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Individuals with depression have an elevated risk of cardiovascular disease (CVD) and metabolic syndrome (MetS) is an important risk factor for CVD. We aimed to clarify the prevalence and correlates of MetS in persons with robustly defined major depressive disorder (MDD). We searched Medline, PsycINFO, EMBASE and CINAHL up until June 2013 for studies reporting MetS prevalences in individuals with MDD. Medical subject headings 'metabolic' OR 'diabetes' or 'cardiovascular' or 'blood pressure' or 'glucose' or 'lipid' AND 'depression' OR 'depressive' were used in the title, abstract or index term fields. Manual searches were conducted using reference lists from identified articles. The initial electronic database search resulted in 91 valid hits. From candidate publications following exclusions, our search generated 18 studies with interview-defined depression (n = 5531, 38.9% male, mean age = 45.5 years). The overall proportion with MetS was 30.5% [95% confidence interval (CI) 26.3-35.1] using any standardized MetS criteria. Compared with age- and gender-matched control groups, individuals with MDD had a higher MetS prevalence [odds ratio (OR) 1.54, 95% CI 1.21-1.97, p = 0.001]. They also had a higher risk for hyperglycemia (OR 1.33, 95% CI 1.03-1.73, p = 0.03) and hypertriglyceridemia (OR 1.17, 95% CI 1.04-1.30, p = 0.008). Antipsychotic use (p < 0.05) significantly explained higher MetS prevalence estimates in MDD. Differences in MetS prevalences were not moderated by age, gender, geographical area, smoking, antidepressant use, presence of psychiatric co-morbidity, and median year of data collection. The present findings strongly indicate that persons with MDD are a high-risk group for MetS and related cardiovascular morbidity and mortality. MetS risk may be highest in those prescribed antipsychotics.

INTRODUCTION AND OBJECTIVES: An obese-type human microbiota with an increased Firmicutes:Bacteroidetes ratio has been described that may link the gut microbiome with obesity and metabolic syndrome (MetS) development. Dietary fat and carbohydrate are modifiable risk factors that may impact on MetS by altering the human microbiome composition. We determined the effect of the amount and type of dietary fat and carbohydrate on faecal bacteria and short chain fatty acid (SCFA) concentrations in people ‘at risk’ of MetS. DESIGN: A total of 88 subjects at increased MetS risk were fed a high saturated fat diet (HS) for 4 weeks (baseline), then randomised onto one of the five experimental diets for 24 weeks: HS; high monounsaturated fat (MUFA)/high glycemic index (GI) (HM/HGI); high MUFA/low GI (HM/LGI); high carbohydrate (CHO)/high GI (HC/HGI); and high CHO/low GI (HC/LGI). Dietary intakes, MetS biomarkers, faecal bacteriology and SCFA concentrations were monitored. RESULTS: High MUFA diets did not affect individual bacterial population numbers but reduced total bacteria and plasma total and LDL-cholesterol. The low fat, HC diets increased faecal Bifidobacterium ( P =0.005, for HC/HGI; P =0.052, for HC/LGI) and reduced fasting glucose and cholesterol compared to baseline. HC/HGI also increased faecal Bacteroides ( P =0.038), whereas HC/LGI and HS increased Faecalibacterium prausnitzii ( P =0.022 for HC/HGI and P =0.018, for HS). Importantly, changes in faecal Bacteroides numbers correlated inversely with body weight ( r =−0.64). A total bacteria reduction was observed for high fat diets HM/HGI and HM/LGI ( P =0.023 and P =0.005, respectively) and HS increased faecal SCFA concentrations ( P <0.01). CONCLUSION: This study provides new evidence from a large-scale dietary intervention study that HC diets, irrespective of GI, can modulate human faecal saccharolytic bacteria, including bacteroides and bifidobacteria. Conversely, high fat diets reduced bacterial numbers, and in the HS diet, increased excretion of SCFA, which may suggest a compensatory mechanism to eliminate excess dietary energy.

