Antony D. Karelis

Characterizing the profile of obese patients who are metabolically healthy

The presence of obesity-related metabolic disturbances varies widely among obese individuals. Accordingly, a unique subset of obese individuals has been described in the medical literature, which seems to be protected or more resistant to the development of metabolic abnormalities associated with obesity. These individuals, now known as ‘metabolically healthy but obese’ (MHO), despite having excessive body fatness, display a favorable metabolic profile characterized by high levels of insulin sensitivity, no hypertension as well as a favorable lipid, inflammation, hormonal, liver enzyme and immune profile. However, recent studies have indicated that this healthier metabolic profile may not translate into a lower risk for mortality. Mechanisms that could explain the favorable metabolic profile of MHO individuals are poorly understood. However, preliminary evidence suggests that differences in visceral fat accumulation, birth weight, adipose cell size and gene expression-encoding markers of adipose cell differentiation may favor the development of the MHO phenotype. Despite the uncertainty regarding the exact degree of protection related to the MHO status, identification of underlying factors and mechanisms associated with this phenotype will eventually be invaluable in helping us understand factors that predispose, delay or protect obese individuals from metabolic disturbances. Collectively, a greater understanding of the MHO individual has important implications for therapeutic decision making, the characterization of subjects in research protocols and medical education.

Metabolically healthy but obese individuals

A subset of obese individuals seems to be protected against obesity-related metabolic complications. These individuals are described as metabolically healthy but obese, or as having uncomplicated obesity, or metabolically benign obesity. Despite having excessive body fat, people who are metabolically healthy but obese have favourable metabolic profi les, characterised by remarkably high insulin sensitivity, no sign of hypertension, and normal lipid, infl ammation, and hormonal profi les (low triglycerides and C-reactive protein concentrations and high HDL cholesterol and adiponectin concentrations). recommendation of developing quantitative measures of drug-induced harm and benchmarks for its recommended behavioural treatments, it does not take a similar approach to this necessary training proposal. The report is unclear about where the newly trained researchers will be deployed. Clinically approved drugs for substance abusers developed in academic settings have failed in multicentre trials for veterans in community settings. A lack of generalisable studies in academic settings underscores the need for some academic researchers to do studies in community settings rather than in academic clinics. There will need to be safeguards against adopting the non-academic benchmarks used in large hospitals, such as scope of clinical practice. Whereas in academia a major benchmark is the number and infl uence of publications, in hospitals the amount of clinical funding alone is often the major benchmark. We must be cautious that academic physicians are held to publication-based standards as opposed to gauging success merely by their ability to procure funding. But publication alone, while important for academic promotion, may not be suffi cient to jump-start translational drug-development. Since the report was written, several double-blind studies have shown that cognitive enhancers promote behavioural treatment of social anxiety and obsessive-compulsive disorders. Although these results are promising, they frustrate the clinician. The fi ndings are either insuffi cient to alter clinical practice or, as is often the case after small phase II academic trials, to satisfy sceptical reviewers. Clearly, industry needs to play the important role in fi lling this void between promising small academic phase II studies and larger phase III trials. That is why the recommendation of the Academy’s report to adopt a fl exible approach to drug pricing—taking account of the overall societal value of such drugs—is important. Orphan drug legislation in the USA has been uniquely successful in spurring industry to quickly develop old drugs for new uses, because time-consuming studies to establish safety have long since been completed. The sheer size of this success, by the type of academic clinical researcher that the report advocates training, begs the question: what if this approach to intellectual property, which (like the report’s recommendation) takes into account overall societal value, were extended to using old drugs for more common conditions. If policy makers embrace this report’s recommendation to expand the number of translational professionals and modernise antiquated intellectual property law. there is hope for at least doubling the rate of drug development.

Metabolically healthy but obese women: effect of an energy-restricted diet.

