Prediction of subclinical atherosclerosis in low Framingham risk score individuals by using the metabolic syndrome criteria and insulin sensitivity index.

Background: Subclinical atherosclerosis can be present in individuals with an optimal cardiovascular risk factor profile. Traditional risk scores such as the Framingham risk score do not adequately capture risk stratification in low-risk individuals. The aim of this study was to determine if markers of metabolic syndrome and insulin resistance can better stratify low-risk individuals. Methods: A cross-sectional study of 101 healthy participants with a low Framingham risk score and no prior morbidities was performed to assess prevalence of subclinical atherosclerosis using computed tomography (CT) and ultrasound. Participants were compared between groups based on Metabolic Syndrome (MetS) and Insulin-Sensitivity Index (ISI-cal) scores. Results: Twenty three individuals (23%) had subclinical atherosclerosis with elevated CT Agatston score ≥1. Presence of both insulin resistance (ISI-cal <9.23) and fulfillment of at least one metabolic syndrome criterion denoted high risk, resulting in significantly improved AUC (0.706 95%CI 0.588-0.822) over the Framingham risk score in predicting elevated CT Agatston score ≥1, with net reclassification index of 50.9 ± 23.7%. High-risk patients by the new classification also exhibited significantly increased carotid intima thickness. Conclusions: The overlap of insulin resistance and presence of ≥1 criterion for metabolic syndrome may play an instrumental role in identifying traditionally low-risk individuals predisposed to future risk of atherosclerosis and its sequelae.

Gender differences in fasting and postprandial metabolic traits predictive of subclinical atherosclerosis in an asymptomatic Chinese population.

The prediction utility of Framingham Risk Score in populations with low conventional cardiovascular risk burden is limited, particularly among women. Gender-specific markers to predict cardiovascular risk in overtly healthy people are lacking. In this study we hypothesize that postprandial responses triggered by a high-calorie meal test differ by gender in their ability to triage asymptomatic subjects into those with and without subclinical atherosclerosis. A total of 101 healthy Chinese subjects (46 females, 55 males) at low risk of coronary heart disease completed the study. Subjects underwent cardiovascular imaging and postprandial blood phenotyping after consuming a standardized macronutrient meal. Prediction models were developed using logistic regression and subsequently subjected to cross-validation to obtain a de-optimized receiver operating characteristic (ROC) curve. Distinctive gender differences in postprandial trajectories of glucose, lipids and inflammatory markers were observed. We used gender-specific association with different combinations of postprandial predictors to develop 2 models for predicting risk of subclinical atherosclerosis in males (ROC AUC = 0.7867, 95% CI 0.6567, 0.9166) and females (ROC AUC = 0.9161, 95% CI 0.8340, 0.9982) respectively. We report novel postprandial models for predicting subclinical atherosclerosis in apparently healthy Asian subjects using a gender-specific approach, complementing the conventional Framingham Risk Score.Clinical Trial Registration: The trial was registered at clinicaltrials.gov as NCT03531879.

Plasma Branched-Chain Amino Acids Are Associated With Greater Fasting and Postprandial Insulin Secretion in Non-diabetic Chinese Adults.

Background: Plasma branched-chain amino acids (BCAA) are consistently elevated in subjects with obesity and type 2 diabetes (T2DM) and correlate with insulin resistance. The association of BCAA with insulin secretion and clearance rates has not been adequately described. Objective: To evaluate the relationships between fasting and postprandial plasma BCAA, insulin secretion and insulin clearance. Design: Ninety-five non-diabetic Chinese subjects (43 females) underwent a mixed-meal tolerance test; blood biomarkers including BCAAs (leucine, isoleucine, valine) were measured for 6 h. Fasting and postprandial insulin secretion rates (ISR) and insulin clearance were determined by oral minimal modeling of glucose and C-peptide. Results: Fasting and postprandial plasma BCAA correlated strongly with each other (ρ = 0.796, P < 0.001), and both were positively associated with basal ISR (ρ = 0.45/0.36, P < 0.001), total postprandial ISR AUC (ρ = 0.37/0.45, P < 0.001), and negatively with insulin clearance (ρ = -0.29/-0.29, P < 0.01), after adjusting for sex and body mass index. These relationships largely persisted after adjusting further for insulin resistance and postprandial glucose. Compared with subjects in the middle and lowest tertiles for fasting or postprandial plasma BCAA, subjects in the highest tertile had significantly greater postprandial glucose (by 7-10%) and insulin (by 74-98%) concentrations, basal ISRs (by 34-53%), postprandial ISR AUCs (by 41-49%), and lower insulin clearance rates (by 17-22%) (all P < 0.05). Conclusions: Fasting and postprandial plasma BCAA levels are associated with greater fasting and postprandial insulin secretion and reduced insulin clearance in healthy Chinese subjects. These observations potentially highlight an additional layer of involvement of BCAA in the regulation of glucose homeostasis.

