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Background/objectives: Obesity is an important risk factor for the development of diseases such as diabetes mellitus, hypertension, and dyslipidemia; however, a small number of individuals with long-standing obesity do not present with these cardiometabolic diseases. Such individuals are referred to as metabolically healthy obese (MHO) and potentially represent a subgroup of the general population with a protective genetic predisposition to obesity-related diseases. We hypothesized that individuals who were metabolically healthy, but significantly obese (BMI ≥ 35 kg/m 2 ) would represent a highly homogenous subgroup, with which to investigate potential genetic associations to obesity. We further hypothesized that such a cohort may lend itself well to investigate potential genotypes that are protective with respect to the development of cardiometabolic disease., Subjects/methods: In the present study, we implemented this novel selection strategy by screening 892 individuals diagnosed as Class 2 or Class 3 obese and identified 38 who presented no manifestations of cardiometabolic disease. We then assessed these subjects for single-nucleotide polymorphisms (SNPs) that associated with this phenotype., Results: Our analysis identified 89 SNPs that reach statistical significance (p < 1 × 10 -5 ), some of which are associated with genes of biological pathways that influences dietary behavior; others are associated with genes previously linked to obesity and cardiometabolic disease as well as neuroimmune disease. This study, to the best of our knowledge, represents the first genetic screening of a cardiometabolically healthy, but significantly obese population.

Background: Obesity during pregnancy is associated with increased risk of gestational diabetes mellitus (GDM) and other complications. Physical activity is a modifiable lifestyle factor that may help to prevent these complications but many women reduce their physical activity levels during pregnancy. Interventions targeting physical activity in pregnancy are on-going but few identify the underlying behaviour change mechanisms by which the intervention is expected to work. To enhance intervention effectiveness, recent tools in behavioural science such as the Theoretical Domains Framework (TDF) and COM-B model (capability, opportunity, motivation and behaviour) have been employed to understand behaviours for intervention development. Using these behaviour change methods, this study aimed to identify the enablers and barriers to physical activity in overweight and obese pregnant women., Methods: Semi-structured interviews were conducted with a purposive sample of overweight and obese women at different stages of pregnancy attending a public antenatal clinic in a large academic maternity hospital in Cork, Ireland. Interviews were recorded and transcribed into NVivo V.10 software. Data analysis followed the framework approach, drawing on the TDF and the COM-B model., Results: Twenty one themes were identified and these mapped directly on to the COM-B model of behaviour change and ten of the TDF domains. Having the social opportunity to engage in physical activity was identified as an enabler; pregnant women suggested being active was easier when supported by their partners. Knowledge was a commonly reported barrier with women lacking information on safe activities during pregnancy and describing the information received from their midwife as 'limited'. Having the physical capability and physical opportunity to carry out physical activity were also identified as barriers; experiencing pain, a lack of time, having other children, and working prevented women from being active., Conclusion: A wide range of barriers and enablers were identified which influenced women's capability, motivation and opportunity to engage in physical activity with "knowledge" as the most commonly reported barrier. This study is a theoretical starting point in making a 'behavioural diagnoses' and the results will be used to inform the development of an intervention to increase physical activity levels among overweight and obese pregnant women.

Over the past years, we have embarked in a systematic analysis of the effect of obesity or fatty acids on circulating monocytes, microvascular endothelial cells, macrophages, and skeletal muscle cells. With the use of cell culture strategies, we have deconstructed complex physiological systems and then reconstructed "partial equations" to better understand cell-to-cell communication. Through these approaches, we identified that in high saturated fat environments, cell-autonomous proinflammatory pathways are activated in monocytes and endothelial cells, promoting monocyte adhesion and transmigration. We think of this as a paradigm of the conditions promoting immune cell infiltration into tissues during obesity. In concert, it is possible that muscle and adipose tissue secrete immune cell chemoattractants, and indeed, our tissue culture reconstructions reveal that myotubes treated with the saturated fatty acid palmitate, but not the unsaturated fatty acid palmitoleate, release nucleotides that attract monocytes and other compounds that promote proinflammatory classically activated "(M1)-like" polarization in macrophages. In addition, palmitate directly triggers an M1-like macrophage phenotype, and secretions from these activated macrophages confer insulin resistance to target muscle cells. Together, these studies suggest that in pathophysiological conditions of excess fat, the muscle, endothelial and immune cells engage in a synergistic crosstalk that exacerbates tissue inflammation, leukocyte infiltration, polarization, and consequent insulin resistance., (Copyright © 2017 the American Physiological Society.)

