups after adjusting for age, sex, race, income, smoking, alcohol, and cognitive status. Results  Compared with the normal group, CVD risk was not significantly elevated within the obese, sarcopenic, or sarcopenic-obese groups as determined by WC and muscle mass. When determined by WC and muscle strength, CVD risk was not significantly increased in the sarcopenic or obese groups, but was increased by 23% (95% confidence interval: 0.99–1.54, P=0.06) within the sarcopenic-obese group. Conclusion  Sarcopenia and obesity alone were not sufficient to increase CVD risk. Sarcopenic-obesity, based on muscle strength but not muscle mass, was modestly associated with increased CVD risk. These findings imply that strength may be more important than muscle mass for CVD protection in old age.     

De quelques maux de la prévention contemporaine. Le cas de l’obésité et du surpoids

Overweight and obesity are considered major public health issues, and many preventive campaigns are designed to prevent unhealthy eating habits among the French. But these campaigns may be ineffective, and even sometimes counterproductive. Firstly, because prevention is a moral enterprise that can lead to stigmatizing targeted people. Secondly, because the ‘merchandization’ of prevention fuels a ‘dietary cacophony’. Thirdly, the medicalisation of overweight/obesity involves some shortcomings: it can prevent us from understanding eating habits, and many general physicians are insufficiently trained to take care of overweight or obese patients.     

Conséquences de l'insuffisance rénale aiguë sur les métabolismes

Acute renal failure (ARF) is associated with a number of metabolic disturbances. ARF does not seem by itself to cause significant alterations of energy expenditure. It induces insulino-resistance and an increase in hepatic gluconeogenesis, which contribute to glucose intolerance. Disturbances of protein metabolism lead to hypercatabolism due to underlying diseases and to renal failure. These abnormalities are linked to ARF-induced metabolic acidosis or to renal failure per se (secretion of catabolic hormones, decrease in muscle protein synthesis, decrease in amino acid production from the kidney, protein losses due to dialysis). Finally ARF is associated with disturbances of lipid metabolism: decrease in lipolytic activity, increase in triglyceridemia, hypocholesterolemia and alterations of lipoprotein profile.These metabolic disturbances can induce malnutrition, which may contribute to the high mortality of ARF. However, assessing the proper role of renal failure remains difficult, and requires further prospective studies using multivariate analysis.     

Associations of Sarcopenia and Sarcopenic Obesity With Metabolic Syndrome Considering Both Muscle Mass and Muscle Strength

Objectives:

We investigated the associations of sarcopenia-defined both in terms of muscle mass and muscle strength-and sarcopenic obesity with metabolic syndrome.

Methods:

Secondary data pertaining to 309 subjects (85 men and 224 women) were collected from participants in exercise programs at a health center in a suburban area. Muscle mass was measured using bioelectrical impedance analysis, and muscle strength was measured via handgrip strength. Sarcopenia based on muscle mass alone was defined as a weight-adjusted skeletal muscle mass index more than two standard deviations below the mean of a sex-specific young reference group (class II sarcopenia). Two cut-off values for low handgrip strength were used: the first criteria were <26 kg for men and <18 kg for women, and the second criteria were the lowest quintile of handgrip strength among the study subjects. Sarcopenic obesity was defined as the combination of class II sarcopenia and being in the two highest quintiles of total body fat percentage among the subjects. The associations of sarcopenia and sarcopenic obesity with metabolic syndrome were evaluated using logistic regression models.

Results:

The age-adjusted risk ratios (RRs) of metabolic syndrome being compared in people with or without sarcopenia defined in terms of muscle mass were 1.25 (95% confidence interval [CI], 1.06 to 1.47, p=0.008) in men and 1.12 (95% CI, 1.06 to 1.19, p<0.001) in women, which were found to be statistically significant relationships. The RRs of metabolic syndrome being compared in people with or without sarcopenic obesity were 1.31 in men (95% CI, 1.10 to 1.56, p=0.003) and 1.17 in women (95% CI, 1.10 to 1.25, p<0.001), which were likewise found to be statistically significant relationships.