Dissociation Between Insulin Resistance and Abnormalities in Lipoprotein Particle Concentrations and Sizes in Normal-Weight Chinese Adults.

Insulin resistance in obesity coincides with abnormalities in lipid profile and lipoprotein subclass distribution and size even before abnormalities in glucose homeostasis manifest. We aimed to assess this relationship in the absence of obesity. Insulin sensitivity (3-h intravenous glucose tolerance test and minimal modeling) and lipoprotein particle concentrations and sizes (proton nuclear magnetic resonance spectroscopy) were evaluated in 15 insulin-resistant and 15 insulin-sensitive lean Asians of Chinese descent with normal glucose tolerance, matched on age, sex, and body mass index. Despite a ~50% lower insulin sensitivity index (Si) in insulin-resistant than in insulin-sensitive subjects, which was accompanied by significantly greater acute insulin response to glucose (AIRg) and fasting insulin concentration but not different fasting glucose concentration, there were no significant differences between groups in the blood lipid profile (p ≥ 0.44) or the lipoprotein subclass concentrations (p ≥ 0.30) and particle sizes (p ≥ 0.43). We conclude that, contrary to observations in subjects with obesity, insulin resistance is not accompanied by unfavorable changes in the plasma lipid profile and lipoprotein particle concentrations and sizes in lean Asians with normal glucose tolerance. Therefore, insulin resistance at the level of glucose metabolism is mechanistically or temporally dissociated from lipid and lipoprotein metabolism. Trial Registration: clinicaltrials.gov, NCT03264001.

Association between Serum Vitamin D Metabolites and Metabolic Function in Healthy Asian Adults.

The association between low vitamin D status and the development of type 2 diabetes mellitus is well established; however, intervention trials that increased serum vitamin D (through ultraviolet B exposure or dietary supplementation) provide mixed outcomes. Recent evidence suggests that metabolites directly related to vitamin D receptor activation-1α,25-dihydroxyvitamin D3 and 24R,25-dihydroxyvitamin D3-may be better markers of vitamin D repletion status. We tested the hypothesis that a vitamin D metabolite (VDM) index, calculated as the sum of normalized fasting serum concentrations of 1α,25-dihydroxyvitamin D3 and 24R,25-dihydroxyvitamin D3, is associated with metabolic function. We measured subcutaneous and visceral adipose tissue volume, intrahepatic triglyceride content, maximum oxygen uptake, insulin sensitivity (4 h hyperinsulinemic-euglycemic clamp), and insulin secretion (3 h meal tolerance test with mathematical modeling) and calculated the VDM index in 65 healthy Asian adults. Subjects with a low VDM index had lower peripheral insulin sensitivity and beta-cell function compared to subjects with a high VDM index (both p < 0.05), matched for age, sex, BMI, and serum 25-hydroxyvitamin D3. Serum 25-hydroxyvitamin D3 was not associated with peripheral insulin sensitivity or beta-cell function. Our results suggest that, rather than enhancing vitamin D substrate availability, upregulation of vitamin D action is more likely to lead to improvements in glucose homeostasis.

Oxytocin and Vasopressin Systems in Obesity and Metabolic Health: Mechanisms and Perspectives.

