Adrenocortical dysfunction in obesity and the metabolic syndrome.

Recently, it has become evident that the adrenals play a key role in obesity as well as in the metabolic syndrome and their complications. On the one hand, adrenal steroids are involved in physiological regulation of adipose tissue and energy homeostasis and in the pathogenesis of cardiometabolic complications. On the other hand, fat cell-derived factors, adipocytokines, and lipids released from adipose tissue are involved in the modulation of adrenal steroidogenesis. Aldosterone plasma levels are elevated in obesity and in patients with the metabolic syndrome. Recent research has provided evidence that adipocytes secrete factors that stimulate adrenal mineralocorticoid release and sensitize the adrenal cortex to angiotensin II.     

Chronobiological aspects of obesity and metabolic syndrome

Circadian rhythms (approximately 24h) are widely characterized at molecular level and their generation is acknowledged to originate from oscillations in expression of several clock genes and from regulation of their protein products. While general entrainment of organisms to environmental light-dark cycles is mainly achieved through the master clock of the suprachiasmatic nucleus in mammals, this molecular clockwork is functional in several organs and tissues. Some studies have suggested that disruption of the circadian system (chronodisruption (CD)) may be causal for manifestations of the metabolic syndrome. This review summarizes (1) how molecular clocks coordinate metabolism and their specific role in the adipocyte; (2) the genetic aspects of and scientific evidence for obesity as a chronobiological illness; and (3) CD and its causes and pathological consequences. Finally, ideas about use of chronobiology for the treatment of obesity are discussed.     

Particular characteristics of the metabolic syndrome in patients with morbid obesity

BackgroundCriteria for the diagnosis of the metabolic syndrome are currently being reconsidered, as their usefulness is not the same for all phenotypes in relation to the risk of cardiovascular disease.AimWe analyzed the changes in metabolic parameters after a fat overload in different groups of patients.Materials and methodsThe study included 20 healthy persons, 30 metabolic syndrome patients without morbid obesity, 80 metabolic syndrome patients with morbid obesity and 16 patients with morbid obesity without the metabolic syndrome. All the participants received a fat overload of 60 g. Measurements were made before the overload and 3 h afterwards of triglycerides, free fatty acids, insulin and uric acid.ResultsMetabolic syndrome patients with morbid obesity had a lower waist-to-hip ratio, and lower plasma free fatty acid and triglycerides levels at baseline and after the overload than patients without morbid obesity. Plasma uric acid levels rose after the fat overload in the metabolic syndrome patients who had morbid obesity but not in the patients without morbid obesity. A positive relation was found between plasma triglycerides and free fatty acid levels in all the patients but not in the controls after the fat overload. A positive relation was also found between uric acid and insulin levels in the metabolic syndrome patients with morbid obesity.ConclusionsMetabolic syndrome patients with and without morbid obesity presented different metabolic characteristics. This suggests that there are 2 different clinical phenotypes, both grouped under the metabolic syndrome umbrella.     

Inflammation, obesity, and the metabolic syndrome.

Adipose tissue expresses cytokines which inhibit insulin signalling pathways. Obesity also results in impairment of endothelium-dependent vasodilatation to insulin. We have previously suggested that adipocytokines might contribute to the coexistence of insulin resistance and endothelial dysfunction. However, the adipocytokine best characterised as causing insulin resistance is tumour necrosis factor-alpha (TNF-alpha), a molecule which under normal circumstances circulates in low concentrations. We propose a vasoregulatory role for local deposits of fat around blood vessels, which may contribute both to insulin action and to vascular endothelial dysfunction. In particular, we propose that the localised fat depot around the origin of skeletal muscle arterioles may play a physiological role in blood flow distribution. Isolated rat arterioles are under dual regulation by insulin, which activates both endothelin-1 mediated vasoconstriction and nitric oxide mediated vasodilatation. In obese rat arterioles, insulin-stimulated nitric oxide synthesis is impaired, resulting in unopposed vasoconstriction. We propose this to be the consequence of production of TNF-alpha from the fat surrounding the vessel origin - a depot to which we ascribe a specialist vasoregulatory role. We suggest that this cytokine accesses the nutritive vascular tree to inhibit insulin-mediated capillary recruitment - a mechanism we term 'vasocrine' signalling. We also suggest a homology between periarteriolar fat and both periarterial and visceral fat, which may, through outside-to-inside signalling, play a direct role in producing the inflammatory changes found in atherosclerotic plaques, so explaining relationships between visceral fat, insulin resistance, and vascular disease.     