Conclusions:

The associations of sarcopenia defined in terms of muscle mass and sarcopenic obesity with metabolic syndrome were statistically significant in both men and women. Therefore, sarcopenia and sarcopenic obesity must be considered as part of the community-based management of non-communicable diseases.     

Nutrition, âge et muscle : sarcopénie ou sarcoporose ?

One of the major impact of the metabolic aging is the reduction of lean body mass which corresponds to a loss of protein, especially in muscle also called sarcopenia. These alterations lead to a decrease in muscle strength leading to a gradual disability and ultimately to an over-morbidity with a social cost still largely unestimated. Therefore, the need to better define this clinical entity in terms of risk is an important objective of the nutritional care. The balance between the process of synthesis and breakdown of proteins result in a positive or negative protein mass, but these changes are difficult to demonstrate in the postabsorptive state in the elderly subjects. However, aging causes a gradual reduction in their muscle capacity to respond to food intake. Thus, in the elderly a lesser postprandial stimulation of protein synthesis, leading to a progressive daily loss of protein was reported as a result of incomplete compensation by post-prandial anabolism of body protein mobilization during post-absorptive state. The decline in physical activity is also an event to consider while in the elderly the muscle contraction induced anabolism still exists and can be used to maintain lean body mass. Based on these observations, new strategies to improve the availability postprandial amino acid can be used and could be combined with nutritional factors, physical and/or hormonal treatments.     

Prevalence of sarcopenia in the French senior population

Introduction A muscle mass normalized for height² (MMI) or for body weight (SMI) below 2SD under the mean for a young population defines sarcopenia. This study aimed at setting the cutoffs and the prevalence of sarcopenia in the French elderly population. Another objective was to compare the results obtained with SMI and MMI.Methods: Muscle mass was assessed by bioelectrical impedance analysis in 782 healthy adults (<40 years) to determine skeletal mass index (SMI, muscle mass*100/weight) and muscle mass index (MMI, muscle mass/height²). Prevalence was estimated in 888 middle aged (40–59 years) and 218 seniors (60–78 years). All were healthy people.Results: For women mean-2SD were 6.2 kg/m² (MMI) and 26.6% (SMI); for men limits were 8.6 kg/m² (MMI) and 34.4% (SMI). In middle aged persons a small number of them were identified as sarcopenic. In healthy seniors, 2.8% of women and 3.6% of men were sarcopenic (MMI). The prevalence was 23.6% in women and 12.5% in men with SMI. MMI and SMI identified different sarcopenic populations, leaner subjects for MMI while fatter subjects for SMI.Conclusion: Cutoff values for the French population were defined. Prevalence of sarcopenia was different from that in the US population.     

Inflammation in Relation to Sarcopenia and Sarcopenic Obesity among Older Adults Living with Chronic Comorbidities: Results from the National Health and Nutrition Examination Survey 1999–2006

Loss of muscle mass and waning in muscle strength are common in older adults, and inflammation may play a key role in pathogenesis. This study aimed to examine associations of C-reactive protein (CRP) and systemic immune-inflammation index (SII) with sarcopenia and sarcopenic obesity in older adults with chronic comorbidities. Cross-sectional data from the National Health and Nutrition Examination Survey (1999–2006) were obtained for participants aged ≥60 years. Sarcopenia was defined by a lean mass and body height (males < 7.26 kg/m², females < 5.45 kg/m²). Sarcopenic obesity was defined by the concurrent presence of sarcopenia and obesity (defined by relative fat mass). Logistic regression was used to assess the associations of CRP and SII with sarcopenia and sarcopenic obesity. The dose–response relationship was examined via restricted cubic splines. Of the participants (n = 2483), 23.1% (n = 574) and 7.7% (n = 190) had sarcopenia and sarcopenic obesity, respectively. The multivariable logistic regression models suggested a positive association of SII with sarcopenia and sarcopenic obesity, but a positive statistically significant association was not consistently observed for CRP. Dose–response curves suggested similar association patterns for these biomarkers. In clinical practice, measures to prevent sarcopenia and sarcopenic obesity are needed for older vulnerable people with high systemic inflammation.     