Metabolic syndrome is a group of obesity-related metabolic abnormalities that increase an individual's risk of developing type 2 diabetes and cardiovascular disease. Here, we show that mice genetically deficient in Toll-like receptor 5 (TLR5), a component of the innate immune system that is expressed in the gut mucosa and that helps defend against infection, exhibit hyperphagia and develop hallmark features of metabolic syndrome, including hyperlipidemia, hypertension, insulin resistance, and increased adiposity. These metabolic changes correlated with changes in the composition of the gut microbiota, and transfer of the gut microbiota from TLR5-deficient mice to wild-type germ-free mice conferred many features of metabolic syndrome to the recipients. Food restriction prevented obesity, but not insulin resistance, in the TLR5-deficient mice. These results support the emerging view that the gut microbiota contributes to metabolic disease and suggest that malfunction of the innate immune system may promote the development of metabolic syndrome.

The insulin receptor substrate proteins IRS1 and IRS2 are key targets of the insulin receptor tyrosine kinase and are required for hormonal control of metabolism. Tissues from insulin-resistant and diabetic humans exhibit defects in IRS-dependent signalling, implicating their dysregulation in the initiation and progression of metabolic disease. However, IRS1 and IRS2 are regulated through a complex mechanism involving phosphorylation of >50 serine/threonine residues (S/T) within their long, unstructured tail regions. In cultured cells, insulin-stimulated kinases (including atypical PKC, AKT, SIK2, mTOR, S6K1, ERK1/2 and ROCK1) mediate feedback (autologous) S/T phosphorylation of IRS, with both positive and negative effects on insulin sensitivity. Additionally, insulin-independent (heterologous) kinases can phosphorylate IRS1/2 under basal conditions (AMPK, GSK3) or in response to sympathetic activation and lipid/inflammatory mediators, which are present at elevated levels in metabolic disease (GRK2, novel and conventional PKCs, JNK, IKKβ, mPLK). An emerging view is that the positive/negative regulation of IRS by autologous pathways is subverted/co-opted in disease by increased basal and other temporally inappropriate S/T phosphorylation. Compensatory hyperinsulinaemia may contribute strongly to this dysregulation. Here, we examine the links between altered patterns of IRS S/T phosphorylation and the emergence of insulin resistance and diabetes.

Hereditary porphyrias are a group of eight metabolic disorders of the haem biosynthesis pathway that are characterised by acute neurovisceral symptoms, skin lesions, or both. Every porphyria is caused by abnormal function of a separate enzymatic step, resulting in a specific accumulation of haem precursors. Seven porphyrias are the result of a partial enzyme deficiency, and a gain of function mechanism has been characterised in a new porphyria. Acute porphyrias present with acute attacks, typically consisting of severe abdominal pain, nausea, constipation, confusion, and seizure, and can be life-threatening. Cutaneous porphyrias present with either acute painful photosensitivity or skin fragility and blisters. Rare recessive porphyrias usually manifest in early childhood with either severe cutaneous photosensitivity and chronic haemolysis or chronic neurological symptoms with or without photosensitivity. Porphyrias are still underdiagnosed, but when they are suspected, and dependent on clinical presentation, simple first-line tests can be used to establish the diagnosis in all symptomatic patients. Diagnosis is essential to enable specific treatments to be started as soon as possible. Screening of families to identify presymptomatic carriers is crucial to decrease risk of overt disease of acute porphyrias through counselling about avoidance of potential precipitants.

Hyperuricemia is strongly associated with obesity and metabolic syndrome and can predict visceral obesity and insulin resistance. Previously, we showed that soluble uric acid directly stimulated the redox-dependent proinflammatory signaling in adipocytes. In this study we demonstrate the role of hyperuricemia in the production of key adipokines. We used mouse 3T3-L1 adipocytes, human primary adipocytes, and a mouse model of metabolic syndrome and hyperuricemia. Uric acid induced in vitro an increase in the production (mRNA and secreted protein) of monocyte chemotactic protein-1 (MCP-1), an adipokine playing an essential role in inducing the proinflammatory state in adipocytes in obesity. In addition, uric acid caused a decrease in the production of adiponectin, an adipocyte-specific insulin sensitizer and anti-inflammatory agent. Uric acid-induced increase in MCP-1 production was blocked by scavenging superoxide or by inhibiting NADPH oxidase and by stimulating peroxisome-proliferator-activated receptor-γ with rosiglitazone. Downregulation of the adiponectin production was prevented by rosiglitazone but not by antioxidants. In obese mice with metabolic syndrome, we observed hyperuricemia. Lowering uric acid in these mice by inhibiting xanthine oxidoreductase with allopurinol could improve the proinflammatory endocrine imbalance in the adipose tissue by reducing production of MCP-1 and increasing production of adiponectin. In addition, lowering uric acid in obese mice decreased macrophage infiltration in the adipose tissue and reduced insulin resistance. Hyperuricemia might be partially responsible for the proinflammatory endocrine imbalance in the adipose tissue, which is an underlying mechanism of the low-grade inflammation and insulin resistance in subjects with the metabolic syndrome.