PURPOSE OF REVIEW: The neurohypophysial endocrine system is identified here as a potential target for therapeutic interventions toward improving obesity-related metabolic dysfunction, given its coinciding pleiotropic effects on psychological, neurological and metabolic systems that are disrupted in obesity. RECENT FINDINGS: Copeptin, the C-terminal portion of the precursor of arginine-vasopressin, is positively associated with body mass index and risk of type 2 diabetes. Plasma oxytocin is decreased in obesity and several other conditions of abnormal glucose homeostasis. Recent data also show non-classical tissues, such as myocytes, hepatocytes and ß-cells, exhibit responses to oxytocin and vasopressin receptor binding that may contribute to alterations in metabolic function. The modulation of anorexigenic and orexigenic pathways appears to be the dominant mechanism underlying the effects of oxytocin and vasopressin on body weight regulation; however, there are apparent limitations associated with their use in direct pharmacological applications. A clearer picture of their wider physiological effects is needed before either system can be considered for therapeutic use.

Dose-Dependent Effects of Exercise and Diet on Insulin Sensitivity and Secretion.

PURPOSE: A single bout of aerobic exercise increases insulin sensitivity the next day. The effects of exercise on insulin secretion, the role of exercise-induced energy deficit, and possible dose-response relationships are not well understood. This study aimed to evaluate insulin sensitivity and insulin secretion after progressively greater negative energy balance induced by exercise or diet. METHODS: Acute energy deficits (20% or 40% of weight maintenance needs) were induced by a single day of aerobic exercise (cycling at moderate intensity, n = 13) or dietary restriction (n = 19) in healthy men and women (age, 26 ± 2 yr; body mass index, 21.8 ± 0.5 kg·m). Intravenous glucose tolerance tests in conjunction with minimal modeling were performed the next morning, and blood samples were collected for 3 h to measure glucose and insulin concentrations. RESULTS: Insulin sensitivity increased linearly after exercise-induced energy deficits (P = 0.007) but did not change after equivalent diet-induced energy deficits (P = 0.673). Acute insulin response decreased after both exercise (P < 0.001) and dietary restriction (P = 0.005). The disposition index and glucose effectiveness were not affected by exercise (P = 0.138 and 0.808, respectively), but both decreased after 40% dietary restriction (P = 0.048 and 0.002, respectively). CONCLUSIONS: These results indicate that insulin sensitivity and insulin secretion are related to exercise energy expenditure, albeit in a different fashion (insulin sensitivity increases linearly, whereas insulin secretion drops to a nadir with a low exercise dose and does not decrease further). These changes cannot be replicated by equivalent energy deficits induced by dietary restriction, suggesting that exercise and diet have different effects on the mechanisms regulating glucose homeostasis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03264001.

Ectopic fat and aerobic fitness are key determinants of glucose homeostasis in nonobese Asians.

BACKGROUND: The importance of ectopic fat deposition and physical fitness in the pathogenesis of insulin resistance and beta cell dysfunction in subjects from the nonobese Asians is not known. MATERIALS AND METHODS: We conducted a cross-sectional study and measured insulin sensitivity (M value; 4-hour hyperinsulinaemic-euglycaemic clamp), insulin secretion rate (3-hour mixed meal tolerance test with oral minimal modelling), percent body fat, visceral adipose tissue, intramyocellular and intrahepatic lipid contents (magnetic resonance imaging and spectroscopy), cardiorespiratory fitness (VO2 max; graded exercise test) and habitual physical activity (short International Physical Activity Questionnaire) in 60 healthy nonobese Asian subjects (BMI = 21.9 ± 1.7 kg/m2 , age = 41.8 ± 13.4 years). RESULTS: M was inversely associated with percent body fat (r = -0.460, P < 0.001), visceral fat (r = -0.623, P < 0.001) and liver fat (r = -0.601, P < 0.001), whereas insulin secretion correlated positively with these adiposity indices (percent body fat: r = 0.303, P = 0.018; visceral fat: r = 0.409, P = 0.010; hepatic fat: r = 0.393, P = 0.002). VO2 max correlated negatively with insulin secretion rate (r = -0.420, P < 0.001) and positively with M (r = 0.658, P < 0.001). The amount of vigorous physical activity was positively associated with VO2 max (r = 0.682, P < 0.001). Multiple stepwise linear regression analyses indicated that VO2 max, age, and IHTG or VAT were independent determinants of insulin sensitivity and secretion (adjusted R2  = 69% and 33%, respectively, P < 0.001). CONCLUSIONS: Increased ectopic fat deposition is associated with reduced insulin sensitivity and increased insulin secretion in healthy nonobese Asians. Poor cardiorespiratory fitness, likely due to inadequate participation in vigorous exercise, is strongly related to suboptimal metabolic function. Interventions to encourage engagement in physical activity may thus be important for improving metabolic health in nonobese Asians.