To the Editor: A unique subset of obese individuals has been identified that appears to be protected against obesityrelated metabolic disturbances [1, 2]. These individuals, now known as ‘metabolically healthy but obese’ (MHO) individuals, display a favourable metabolic profile, characterised by high levels of insulin sensitivity, normal lipid and inflammation profiles and no sign of hypertension, despite having excessive body fatness. In fact, the metabolic profiles of MHO postmenopausal women are virtually indistinguishable from those of young lean women [3]. Interestingly, a recent longitudinal study reported that the protective metabolic profile observed in MHO individuals was associated with lower incidences of type 2 diabetes and cardiovascular diseases [4]. Moreover, evidence suggests that MHO individuals may account for as much as 20–30% of the obese population [5]. An important question that seems to be unresolved is whether MHO individuals would gain any metabolic benefit from weight loss. Indeed, several studies have shown that weight loss improves insulin sensitivity and metabolic abnormalities and reduces the risk for type 2 diabetes in obese individuals [6, 7]. However, attempts to achieve weight loss in MHO individuals, by way of diet, may be actually counterproductive and potentially harmful. One may even question the need to aggressively treat MHO individuals given their favourable metabolic profile. Therefore, the aim of the present study was to investigate the effect of a 6 month energy-restricted diet on insulin sensitivity using the euglycaemic–hyperinsulinaemic clamp technique in a sample of MHO postmenopausal women. This study was approved by the ethics committee of the University of Montreal. After reading and signing the consent form, each participant was invited to the Metabolic Unit for testing. The women then entered a medically supervised 6 month weight loss programme, which aimed to reduce body weight by 10%. To achieve a level of energy restriction, the baseline resting metabolic rate was extrapolated over a 24 h period (kcal/min×1,440 min) and multiplied by an activity factor of 1.4, which corresponds to a sedentary state. Thereafter, instructions on how to follow a hypoenergetic diet Diabetologia (2008) 51:1752–1754 DOI 10.1007/s00125-008-1038-4

Menopause and sarcopenia : A potential role for sex hormones.

Menopause is associated with a decline in estrogen levels, which could lead to an increase in visceral adiposity as well as a decrease in bone density, muscle mass and muscle strength. This decline in muscle mass, known as sarcopenia, is frequently observed in postmenopausal women. Potential causes of sarcopenia include age-related changes in the hormonal status, low levels of physical activity, reduced protein intake and increased oxidative stress. However, the role of sex hormones, specifically estrogens, on the onset of sarcopenia is controversial. Preventing sarcopenia and preserving muscle strength are highly relevant in order to prevent functional impairment and physical disability. To date, resistance training has been shown to be effective in attenuating age-related muscle loss and strength. However, results on the effect of hormonal supplementation to treat or prevent sarcopenia are contradictory. Further research is needed to identify other potential mechanisms of sarcopenia as well as effective interventions for the prevention and treatment of sarcopenia. Therefore, the purpose of this review will be to examine the role of sex hormonal status in the development of sarcopenia. We will also overview the physical as well as metabolic consequences of sarcopenia and the efficiency of different interventions for the prevention and treatment of sarcopenia.

Identifying metabolically healthy but obese individuals in sedentary postmenopausal women.

The purpose of this study was to compare different methods to identify metabolically healthy but obese (MHO) individuals in a cohort of obese postmenopausal women. We examined the anthropometric and metabolic characteristics of 113 obese (age: 57.3 ± 4.8 years; BMI: 34.2 ± 2.7 kg/m2), sedentary postmenopausal women. The following methods were used to identify MHO subjects: the hyperinsulinemic–euglycemic clamp (MHO: upper quartile of glucose disposal rates); the Matsuda index (MHO: upper quartile of the Matsuda index); the homeostasis model assessment (HOMA) index (MHO: lower quartile of the HOMA index); having 0–1 cardiometabolic abnormalities (systolic/diastolic blood pressure ≥130/85 mm Hg, triglycerides (TG) ≥1.7 mmol/l, glucose ≥5.6 mmol/l, HOMA >5.13, high‐sensitive C‐reactive protein (hsCRP) >0.1 mg/l, high‐density lipoprotein‐cholesterol (HDL‐C) <1.3 mmol/l); and meeting four out of five metabolic factors (HOMA ≤2.7, TG ≤1.7 mmol/l, HDL‐C ≥1.3 mmol/l, low‐density lipoprotein‐cholesterol ≤2.6 mmol/l, hsCRP ≤3.0 mg/l). Thereafter, we measured insulin sensitivity, body composition (dual‐energy X‐ray absorptiometry), body fat distribution (computed tomography scan), energy expenditure, plasma lipids, inflammation markers, resting blood pressure, and cardiorespiratory fitness. We found significant differences in body composition (i.e., peripheral fat mass, central lean body mass (LBM)) and metabolic risk factors (i.e., HDL‐C, hsCRP) between MHO and at risk individuals using the different methods to identify both groups. In addition, significant differences between MHO subjects using the different methods to identify MHO individuals were observed such as age, TG/HDL, hsCRP, and fasting insulin. However, independently of the methods used, we noted some recurrent characteristics that identify MHO subjects such as TG, apolipoprotein B, and ferritin. In conclusion, the present study shows variations in body composition and metabolic profile based on the methods studied to define the MHO phenotype. Therefore, an expert consensus may be needed to standardize the identification of MHO individuals.