Obesity is associated with metabolic tissue infiltration by monocyte-derived macrophages. Saturated fatty acids contribute to proinflammatory gene induction in tissue-embedded immune cells. However, it is unknown how circulating monocytes, the macrophage precursors, react to high-fat environments. In macrophages, saturated fatty acids activate inflammatory pathways and, notably, prime caspase-associated inflammasomes. Inflammasome-activated IL-1β contributes to type 2 diabetes. We hypothesized that 1) human monocytes from obese patients show caspase activation, and 2) fatty acids trigger this response and consequent release of IL-1β/IL-18. Human peripheral blood monocytes were sorted by flow cytometry, and caspase activity was measured with a FLICA dye-based assay. Blood monocytes from obese individuals exhibited elevated caspase activity. To explore the nature and consequence of this activity, human THP1 monocytes were exposed to saturated or unsaturated fatty acids. Caspase activity was revealed by isoform-specific cleavage and enzymatic activity; cytokine expression/release was measured by qPCR and ELISA. Palmitate, but not palmitoleate, increased caspase activity in parallel to the release of IL-1β and IL-18. Palmitate induced eventual monocyte cell death with features of pyroptosis (an inflammation-linked cell death program involving caspase-4/5), scored through LDH release, vital dye influx, cell volume changes, and nuclear morphology. Notably, selective gene silencing or inhibition of caspase-4/5 reduced palmitate-induced release of IL-1β and IL-18. In summary, monocytes from obese individuals present elevated caspase activity. Mechanistically, palmitate activates a pyroptotic program in monocytes through caspase-4/5, causing inflammatory cytokine release, additional to inflammasomes. These caspases represent potential, novel, therapeutic targets to taper obesity-associated inflammation., (Copyright © 2016 the American Physiological Society.)

Background: Obesity has been associated with increased risk of antenatal depression, but little is known about this relationship. This study tested whether socio-economic status (SES) influences the relationship between obesity and antenatal depression., Methods: Data were taken from the Screening for Pregnancy Endpoints (SCOPE) cohort. BMI was calculated from measured height and weight at 15±1 weeks' gestation. Underweight women were excluded. SES was indicated by self-reported household income (dichotomised around the median: low SES ≤£45,000; high SES >£45,000). Antenatal depression was defined as scoring ≥13 on the Edinburgh Postnatal Depression Scale at both 15±1 and 20±1 weeks' gestation, to identify persistently elevated symptoms of depression., Results: Five thousand five hundred and twenty two women were included in these analyses and 5.5% had persistently elevated antenatal depression symptoms. There was a significant interaction between SES and BMI on the risk of antenatal depression (p=0.042). Among high SES women, obese women had approximately double the odds of antenatal depression than normal weight controls (AOR 2.11, 95%CI 1.16-3.83, p=0.014, adjusted for confounders). Among low SES women there was no association between obesity and antenatal depression. The interaction effect was robust to alternative indicators of SES in sensitivity analyses., Limitations: 1) Antenatal depression was assessed with a self-reported screening measure; and 2) potential mediators such as stigma and poor body-image could not be examined., Conclusions: Obesity was only associated with increased risk of antenatal depression among high SES women in this sample. Healthcare professionals should be aware that antenatal depression is more common among low SES women, regardless of BMI category., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Background/objectives: To conduct an analysis of associations between eating behaviours and weight status in 2-year-old children., Subjects/methods: Data were collected prospectively in the maternal-infant dyad Cork BASELINE Birth Cohort Study. The weight status of children aged 2 years (n=1189) was assigned using the International Obesity Task Force BMI cutoffs using measured heights and weights. Eating behaviours were assessed using the Children's Eating Behaviour Questionnaire (CEBQ)., Results: Eighty percent of children were of normal weight, 14% were overweight or obese and 6% were underweight. From the CEBQ, food approach behaviours including Enjoyment of Food (odds ratio (OR)=1.90, 95% confidence interval (CI)=1.46-2.48) and Food Responsiveness (OR=1.73, 95% CI=1.47-2.03) were associated with overweight/obesity (all P<0.001). The food avoidant behaviours of Satiety Responsiveness (OR=2.03, 95% CI=1.38-2.98) and Slowness in Eating (OR=1.44, 95% CI=1.01-2.04) were associated with underweight at 2 years (all P<0.05)., Conclusions: Eating behaviours are associated with weight status as early as 2 years of age.