Dénutrition chez le sujet âgé obèse

The aging population grows quickly, the prevalence of obesity increases in all age categories, and the prevalence of disease and disease related malnutrition is bound to increase with age. In subject aged 70 and older, the prevalence of obesity is 15 to 17 % and the prevalence of malnutrition is 4 to 10 %. The number of older persons both obese and malnourished has not been estimated, and there are no specific recommendations for nutritional care. Nevertheless, the obese older subjects can be frail, sarcopenic or malnourished and thus present a high risk for mobility disorders, falls, fractures, hospitalization and institutionalization. Data from the literature may help practitioners to diagnose and care for these older persons.     

The Administration of Panax Ginseng Berry Extract Attenuates High-Fat-Diet-Induced Sarcopenic Obesity in C57BL/6 Mice

Sarcopenia and obesity are serious health problems that are highly related to several metabolic diseases. Sarcopenic obesity, a combined state of sarcopenia and obesity, results in higher risks of metabolic diseases and even mortality than sarcopenia or obesity alone. Therefore, the development of therapeutic agents for sarcopenic obesity is crucial. C57BL/6 mice were fed with a high-fat diet (HFD) for 9 weeks. Then, mice were administered with Panax ginseng berry extract (GBE) for an additional 4 weeks, with continuous HFD intake. GBE significantly decreased the food efficiency ratio, serum lipid and insulin levels, adipose tissue weights, and adipocyte size. It significantly increased the grip strength, muscle masses, and myofiber cross-sectional area. It deactivated the protein kinase C (PKC) theta and zeta, resulting in activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, which is known to regulate muscle synthesis and degradation. Furthermore, it inhibited the production of inflammatory cytokines in the muscle tissue. GBE attenuated both obesity and sarcopenia. Thus, GBE is a potential agent to prevent or treat sarcopenic obesity.     

Validation of several established equations for resting metabolic rate in obese and nonobese people

OBJECTIVE: To evaluate several equations for predicting resting metabolic rate against measured values in obese and nonobese people. DESIGN: Resting metabolic rate was measured with indirect calorimetry. Four calculation standards using various combinations of weight, height, and age were used to predict resting metabolic rate: a) Harris-Benedict equation, b) Harris-Benedict equation using adjusted body weight in obese individuals, c) Owen, and d) Mifflin. Main outcome was percentage of subjects whose calculated metabolic rate was outside a +/-10% limit from measured values. Subjects/Setting 130 nonhospitalized adult volunteers grouped by degree of obesity (range of body mass index, 18.8 to 96.8). Statistical Analysis Performed Analysis of proportions was used to determine differences in the percentage of subjects estimated accurately by each equation; alpha was set at 0.05. RESULTS: Calculated resting metabolic rate was more than 10% different from measured in 22% of subjects using the Mifflin equation, 33% using the Harris-Benedict equation (P=.05 vs Mifflin), and 35% using the Owen equation (P<.05 vs Mifflin). The error rate using Harris-Benedict with adjusted weight in obesity was 74% (vs 36% in obese subjects using actual weight in the standard Harris-Benedict equation). APPLICATIONS/CONCLUSION: Of the calculation standards tested, the Mifflin standard provided an accurate estimate of actual resting metabolic rate in the largest percentage of nonobese and obese individuals and therefore deserves consideration as the standard for calculating resting metabolic rate in obese and nonobese adults. Use of adjusted body weight in the Harris-Benedict equation led to less overestimation by that equation in obese people at the expense of increased incidence of underestimation.