Metabolically healthy but obese individuals: relationship with hepatic enzymes

The purpose of this study was to investigate the level of plasma hepatic enzymes in obese women displaying the metabolically healthy but obese (MHO) phenotype. We studied 104 obese, sedentary, postmenopausal women. Subjects were classified as MHO or at risk based on insulin sensitivity as assessed with the oral glucose tolerance test-derived Matsuda index. Subjects were divided into quartiles according to insulin sensitivity values. Subjects in the upper quartile were categorized as MHO, whereas subjects in the lower 3 quartiles represented at-risk subjects. Outcome measures were hepatic enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, and gamma-glutamyltransferase [GGT]], high-density lipoprotein cholesterol, triglycerides, triglycerides to high-density lipoprotein cholesterol ratio, apolipoprotein B, fatty liver index, body composition (dual-energy x-ray absorptiometry), and visceral adipose tissue (computed tomography). The MHO individuals had significantly lower concentrations of ALT, AST, and GGT as well as a lower fatty liver index compared with at-risk subjects (P < .05). In addition, lean body mass index and visceral adipose tissue were significantly lower in MHO individuals (P < .05). Moreover, stepwise regression analysis showed that ALT explained 17.9% of the variation in insulin sensitivity in our cohort, which accounted for the greatest source of unique variance. Results of the present study indicate that postmenopausal women displaying the MHO phenotype present favorable levels of ALT, AST, and GGT. Lower concentrations of hepatic enzymes, in particular, lower circulating ALT levels, in MHO individuals may reflect lower hepatic insulin resistance and lower liver fat content; and this could be involved, at least in part, in the protective profile of MHO individuals.

Contribution of the lean body mass to insulin resistance in postmenopausal women with visceral obesity : a Monet study.

Some insulin‐resistant obese postmenopausal (PM) women are characterized by an android body fat distribution type and higher levels of lean body mass (LBM) compared to insulin‐sensitive obese PM women. This study investigates the independent contribution of LBM to the detrimental effect of visceral fat (VF) levels on the metabolic profile. One hundred and three PM women (age: 58.0 ± 4.9 years) were studied and categorized in four groups on the basis of their VF (higher vs. lower) and lean BMI (LBMI = LBM (kg)/height (m2); higher vs. lower). Measures included: fasting lipids, glucose homeostasis (by euglycemic/hyperinsulinemic clamp technique and 2‐h oral glucose tolerance test (OGTT)), C‐reactive protein (CRP) levels, fat distribution (by computed tomography (CT) scan), and body composition (by dual‐energy X‐ray absorptiometry). Women in the higher VF/higher LBMI group had lower glucose disposal and higher plasma insulin levels compared to the other groups. They also had higher plasma CRP levels than the women in the lower VF/lower LBMI group. VF was independently associated with insulin levels, measures of glucose disposal, and CRP levels (P < 0.05). LBMI was also independently associated with insulin levels, glucose disposal, and CRP levels (P < 0.05). Finally, significant interactions were observed between LBMI and VF levels for insulin levels during the OGTT and measures of glucose disposal (P < 0.05). In conclusion, VF and LBMI are both independently associated with alterations in glucose homeostasis and CRP levels. The contribution of VF to insulin resistance seems to be exacerbated by increased LBM in PM women.

Inclusion of C-reactive protein in the identification of metabolically healthy but obese (MHO) individuals.

iet alone [1]. In patients in remission, progressive hyperglycaeia precedes, and is a strong risk factor for subsequent relapse 2]. More recently, short-term studies have shown that glucooxicity, but not lipotoxicity, is involved in the occurrence of -cell dysfunction and abnormal muscle insulin signalling [3]. hus, both insulin secretion defect and insulin resistance may e involved in relapse. The case we have described shows that the insulin resistance ormally associated with pregnancy was not sufficient to triger metabolic decompensation in our patient. This suggests that, espite the severe initial presentation, recovery of -cell function as near-normal, or at least able to counteract insulin resisance. Since glucotoxicity is a major determinant of the insulin ecretion defect observed in ketosis-prone type 2 diabetes, mainenance of normal glucose control is crucial to avoid relapse of etabolic decompensation. In this respect, monotherapy with etformin, which is not associated with the risk of hypoglycaeia, should be used during the remission phase in patients who ave ketosis-prone type 2 diabetes.