A rise in tissue-embedded macrophages displaying "M1-like" proinflammatory polarization is a hallmark of metabolic inflammation during a high fat diet or obesity. Here we show that bone marrow-derived macrophages (BMDM) from high fat-fed mice retain a memory of their dietary environment in vivo (displaying the elevated proinflammatory genes Cxcl1, Il6, Tnf, Nos2) despite 7-day differentiation and proliferation ex vivo. Notably, 6-h incubation with palmitoleate (PO) reversed the proinflammatory gene expression and cytokine secretion seen in BMDM from high fat-fed mice. BMDM from low fat-fed mice exposed to palmitate (PA) for 18 h ex vivo also showed elevated expression of proinflammatory genes (Cxcl1, Il6, Tnf, Nos2, and Il12b) associated with M1 polarization. Conversely, PO treatment increased anti-inflammatory genes (Mrc1, Tgfb1, Il10, Mgl2) and oxidative metabolism, characteristic of M2 macrophages. Therefore, saturated and unsaturated fatty acids bring about opposite macrophage polarization states. Coincubation of BMDM with both fatty acids counteracted the PA-induced Nos2 expression in a PO dose-dependent fashion. PO also prevented PA-induced IκBα degradation, RelA nuclear translocation, NO production, and cytokine secretion. Mechanistically, PO exerted its anti-inflammatory function through AMP-activated protein kinase as AMP kinase knockout or inhibition by Compound C offset the PO-dependent prevention of PA-induced inflammation. These results demonstrate a nutritional memory of BMDM ex vivo, highlight the plasticity of BMDM polarization in response to saturated and unsaturated fatty acids, and identify the potential to reverse diet- and saturated fat-induced M1-like polarization by administering palmitoleate. These findings could have applicability to reverse obesity-linked inflammation in metabolically relevant tissues., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

In this review, we discuss the potential role of metabolomics to enhance understanding of obesity-related developmental origins of health and disease (DOHaD). We first provide an overview of common techniques and analytical approaches to help interested investigators dive into this relatively novel field. Next, we describe how metabolomics may capture exposures that are notoriously difficult to quantify, and help to further refine phenotypes associated with excess adiposity and related metabolic sequelae over the life course. Together, these data can ultimately help to elucidate mechanisms that underlie fetal metabolic programming. Finally, we review current gaps in knowledge and identify areas where the field of metabolomics is likely to provide insights into mechanisms linked to DOHaD in human populations.

The increasing prevalence of obesity is presenting a critical challenge to healthcare services. We examined the effect of Body Mass Index in early pregnancy on adverse pregnancy outcome. We performed a population register-based cohort study using data from the North Western Perinatal survey (N = 99,403 babies born during 2004-2006), based at The University of Manchester, UK. The main outcome measures were Caesarean section delivery, preterm birth, neonatal death, stillbirth, Macrosomia, small for gestational age and large for gestational age. The risk of preterm birth was reduced by almost 10% in overweight (RR = 0.89, [95% CI: 0.83, 0.95]) and obese women (RR = 0.90, [95% CI: 0.84, 0.97]) and was increased in underweight women (RR = 1.33, [95% CI: 1.16, 1.53]). Overweight (RR = 1.17, [95% CI: 1.09, 1.25]), obese (RR = 1.35, [95% CI: 1.25, 1.45]) and morbidly obese (RR = 1.24, [95% CI: 1.02, 1.52]) women had an elevated risk of post-term birth compared to normal women. The risk of fetal macrosomia and operative delivery increased with BMI such that morbidly obese women were at greatest risk of both (RR of macrosomia = 4.78 [95% CI: 3.86, 5.92] and RR of Caesarean section = 1.66 [95% CI: 1.61, 1.71] and a RR of emergency Caesarean section = 1.59 [95% CI: 1.45, 1.75]). Excessive leanness and obesity are associated with different adverse pregnancy outcomes with major maternal and fetal complications. Overweight and obese women have a higher risk of macrosomia and Caesarean delivery and lower risk of preterm delivery. The mechanism underlying this association is unclear and is worthy of further investigation.