The epidemiology of obesity.

Obesity is a complex multifactorial disease. The worldwide prevalence of overweight and obesity has doubled since 1980 to an extent that nearly a third of the world's population is now classified as overweight or obese. Obesity rates have increased in all ages and both sexes irrespective of geographical locality, ethnicity or socioeconomic status, although the prevalence of obesity is generally greater in older persons and women. This trend was similar across regions and countries, although absolute prevalence rates of overweight and obesity varied widely. For some developed countries, the prevalence rates of obesity seem to have levelled off during the past few years. Body mass index (BMI) is typically used to define overweight and obesity in epidemiological studies. However, BMI has low sensitivity and there is a large inter-individual variability in the percent body fat for any given BMI value, partly attributed to age, sex, and ethnicity. For instance, Asians have greater percent body fat than Caucasians for the same BMI. Greater cardiometabolic risk has also been associated with the localization of excess fat in the visceral adipose tissue and ectopic depots (such as muscle and liver), as well as in cases of increased fat to lean mass ratio (e.g. metabolically-obese normal-weight). These data suggest that obesity may be far more common and requires more urgent attention than what large epidemiological studies suggest. Simply relying on BMI to assess its prevalence could hinder future interventions aimed at obesity prevention and control.

Sex Differences in Glucose and Fatty Acid Metabolism in Asians Who Are Nonobese.

Context: The prevalence of diabetes is increasing throughout Asia, even in the absence of obesity, and is lower in women than in men. The underlying mechanisms are not well understood. Objective: To evaluate the sex differences in glucose and fatty acid metabolism in Asians who are nonobese. Design: Cross-sectional study. Setting: Clinical Nutrition Research Centre, Singapore. Participants: Healthy Asian men (n = 32; body mass index, 21.8 ± 1.5 kg/m2; age, 42 ± 14 years) and women (n = 28; body mass index, 21.4 ± 2.0 kg/m2; age, 41 ± 13 years). Main Outcome Measures: Insulin sensitivity (insulin-mediated glucose uptake normalized for steady-state insulin; hyperinsulinemic-euglycemic clamp), postprandial glucose, insulin and fatty acid concentrations, insulin secretion (mixed meal tolerance test with mathematical modeling), insulin clearance, body composition and fat distribution (dual-energy X-ray absorptiometry, MRI, and spectroscopy), cardiorespiratory fitness (maximal oxygen uptake; graded exercise test), and handgrip strength (dynamometry). Results: Women had more total body fat but less visceral fat than men; liver and muscle lipid contents were not different. Maximal oxygen uptake and handgrip strength were lower in women than men. The postprandial glucose concentrations were ~8% lower, the insulin-mediated glucose uptake was ~16% greater, and the meal-induced suppression of fatty acid concentrations was significantly greater in women than in men (P < 0.05 for all). However, muscle insulin sensitivity was not different between the sexes. No differences were found in postprandial insulin secretion and clearance rates; however, the steady-state insulin clearance was ~17% lower in women. Conclusions: Asian women who are nonobese are more insulin-sensitive than men at the level of adipose tissue but not skeletal muscle. Therefore, sex differences in glucose tolerance are likely the result of sexual dimorphism in hepatic insulin action.

Lipoprotein Subclass Profile after Progressive Energy Deficits Induced by Calorie Restriction or Exercise.

Weight loss, induced by chronic energy deficit, improves the blood lipid profile. However, the effects of an acute negative energy balance and the comparative efficacy of diet and exercise are not well-established. We determined the effects of progressive, acute energy deficits (20% or 40% of daily energy requirements) induced by a single day of calorie restriction (n = 19) or aerobic exercise (n = 13) in healthy subjects (age: 26 ± 9 years; body mass index (BMI): 21.8 ± 2.9 kg/m²). Fasting plasma concentrations of very low-, intermediate-, low-, and high-density lipoprotein (VLDL, LDL, IDL, and HDL, respectively) particles and their subclasses were determined using nuclear magnetic resonance. Total plasma triglyceride and VLDL-triglyceride concentrations decreased after calorie restriction and exercise (all p ≤ 0.025); the pattern of change was linear with an increasing energy deficit (all p < 0.03), with no evidence of plateauing. The number of circulating large and medium VLDL particles decreased after diet and exercise (all p < 0.015), with no change in small VLDL particles. The concentrations of IDL, LDL, and HDL particles, their relative distributions, and the particle sizes were not altered. Our data indicate that an acute negative energy balance induced by calorie restriction and aerobic exercise reduces triglyceride concentrations in a dose-dependent manner, by decreasing circulating large and medium VLDL particles.