Increased prevalence of metabolic syndrome in patients with acne inversa

Background

Acne inversa (AI; also designated as Hidradenitis suppurativa) is a common chronic inflammatory skin disease, localized in the axillary, inguinal and perianal skin areas that causes painful, fistulating sinuses with malodorous purulence and scars. Several chronic inflammatory diseases are associated with the metabolic syndrome and its consequences including arteriosclerosis, coronary heart disease, myocardial infraction, and stroke. So far, the association of AI with systemic metabolic alterations is largely unexplored.

Methods and Findings

A hospital-based case-control study in 80 AI patients and 100 age- and sex-matched control participants was carried out. The prevalence of central obesity (odds ratio 5.88), hypertriglyceridemia (odds ratio 2.24), hypo-HDL-cholesterolemia (odds ratio 4.56), and hyperglycemia (odds ratio 4.09) in AI patients was significantly higher than in controls. Furthermore, the metabolic syndrome, previously defined as the presence of at least three of the five alterations listed above, was more common in those patients compared to controls (40.0% versus 13.0%; odds ratio 4.46, 95% confidence interval 2.02 to 9.96; P<0.001). AI patients with metabolic syndrome also had more pronounced metabolic alterations than controls with metabolic syndrome. Interestingly, there was no correlation between the severity or duration of the disease and the levels of respective parameters or the number of criteria defining the metabolic syndrome. Rather, the metabolic syndrome was observed in a disproportionately high percentage of young AI patients.

Conclusions

This study shows for the first time that AI patients have a high prevalence of the metabolic syndrome and all of its criteria. It further suggests that the inflammation present in AI patients does not have a major impact on the development of metabolic alterations. Instead, evidence is given for a role of metabolic alterations in the development of AI. We recommend monitoring of AI patients in order to correct their modifiable cardiovascular risk factors.     

Hyperuricemia and metabolic syndrome in children with overweight and obesity

ObjectiveTo study the prevalence of hyperuricemia in children with overweight or obesity and analyze the relation with metabolic syndrome and the diseases that define it.Materials and methodsThis is a cross-sectional prevalence study in 148 children recruited from pediatric endocrinology consultation, with overweight or obesity (12 ± 3 years, 48% boys, BMI 31.8 ± 6.1). We measured BMI, waist-height, waist circumference, blood pressure with standard instrumentation and glucose (fasting and after overload with 75 g), insulin resistance, cholesterol HDL, triglycerides and uric acid.ResultsThe prevalence of hyperuricemia was 53%. Patients with hyperuricemia had greater BMI (33.9 vs 30.6, p = 0.003), plus waist circumference (101.4 vs 91.1 cm, p < 0.001), higher blood pressure: systolic (123.4 vs 111.9 mm Hg, p < 0.001), diastolic (78.2 vs 68.7 mm Hg, p < 0.001). They presented greater blood glucose after overload oral glucose (107.5 vs 100.7 mg/dl, p = 0.03), insulin was higher (29.2 vs 20.7 mg/dl, p = 0.001) as well as HOMA IR (6.5 vs 4.4, p < 0.001) and HDL levels were lower (49.5 vs 54.4 mg/dl, p = 0.02).Uric acid's level which most is the likely diagnosis of metabolic syndrome corresponds to 5.4 mg/dl in our sample (sensitivity: 64% and specificity 62%).ConclusionThe prevalence of hyperuricemia in children with overweight and obesity is high. In the group of patients with obesity and hyperuricemia, we found out that the parameters measured to diagnose with metabolic syndrome were less favorable. Uric acid's level from where there is a higher possibility to see metabolic syndrome is 5.4 mg/dl.     

Metabolic programming: fetal origins of obesity and metabolic syndrome in the adult

Exposure of the fetus to the intrauterine milieu can have profound effects on the health of the offspring in adulthood. Results of a series of studies demonstrate the powerful influence of the mother's metabolic state on whether the emerging adult develops obesity and hyperinsulinemia. Importantly, these attributes can be passed on to the next generation nongenetically and can be reversed and prevented.     