Carbohydrate administration and exercise performance : what are the potential mechanisms involved ?

It is well established that carbohydrate (CHO) administration increases performance during prolonged exercise in humans and animals. The mechanism( s), which could mediate the improvement in exercise performance associated with CHO administration, however, remain(s) unclear. This review focuses on possible underlying mechanisms that could explain the increase in exercise performance observed with the administration of CHO during prolonged muscle contractions in humans and animals. The beneficial effect of CHO ingestion on performance during prolonged exercise could be due to several factors including (i) an attenuation in central fatigue; (ii) a better maintenance of CHO oxidation rates; (iii) muscle glycogen sparing; (iv) changes in muscle metabolite levels; (v) reduced exercise-induced strain; and (vi) a better maintenance of excitation-contraction coupling. In general, the literature indicates that CHO ingestion during exercise does not reduce the utilization of muscle glycogen. In addition, data from a meta-analysis suggest that a dose-dependent relationship was not shown between CHO ingestion during exercise and an increase in performance. This could support the idea that providing enough CHO to maintain CHO oxidation during exercise may not always be associated with an increase in performance. Emerging evidence from the literature shows that increasing neural drive and attenuating central fatigue may play an important role in increasing performance during exercise with CHO supplementation. In addition, CHO administration during exercise appears to provide protection from disrupted cell homeostasis/integrity, which could translate into better muscle function and an increase in performance. Finally, it appears that during prolonged exercise when the ability of metabolism to match energy demand is exceeded, adjustments seem to be made in the activity of the Na+/K+ pump. Therefore, muscle fatigue could be acting as a protective mechanism during prolonged contractions. This could be alleviated when CHO is administered resulting in the better maintenance of the electrical properties of the muscle fibre membrane. The mechanism(s) by which CHO administration increases performance during prolonged exercise is(are) complex, likely involving multiple factors acting at numerous cellular sites. In addition, due to the large variation in types of exercise, durations, intensities, feeding schedules and CHO types it is difficult to assess if the mechanism(s) that could explain the increase in performance with CHO administration during exercise is(are) similar in different situations. Experiments concerning the identification of potential mechanism(s) by which performance is increased with CHO administration during exercise will add to our understanding of the mechanism(s) of muscle/central fatigue. This knowledge could have significant implications for improving exercise performance.

Crosstalk between intestinal microbiota, adipose tissue and skeletal muscle as an early event in systemic low-grade inflammation and the development of obesity and diabetes

Obesity is associated with a systemic chronic low‐grade inflammation that contributes to the development of metabolic disorders such as cardiovascular diseases and type 2 diabetes. However, the etiology of this obesity‐related pro‐inflammatory process remains unclear. Most studies have focused on adipose tissue dysfunctions and/or insulin resistance in skeletal muscle cells as well as changes in adipokine profile and macrophage recruitment as potential sources of inflammation. However, low‐grade systemic inflammation probably involves a complex network of signals interconnecting several organs. Recent evidences have suggested that disturbances in the composition of the gut microbial flora and alterations in levels of gut peptides following the ingestion of a high‐fat diet may be a cause of low‐grade systemic inflammation that may even precede and predispose to obesity, metabolic disorders or type 2 diabetes. This hypothesis is appealing because the gastrointestinal system is first exposed to nutrients and may thereby represent the first link in the chain of events leading to the development of obesity‐associated systemic inflammation. Therefore, the present review will summarize the latest advances interconnecting intestinal mucosal bacteria‐mediated inflammation, adipose tissue and skeletal muscle in a coordinated circuitry favouring the onset of a high‐fat diet‐related systemic low‐grade inflammation preceding obesity and predisposing to metabolic disorders and/or type 2 diabetes. A particular emphasis will be given to high‐fat diet‐induced alterations of gut homeostasis as an early initiator event of mucosal inflammation and adverse consequences contributing to the promotion of extended systemic inflammation, especially in adipose and muscular tissues. Copyright