Visceral adipose tissue tracks more closely with metabolic dysfunction than intrahepatic triglyceride in lean Asians without diabetes.

Increased visceral adipose tissue (VAT) and intrahepatic triglyceride (IHTG) are important risk factors for the development of type 2 diabetes in subjects with obesity. The relative contribution of these ectopic fat depots to cardiometabolic risk differs between populations, depends on the degree of obesity and the level of cardiorespiratory fitness, and is difficult to dissect because VAT and IHTG typically covary. The aim of this study was to evaluate the effect of an isolated increase in VAT or IHTG on insulin sensitivity and insulin secretion in apparently healthy normal-weight Asian subjects. Total body fat (dual X-ray absorptiometry), VAT and IHTG (magnetic resonance), insulin sensitivity (4-h hyperinsulinemic-euglycemic clamp), beta cell responsivity and insulin secretion rate (3-h mixed meal with mathematical modeling), and cardiorespiratory fitness (maximal oxygen consumption [V̇o2max]) were evaluated in groups of lean subjects with low or high VAT (687 ± 94 vs. 1,279 ± 197 ml, matched for IHTG; n = 13 each) and low or high IHTG (1.7 ± 0.3 vs. 6.7 ± 2.0%, matched for VAT; n = 15 each). All groups were matched for age, sex, total body fat, and V̇o2max. High-VAT subjects had ~25% lower insulin sensitivity, ~20%-40% greater beta cell responsivity and insulin secretion rate, ~35% greater fasting triglyceride concentration, and ~40% lower adiponectin concentration than low-VAT subjects (all P < 0.05). No differences were observed between low-IHTG and high-IHTG subjects. Accumulation of excess fat in the intra-abdominal area is more strongly associated with metabolic dysfunction than accumulation of liver fat in lean Asians without diabetes. NEW & NOTEWORTHY It is not known whether metabolic abnormalities in Asians without obesity track more closely with visceral or liver fat. We found an isolated increase in visceral fat was associated with reduced insulin sensitivity, greater insulin secretion, greater triglyceride, and lower adiponectin concentrations; no differences were observed with an isolated increase in liver fat. These results suggest that visceral fat is a better correlate of metabolic dysfunction than liver fat in Asians without obesity.

Moderate Weight Loss Improves Body Composition and Metabolic Function in Metabolically Unhealthy Lean Subjects.

OBJECTIVE: Individuals who have "metabolically obese normal weight" (MONW) have an increased risk for cardiometabolic disease. Moderate weight loss has multiple benefits in people with obesity, but its effects in lean people are unknown. Thus, the effects of diet-induced 5% weight loss on body composition and metabolic function in MONW subjects were evaluated. METHODS: Total body fat, visceral adipose tissue (VAT) and subcutaneous abdominal adipose tissue (SAT) volumes, intrahepatic and intramyocellular lipid contents, insulin sensitivity (hyperinsulinemic-euglycemic clamp), glucose tolerance, and postprandial insulin secretion and clearance rates (mixed meal with minimal modeling) were measured before and after 4.8% ± 0.5% weight loss in 11 MONW Asians (48 ± 3 years old, six men and five women, BMI 22.7 ± 0.4 kg/m2 ). RESULTS: Weight loss decreased total fat mass by ∼9%, VAT and SAT volumes by ∼11% and ∼17%, respectively, and intrahepatic fat by ∼50% (all P < 0.05). Fasting plasma insulin, triglyceride, and total low- and high-density lipoprotein cholesterol concentrations were also reduced (P < 0.05). Insulin sensitivity indexes (M-value and M/I ratio) increased by 21% to 26% (both P < 0.05); ß-cell responsivity and postprandial insulin secretion rate did not change, but insulin clearance rate increased by 16% (P < 0.05). CONCLUSIONS: Diet-induced moderate weight loss improves body composition, lipid profile, and insulin sensitivity and thereby reduces cardiometabolic risk in MONW Asians.