Methylation of SOCS3 is inversely associated with metabolic syndrome in an epigenome-wide association study of obesity

Epigenetic mechanisms, including DNA methylation, mediate the interaction between gene and environment and may play an important role in the obesity epidemic. We assessed the relationship between DNA methylation and obesity in peripheral blood mononuclear cells (PBMCs) at 485,000 CpG sites across the genome in family members (8-90 y of age) using a discovery cohort (192 individuals) and a validation cohort (1,052 individuals) of Northern European ancestry. After Bonferroni-correction (P_α=0.05 = 1.31 × 10^?7) for genome-wide significance, we identified 3 loci, cg18181703 (SOCS3), cg04502490 (ZNF771), and cg02988947 (LIMD2), where methylation status was associated with body mass index percentile (BMI%), a clinical index for obesity in children, adolescents, and adults. These sites were also associated with multiple metabolic syndrome (MetS) traits, including central obesity, fat depots, insulin responsiveness, and plasma lipids. The SOCS3 methylation locus was also associated with the clinical definition of MetS. In the validation cohort, SOCS3 methylation status was found to be inversely associated with BMI% (P = 1.75 × 10^?6), waist to height ratio (P = 4.18 × 10^?7), triglycerides (P = 4.01 × 10^?4), and MetS (P = 4.01 × 10^?7), and positively correlated with HDL-c (P = 4.57 × 10^?8). Functional analysis in a sub cohort (333 individuals) demonstrated SOCS3 methylation and gene expression in PBMCs were inversely correlated (P = 2.93 × 10^?4) and expression of SOCS3 was positively correlated with status of MetS (P = 0.012). We conclude that epigenetic modulation of SOCS3, a gene involved in leptin and insulin signaling, may play an important role in obesity and MetS.     

A pilot study on the prevalence of maternal obesity in selected Greek counties

ObjectiveTo report a pilot prevalence of maternal overweight, obesity and underweight in selected Greek counties.MethodsA total of 441 adult childbearing women were recruited from maternity clinics in 6 Greek counties for this cross-sectional study. Pre-gravid weight status was defined according to the WHO cut-offs and gravid weight status was diagnosed with the Mardones and Rosso weight gain chart.ResultsDuring gestation the majority of the participants were of normal body weight (BW) (34.0%), obesity was apparent in 25.6% of the sample, 23.8% of the participants were underweight, and the remaining 16.6% were overweight. Overall, pregnancy tripled the prevalence of underweight, increased the prevalence of obesity (by 388.0%) and decreased the number of participants in the normal BW category (p ≤ 0.001 for all). The majority of participants classified in each pre-gravid weight-category remained in the same weight category during their gestation. All the pre-gravidly obese women were also obese during pregnancy. Underweight was more prevalent in Kavala (37.5%) and obesity was more frequent in Thessaloniki (30.8%). Women who were overweight prior to conception were highly likely to be overweight/obese during pregnancy (OR: 23.8, CI: 11.1–51.0).ConclusionsThe results indicate a high prevalence of overweight, obesity and underweight among pregnant women in Greece.     

The association of lipoprotein lipase PvuII polymorphism and niacin intake in the prevalence of metabolic syndrome: a KMSRI-Seoul study

Lipoprotein lipase (LPL) polymorphism correlated with LPL activity is associated with plasma lipid and lipoprotein levels. We aimed to investigate the frequency of LPL PvuII polymorphism and effects of LPL PvuII polymorphism and niacin intake on the prevalence of metabolic syndrome (MetSyn) in Koreans. Lifestyle questionnaires, anthropometry, and dietary records were completed, and LPL PvuII polymorphism, LPL mass, and lipid profiles were determined in 548 Koreans (MetSyn: 278, Non-MetSyn: 270). The MetSyn group showed a significantly lower frequency of P1P1 (wild type) and a higher frequency of P1P2 (hetero type) than the non-MetSyn group. The P2P2 (mutant type) group significantly showed lower levels of HDLc and LPL mass and a higher level of TG than the P1P1 group. As niacin intake increased, LPL mass decreased in the P2P2 group (r ² = 0.07). In particular, the lowest niacin intake group (≤14.82 mg/day) increased more than 3 times with regard to a higher risk of MetSyn than the others in the P2P2 mutant groups. However, the MetSyn risk declined 74% at the optimal levels of niacin intake (14.83–17.80 mg/day) in the P2P2 group compared to those of the P1 allele group. The findings indicate that optimal levels of niacin intake effectively decreased Korean MetSyn prevalence in the P2P2 mutant group.     

Seasonal changes in mood and behavior are linked to metabolic syndrome

Background

Obesity is a major public health problem worldwide. Metabolic syndrome is a risk factor to the cardiovascular diseases. It has been reported that disruptions of the circadian clockwork are associated with and may predispose to metabolic syndrome.

Methodology and Principal Findings

8028 individuals attended a nationwide health examination survey in Finland. Data were collected with a face-to-face interview at home and during an individual health status examination. The waist circumference, height, weight and blood pressure were measured and samples were taken for laboratory tests. Participants were assessed using the ATP-III criteria for metabolic syndrome and with the Seasonal Pattern Assessment Questionnaire for their seasonal changes in mood and behavior. Seasonal changes in weight in particular were a risk factor of metabolic syndrome, after controlling for a number of known risk and potential confounding factors.