Despite increased cardiometabolic risk in individuals with mental illness taking antipsychotic medication, metabolic screening practices are often incomplete or inconsistent. We undertook a systematic search and a PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) meta-analysis of studies examining routine metabolic screening practices in those taking antipsychotics both for patients in psychiatric care before and following implementation of monitoring guidelines. We identified 48 studies (n=290 534) conducted between 2000 and 2011 in five countries; 25 studies examined predominantly schizophrenia-spectrum disorder populations; 39 studies (n=218 940) examined routine monitoring prior to explicit guidelines; and nine studies (n=71 594) reported post-guideline monitoring. Across 39 studies, routine baseline screening was generally low and above 50% only for blood pressure [69.8%, 95% confidence interval (CI) 50.9-85.8] and triglycerides (59.9%, 95% CI 36.6-81.1). Cholesterol was measured in 41.5% (95% CI 18.0-67.3), glucose in 44.3% (95% CI 36.3-52.4) and weight in 47.9% (95% CI 32.4-63.7). Lipids and glycosylated haemoglobin (HbA1c) were monitored in less than 25%. Rates were similar for schizophrenia patients, in US and UK studies, for in-patients and out-patients. Monitoring was non-significantly higher in case-record versus database studies and in fasting samples. Following local/national guideline implementation, monitoring improved for weight (75.9%, CI 37.3-98.7), blood pressure (75.2%, 95% CI 45.6-95.5), glucose (56.1%, 95% CI 43.4-68.3) and lipids (28.9%, 95% CI 20.3-38.4). Direct head-to-head pre-post-guideline comparison showed a modest but significant (15.4%) increase in glucose testing (p=0.0045). In routine clinical practice, metabolic monitoring is concerningly low in people prescribed antipsychotic medication. Although guidelines can increase monitoring, most patients still do not receive adequate testing.

The intracellular storage and utilization of lipids are critical to maintain cellular energy homeostasis. During nutrient deprivation, cellular lipids stored as triglycerides in lipid droplets are hydrolysed into fatty acids for energy. A second cellular response to starvation is the induction of autophagy, which delivers intracellular proteins and organelles sequestered in double-membrane vesicles (autophagosomes) to lysosomes for degradation and use as an energy source. Lipolysis and autophagy share similarities in regulation and function but are not known to be interrelated. Here we show a previously unknown function for autophagy in regulating intracellular lipid stores (macrolipophagy). Lipid droplets and autophagic components associated during nutrient deprivation, and inhibition of autophagy in cultured hepatocytes and mouse liver increased triglyceride storage in lipid droplets. This study identifies a critical function for autophagy in lipid metabolism that could have important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome. Lipid droplets and autophagy Lipid droplets are cytoplasmic organelles that store lipids such as triglycerides and cholesterol. Under conditions of nutrient deprivation, droplet triglycerides are hydrolysed to generate free fatty acids that are oxidized to provide energy. A second cellular response to starvation is autophagy, in which the cell digests its own components to provide nutrients. Singh et al . describe a novel function for autophagy in regulating lipid metabolism, which they term 'macrolipophagy'. In this process, lipid droplets and autophagic components associate during starvation and inhibition of autophagy increases lipid storage in lipid droplets. Autophagy promotes lipid hydrolysis and generation of free fatty acids by releasing the content of lipid droplets to lysosomes for degradation. This work identifies a critical role of autophagy in regulating lipid metabolism and may provide a new approach to the prevention of lipid accumulation in disease. Description of a novel function for autophagy in regulating lipid metabolism, called 'macrolipophagy', in which lipid droplets and autophagic components associate during starvation and inhibition of autophagy increases lipid storage in lipid droplets. A critical role of autophagy in regulating lipid metabolism is identified, and may provide a new approach to prevent lipid accumulation in disease.