Regulation of glucose metabolism in nondiabetic, metabolically obese normal-weight Asians.

Type 2 diabetes in Asia occurs largely in the absence of obesity. The metabolically obese normal-weight (MONW) phenotype refers to lean subjects with metabolic dysfunction that is typically observed in people with obesity and is associated with increased risk for diabetes. Previous studies evaluated MONW subjects who had greater body mass index (BMI) or total body fat than respective control groups, making interpretation of the results difficult. We evaluated insulin sensitivity (hyperinsulinemic-euglycemic clamp); insulin secretion (mixed meal with oral minimal modeling); intra-abdominal, muscle, and liver fat contents (magnetic resonance); and fasting and postprandial glucose and insulin concentrations in 18 MONW subjects and 18 metabolically healthy controls matched for age (43 ± 3 and 40 ± 3 yr; P = 0.52), BMI (both 22 ± 1 kg/m2; P = 0.69), total body fat (17 ± 1 and 16 ± 1 kg; P = 0.33), and sex (9 men and 9 women in each group). Compared with controls, MONW subjects had an approximately twofold greater visceral adipose tissue volume and an approximately fourfold greater intrahepatic fat content (but similar muscle fat), 20-30% lower glucose disposal rates and insulin sensitivity, and 30-40% greater insulin secretion rates (all P < 0.05). The disposition index, fasting glucose, and HbA1c concentrations were not different between groups, whereas postprandial glucose and insulin concentrations were ~15% and ~65% greater, respectively, in MONW than control subjects (both P < 0.05). We conclude that the MONW phenotype is associated with accumulation of fat in the intra-abdominal area and the liver, profound insulin resistance, but also a robust ß-cell insulin secretion response that compensates for insulin resistance and helps maintain glucose homeostasis.

Metabolic Effects Associated with ICS in Patients with COPD and Comorbid Type 2 Diabetes: A Historical Matched Cohort Study.

BACKGROUND: Management guidelines for chronic obstructive pulmonary disease (COPD) recommend that inhaled corticosteroids (ICS) are prescribed to patients with the most severe symptoms. However, these guidelines have not been widely implemented by physicians, leading to widespread use of ICS in patients with mild-to-moderate COPD. Of particular concern is the potential risk of worsening diabetic control associated with ICS use. Here we investigate whether ICS therapy in patients with COPD and comorbid type 2 diabetes mellitus (T2DM) has a negative impact on diabetic control, and whether these negative effects are dose-dependent. METHODS AND FINDINGS: This was a historical matched cohort study utilising primary care medical record data from two large UK databases. We selected patients aged ≥40 years with COPD and T2DM, prescribed ICS (n = 1360) or non-ICS therapy (n = 2642) between 2008 and 2012. The primary endpoint was change in HbA1c between the baseline and outcome periods. After 1:1 matching, each cohort consisted of 682 patients. Over the 12-18-month outcome period, patients prescribed ICS had significantly greater increases in HbA1c values compared with those prescribed non-ICS therapies; adjusted difference 0.16% (95% confidence interval [CI]: 0.05-0.27%) in all COPD patients, and 0.25% (95% CI: 0.10-0.40%) in mild-to-moderate COPD patients. Patients in the ICS cohort also had significantly more diabetes-related general practice visits per year and received more frequent glucose strip prescriptions, compared with those prescribed non-ICS therapies. Patients prescribed higher cumulative doses of ICS (>250 mg) had greater odds of increased HbA1c and/or receiving additional antidiabetic medication, and increased odds of being above the Quality and Outcomes Framework (QOF) target for HbA1c levels, compared with those prescribed lower cumulative doses (≤125 mg). CONCLUSION: For patients with COPD and comorbid T2DM, ICS therapy may have a negative impact on diabetes control. Patients prescribed higher cumulative doses of ICS may be at greater risk of diabetes progression. TRIAL REGISTRATION: ENCePP ENCEPP/SDPP/6804.

Lean, but not healthy: the 'metabolically obese, normal-weight' phenotype.