Insulin resistance is a chronic inflammatory condition accompanying obesity or high fat diets that leads to type 2 diabetes. It is hypothesized that lipids and gut bacterial compounds in particular contribute to metabolic inflammation by activating the immune system; however, the receptors detecting these “instigators” of inflammation remain largely undefined. Here, we show that circulating activators of NOD1, a receptor for bacterial peptidoglycan, increase with high fat feeding in mice, suggesting that NOD1 could be a critical sensor leading to metabolic inflammation. Hematopoietic depletion of NOD1 did not prevent weight gain but protected chimeric mice against diet-induced glucose and insulin intolerance. Mechanistically, while macrophage infiltration of adipose tissue persisted, notably these cells were less pro-inflammatory, had lower CXCL1 production, and consequently, lower neutrophil chemoattraction into the tissue. These findings reveal macrophage NOD1 as a cell-specific target to combat diet-induced inflammation past the step of macrophage infiltration, leading to insulin resistance.

Summary Insulin resistance is a chronic inflammatory condition accompanying obesity or high fat diets that leads to type 2 diabetes. It is hypothesized that lipids and gut bacterial compounds in particular contribute to metabolic inflammation by activating the immune system; however, the receptors detecting these “instigators” of inflammation remain largely undefined. Here, we show that circulating activators of NOD1, a receptor for bacterial peptidoglycan, increase with high fat feeding in mice, suggesting that NOD1 could be a critical sensor leading to metabolic inflammation. Hematopoietic depletion of NOD1 did not prevent weight gain but protected chimeric mice against diet-induced glucose and insulin intolerance. Mechanistically, while macrophage infiltration of adipose tissue persisted, notably these cells were less pro-inflammatory, had lower CXCL1 production, and consequently, lower neutrophil chemoattraction into the tissue. These findings reveal macrophage NOD1 as a cell-specific target to combat diet-induced inflammation past the step of macrophage infiltration, leading to insulin resistance. [ABSTRACT FROM AUTHOR]

Chronic low-grade inflammation is an important contributor to the development of insulin resistance, a hallmark of type 2 diabetes mellitus (T2DM). Obesity and high-fat feeding lead to infiltration of immune cells into metabolic tissues, promoting inflammation and insulin resistance. We hypothesized that macrophages from mice lacking NOX2 (Cybb), an essential component of the NADPH oxidase complex highly expressed in immune cells and associated with their inflammatory response, would be less inflammatory and that these mice would be protected from the development of high-fat-induced insulin resistance. Bone marrowderived macrophages from NOX2 knockout (NOX2-KO) mice expressed lower levels of inflammatory markers (Nos2, Il6); however, NOX2-KO mice were hyperphagic and gained more weight than wild-type (WT) mice when fed either a chow or a high-fat (HF) diet. Surprisingly, NOX2-KO mice stored less lipid in epididymal white adipose tissue but more lipid in liver and had higher indexes of liver inflammation and macrophage infiltration than WT mice. Contrary to our hypothesis, HF-fed NOX2-KO mice were hyperinsulinemic and more insulin resistant than HF-fed WT mice, likely as a result of their higher hepatic steatosis and inflammation. In summary, NOX2 depletion promoted hyperphagia, hepatic steatosis, and inflammation with either normal or high-fat feeding, exacerbating insulin resistance. We propose that NOX2 participates in food intake control and lipid distribution in mice. [ABSTRACT FROM AUTHOR]