Conclusions and Significance

Metabolic syndrome is associated with high global scores on the seasonal changes in mood and behavior, and with those in weight in particular. Assessment of these changes may serve as a useful indicator of metabolic syndrome, because of easy assessment. Abnormalities in the circadian clockwork which links seasonal fluctuations to metabolic cycles may predispose to seasonal changes in weight and to metabolic syndrome.     

Monitoring and prevalence rates of metabolic syndrome in military veterans with serious mental illness

Background

Cardiovascular disease is the leading cause of mortality among patients with serious mental illness (SMI) and the prevalence of metabolic syndrome—a constellation of cardiovascular risk factors—is significantly higher in these patients than in the general population. Metabolic monitoring among patients using second generation antipsychotics (SGAs)—a risk factor for metabolic syndrome—has been shown to be inadequate despite the release of several guidelines. However, patients with SMI have several factors independent of medication use that predispose them to a higher prevalence of metabolic syndrome. Our study therefore examines monitoring and prevalence of metabolic syndrome in patients with SMI, including those not using SGAs.

Methods and Findings

We retrospectively identified all patients treated at a Veterans Affairs Medical Center with diagnoses of schizophrenia, schizoaffective disorder or bipolar disorder during 2005–2006 and obtained demographic and clinical data. Incomplete monitoring of metabolic syndrome was defined as being unable to determine the status of at least one of the syndrome components. Of the 1,401 patients included (bipolar disorder: 822; schizophrenia: 222; and schizoaffective disorder: 357), 21.4% were incompletely monitored. Only 54.8% of patients who were not prescribed SGAs and did not have previous diagnoses of hypertension or hypercholesterolemia were monitored for all metabolic syndrome components compared to 92.4% of patients who had all three of these characteristics. Among patients monitored for metabolic syndrome completely, age-adjusted prevalence of the syndrome was 48.4%, with no significant difference between the three psychiatric groups.

Conclusions

Only one half of patients with SMI not using SGAs or previously diagnosed with hypertension and hypercholesterolemia were completely monitored for metabolic syndrome components compared to greater than 90% of those with these characteristics. With the high prevalence of metabolic syndrome seen in this population, there appears to be a need to intensify efforts to reduce this monitoring gap.     

Use of methotrexate therapy is not associated with decreased prevalence of metabolic syndrome

With great interest, we read the article by Toms and colleagues [1] in the previous issue of Arthritis Research & Therapy, in which they assessed prevalences of metabolic syndrome (MetS) in rheumatoid arthritis (RA) patients. Moreover, they identified demographic and clinical factors that may be associated with MetS. Toms and colleagues found prevalences of up to 45% of MetS and demonstrated older age and health status (health assessment questionnaire) to be associated with MetS irrespectively of the definition used. Of most interest, an association between methotrexate (MTX) use and decreased presence of MetS was observed in patients more than 60 years of age. The investigators hypothesized that this may be attributed to a drug-specific effect (and not to an anti-inflammatory effect) either by changing levels of adenosine, which is known to interact with glucose and lipid metabolism, or by an indirect effect mediated through concomitant folic acid administration, thereby decreasing homocysteine levels.Recently, we also examined the prevalence of MetS in (a subgroup of) RA patients in the CARRÉ investigation, a prospective cohort study on prevalent and incident cardiovascular disease and its underlying cardiovascular risk factors [2]. The findings of Toms and colleagues stimulated us to perform additional analyses in our total study population (n = 353).The prevalences of MetS were 35% and 25% (Table ​(Table1)1) according to criteria of National Cholesterol Education Program (NCEP) 2004 and NCEP 2001, respectively. In multivariate backward regression analyses, we found significant associations between body mass index, pulse rate, creatinine levels, hypothyroidism and diabetes mellitus and the presence of MetS independently of the criteria used (Table ​(Table2).2). However, an independent association between single use of MTX or use of MTX in combination with other disease-modifying antirheumatic drugs, on the one hand, and a decreased prevalence of MetS, on the other hand, could not be demonstrated (even in the subgroup of patients over the age of 60).

Table 1

Characteristics of the study population

Pathogenesis of insulin resistance in metabolic obesity

This review considers molecular mechanisms of insulin resistance developed under conditions of metabolic inflammation; special attention is paid to analysis of the results of experimental and clinical studies work aimed at identifying molecular targets for the development of new methods for prevention and treatment of insulin resistance.