PURPOSE OF REVIEW: Obesity is commonly associated with metabolic dysfunction but there are obese persons who are metabolically healthy. On the opposite side of the coin, there are lean persons who carry multiple cardiometabolic risk factors, typically referred to as metabolically obese, normal-weight (MONW). This has called into question our understanding of obesity and metabolic dysfunction, as an appearance of normal weight may mask significant comorbidities and delay health interventions. RECENT FINDINGS: High heterogeneity in MONW prevalence rates has been observed, with estimates ranging from as low as 5% to as high as 45%. Reasons for this include sample size effects, differences in MONW definition, social and demographic factors, as well as assumptions made in establishing normal weight. MONW study participants are often characterized by excess visceral adipose tissue and ectopic fat deposition, adipose tissue inflammation, altered inflammatory and adipokine profiles, reduced skeletal muscle mass and low cardiorespiratory fitness. However, more often than not, groups of MONW study participants have been somewhat 'fatter' than the control groups of metabolically healthy lean study participants, which in itself could be responsible for some of the observed differences. Very limited data are available regarding interventions to improve metabolic function in MONW study participants. SUMMARY: There is a need for more research to better understand the characteristics of the MONW phenotype, the cause of metabolic dysfunction in the absence of obesity, and evaluate potential therapies so as to facilitate the establishment of clinical guidelines.

Interleukin-1ß mediates macrophage-induced impairment of insulin signaling in human primary adipocytes.

Adipose tissue expansion during obesity is associated with increased macrophage infiltration. Macrophage-derived factors significantly alter adipocyte function, inducing inflammatory responses and decreasing insulin sensitivity. Identification of the major factors that mediate detrimental effects of macrophages on adipocytes may offer potential therapeutic targets. IL-1ß, a proinflammatory cytokine, is suggested to be involved in the development of insulin resistance. This study investigated the role of IL-1ß in macrophage-adipocyte cross-talk, which affects insulin signaling in human adipocytes. Using macrophage-conditioned (MC) medium and human primary adipocytes, we examined the effect of IL-1ß antagonism on the insulin signaling pathway. Gene expression profile and protein abundance of insulin signaling molecules were determined, as was the production of proinflammatory cytokine/chemokines. We also examined whether IL-1ß mediates MC medium-induced alteration in adipocyte lipid storage. MC medium and IL-1ß significantly reduced gene expression and protein abundance of insulin signaling molecules, including insulin receptor substrate-1, phosphoinositide 3-kinase p85α, and glucose transporter 4 and phosphorylation of Akt. In contrast, the expression and release of the proinflammatory markers, including IL-6, IL-8, monocyte chemotactic protein-1, and chemokine (C-C motif) ligand 5 by adipocytes were markedly increased. These changes were significantly reduced by blocking IL-1ß activity, its receptor binding, or its production by macrophages. MC medium-inhibited expression of the adipogenic factors and -stimulated lipolysis was also blunted with IL-1ß neutralization. We conclude that IL-1ß mediates, at least in part, the effect of macrophages on insulin signaling and proinflammatory response in human adipocytes. Blocking IL-1ß could be beneficial for preventing obesity-associated insulin resistance and inflammation in human adipose tissue.

Circulating anti-inflammatory adipokines High Molecular Weight Adiponectin and Zinc-α2-glycoprotein (ZAG) are inhibited in early sepsis, but increase with clinical recovery: a pilot study.

BACKGROUND: Adipose tissue has been identified as an endocrine organ secreting adipokines involved in metabolic and inflammatory pathways. Adiponectin, an anti-inflammatory adipokine, is reduced in sepsis. High Molecular Weight (HMW) adiponectin, the biologically most relevant molecule, has been investigated very little in human sepsis. Zinc-alpha2-glycoprotein (ZAG) is a novel adipokine and its expression in adipose tissue is positively correlated with adiponectin expression. It is not yet known whether ZAG has a role in sepsis. In this study we assessed levels of HMW adiponectin and ZAG during different stages of sepsis. METHODS: A prospective observational pilot study was carried out on 21 septic patients. Serum samples were taken on day 1 and 2 post ICU admission and on day of discharge. Samples were analysed for total and HMW adiponectin, HMW/total adiponectin ratio, and ZAG. Results were correlated with clinical and metabolic data. RESULTS: There were no differences in total adiponectin, HMW adiponectin and ZAG plasma concentrations between day 1 (admission) and day 2 of the sepsis episode. Compared to admission, a significant increase in total and HMW adiponectin and ZAG was observed on the day of discharge when clinical improvement had been achieved. There was also an increase in the HMW/total adiponectin ratio at that time. CONCLUSIONS: Our data demonstrate an increase in both HMW adiponectin and total adiponectin in patients who had clinically recovered from sepsis. The increase in HMW/total adiponectin ratio with improvement of the clinical condition suggests that HMW adiponectin may have a greater role in the inflammatory process and insulin resistance seen in sepsis. In this pilot study, we have also demonstrated a significant increase in ZAG in critically ill patients temporally related to recovery from sepsis.