Obesity has complex multifactorial aetiology. It has been suggested by many, but not all, reports that earlier pubertal maturation may increase adult obesity risk. We conducted a systemic review and meta-analysis in both women and men, and hypothesised that any association between pubertal timing and adult obesity is likely to be confounded by childhood adiposity. In addition, we investigated whether pubertal timing is related to other cardiometabolic risk and long-term cardiovascular morbidity/mortality. Literature search was undertaken using MEDLINE, EMBASE, Web of Knowledge and TRIP databases, with a hand search of references. Both authors independently reviewed and extracted pre-defined data from all selected papers. Meta-analyses were conducted using Review Manager (RevMan) 5.0.24. A total of 48 papers were identified. Out of 34 studies, 30 reported an inverse relationship between pubertal timing and adult body mass index (BMI), the main adiposity measure used. Meta-analysis of 10 cohorts showed association between early menarche (menarche <12 vs ⩾12 years) and increased adult BMI, with a standardised mean difference of 0.34 kg m −2 (95% confidence interval: 0.33–0.34). Heterogeneity was large ( I 2 =92%) but reduced significantly when grouped by outcome age. Late menarche (menarche ⩾15 vs <15 years) was associated with decreased adult BMI, with a standardised mean difference of −0.26 kg m −2 (95% confidence interval: −0.36, −0.21) (seven cohorts). Only eight papers included data on childhood BMI; the majority reported that childhood BMI only partially attenuated association between early menarche and later obesity. Although not suitable for meta-analysis, data on cardiometabolic risk factors and puberty suggested negative association between earlier pubertal timing and cardiovascular mortality, hypertension, metabolic syndrome (MetS) and abnormal glycaemia. Earlier pubertal timing is predictive of higher adult BMI and greater risk of obesity. This effect appears to be partially independent of childhood BMI. Earlier pubertal development appears to also be inversely correlated with risk of other cardiometabolic risk factors and cardiovascular mortality. Further work is needed to examine potential mechanisms and the level at which interventions may be targeted.

Background: While many studies have demonstrated positive associations between childhood obesity and adult metabolic risk, important questions remain as to the nature of the relationship. In particular, it is unclear whether the associations reflect the tracking of body mass index (BMI) from childhood to adulthood or an independent level of risk. This systematic review aimed to investigate the relationship between childhood obesity and a range of metabolic risk factors during adult life. Objective: To perform an unbiased systematic review to investigate the association between childhood BMI and risk of developing components of metabolic disease in adulthood, and whether the associations observed are independent of adult BMI. Design: Electronic databases were searched from inception until July 2010 for studies investigating the association between childhood BMI and adult metabolic risk. Two investigators independently reviewed studies for eligibility according to the inclusion/exclusion criteria, extracted the data and assessed study quality using the Newcastle–Ottawa Scale. Results: The search process identified 11 articles that fulfilled the inclusion and exclusion criteria. Although several identified weak positive associations between childhood BMI and adult total cholesterol, low-density lipo protein-cholesterol, triglyceride and insulin concentrations, these associations were ameliorated or inversed when adjusted for adult BMI or body fatness. Of the four papers that considered metabolic syndrome as an end point, none showed evidence of an independent association with childhood obesity. Conclusions: Little evidence was found to support the view that childhood obesity is an independent risk factor for adult blood lipid status, insulin levels, metabolic syndrome or type 2 diabetes. The majority of studies failed to adjust for adult BMI and therefore the associations observed may reflect the tracking of BMI across the lifespan. Interestingly, where adult BMI was adjusted for, the data showed a weak negative association between childhood BMI and metabolic variables, with those at the lower end of the BMI range in childhood, but obese during adulthood at particular risk.