1,25-dihydroxyvitamin D3 protects against macrophage-induced activation of NFκB and MAPK signalling and chemokine release in human adipocytes.

Increased accumulation of macrophages in adipose tissue in obesity is linked to low-grade chronic inflammation, and associated with features of metabolic syndrome. Vitamin D3 may have immunoregulatory effects and reduce adipose tissue inflammation, although the molecular mechanisms remain to be established. This study investigated the effects of vitamin D3 on macrophage-elicited inflammatory responses in cultured human adipocytes, particularly the signalling pathways involved. Macrophage-conditioned (MC) medium (25% with adipocyte maintenance media) markedly inhibited protein expression of the nuclear factor-κB (NFκB) subunit inhibitor κBα (IκBα) (71%, P<0.001) and increased NFκB p65 (1.5-fold, P = 0.026) compared with controls. Treatment with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) abolished macrophage-induced activation of NFκB signalling by increasing IκBα expression (2.7-fold, P = 0.005) and reducing NFκB p65 phosphorylation (68%; P<0.001). The mitogen-activated protein kinase (MAPK) signalling was activated by MC medium, which was also blunted by 1,25(OH)2D3 with a downregulation of phosphorylated p38 MAPK (32%, P = 0.005) and phosphorylated Erk1/2 (49%, P = 0.001). Furthermore, MC medium (12.5% or 25%) dose-dependently upregulated secretion of key proinflammatory chemokines/cytokines (22-368-fold; all P<0.001) and this was significantly decreased by 1,25(OH)2D3: IL-8 (61% and 31%, P<0.001), MCP-1 (37%, P<0.001 and 36%, P = 0.002), RANTES (78% and 62%, P<0.001) and IL-6 (29%, P<0.001 and 34%, P = 0.019). Monocyte migration-elicited by adipocytes treated with 1,25(OH)2D3 was also reduced (up to 25%, P<0.001). In conclusion, vitamin D3 could be anti-inflammatory in adipose tissue, decreasing macrophage-induced release of chemokines and cytokines by adipocytes and the chemotaxis of monocytes. Our data suggests these effects are mediated by inhibition of the NFκB and MAPK signalling pathways.

Vitamin D signalling in adipose tissue.

Vitamin D deficiency and the rapid increase in the prevalence of obesity are both considered important public health issues. The classical role of vitamin D is in Ca homoeostasis and bone metabolism. Growing evidence suggests that the vitamin D system has a range of physiological functions, with vitamin D deficiency contributing to the pathogenesis of several major diseases, including obesity and the metabolic syndrome. Clinical studies have shown that obese individuals tend to have a low vitamin D status, which may link to the dysregulation of white adipose tissue. Recent studies suggest that adipose tissue may be a direct target of vitamin D. The expression of both the vitamin D receptor and 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1) genes has been shown in murine and human adipocytes. There is evidence that vitamin D affects body fat mass by inhibiting adipogenic transcription factors and lipid accumulation during adipocyte differentiation. Some recent studies demonstrate that vitamin D metabolites also influence adipokine production and the inflammatory response in adipose tissue. Therefore, vitamin D deficiency may compromise the normal metabolic functioning of adipose tissue. Given the importance of the tissue in energy balance, lipid metabolism and inflammation in obesity, understanding the mechanisms of vitamin D action in adipocytes may have a significant impact on the maintenance of metabolic health. In the present review, we focus on the signalling role of vitamin D in adipocytes, particularly the potential mechanisms through which vitamin D may influence adipose tissue development and function.