The Omics of Obesity

Obesity is a complex multi‐faceted disease affecting billions of people worldwide. Traditionally, obesity was thought to be a consequence of having access to energy dense food and busy lifestyles that do not factor in sufficient physical activity. Although diet and exercise play a major role in obesity development, these are not the only contributors. It is widely accepted that genetic and epigenetic factors also play a major role in obesity development and these in turn affect the lipidome, metabolome and proteome. With new technological advances, it is now possible to delve into these specific areas to further understand the mechanisms involved in obesity development. These technologies are collectively termed “omics” technologies, and this chapter will summarise the recent advances in obesity and metabolism research and describe new technologies that have been used to identify mechanisms that play a major role in the development of obesity. In particular, we will examine the different omics platforms that are available and have been used to study obesity. Collectively, these studies will be fundamental in identifying new and effective treatment strategies

Elevated Chemerin Levels in Pakistani Men: An Interrelation with Metabolic Syndrome Phenotypes

Chemerin is a novel protein linked to adipocyte differentiation and the development of metabolic imbalances. We sought to examine the relationship of chemerin with metabolic syndrome disturbances including body fat percentage, serum lipid, glucose, insulin levels and body fat percentage in lean and obese volunteers. A cross-sectional study of 90 randomly selected healthy males from Pakistan were divided into three groups as per Body Mass Index (BMI) criteria for South Asian Population. Anthropometric measurements were taken for BMI, waist circumference, hip circumference and body fat percentage, while serum analyses were performed for fasting blood glucose, fasting insulin, fasting lipid profile and serum chemerin. Associations between serum chemerin levels and body fat and other metabolic syndrome parameters were performed using ANOVA and multiple regression analyses. Data was presented as Mean±SD. In all statistical analyses p-values \u3c0.05 were considered significant. Circulating chemerin levels were significantly higher in obese subjects with BMI greater than 25 kg/m(2) compared with those with a BMI below 25 kg/m(2) (P = 0.001). Serum chemerin levels were found to be independently and significantly associated with serum levels of cholesterol (P = 0.0160; r = 0.255), fasting glucose (P = 0.002; r = 0.323), HOMA-IR (P = 0.004; r = 0.300) and hip circumference (P = 0.021; r = 0.246). This demonstrates that chemerin levels are associated with obesity and dyslipidemia and may play a role in the development of insulin resistance. This data suggests that chemerin may serve as an independent marker in diagnosing these conditions even before they become clinically symptomati

Reduced expression of chemerin in visceral adipose tissue associates with hepatic steatosis in patients with obesity

Objective: This study aimed to evaluate whether circulating levels and/or visceral adipose tissue (VAT) expression of recently described adipokines associate with histopathological severity of nonalcoholic fatty liver disease (NAFLD), independent of obesity and insulin resistance. Methods: Serum levels of adiponectin, omentin, chemerin, monocyte chemoattractant protein-1, and secreted frizzled-related protein 4 were measured using enzyme-linked immunosorbent assay in 81 patients with obesity and NAFLD and 18 lean control subjects. Expression in VAT was measured using real-time PCR and histopathological grading was scored using the NAFLD activity score (NAS). Results: When NAFLD patients were subdivided into groups with simple steatosis, borderline nonalcoholic steatohepatitis (NASH), and NASH, adiponectin serum levels and omentin expression were lower in NASH versus simple steatosis patients. Serum adiponectin was generally lower with higher histopathological grading. Chemerin VAT expression was negatively associated with NAS (r = -0.331, P = 0.022) and steatosis score (r = -0.335, P = 0.020), independent of age, BMI, and HOMA-IR. In addition, adjusting for chemerin VAT expression in a multivariate model explained part of the association between NAS and HOMA-IR. Conclusions: These findings suggest that lower VAT expression of chemerin in patients with obesity may be involved in the pathophysiology of hepatic steatosis, potentially by modulating the link between insulin resistance and NAFLD

Relationship between Chemerin Levels and Cardiometabolic Parameters and Degree of Coronary Stenosis in Korean Patients with Coronary Artery Disease

BackgroundChemerin is a novel adipokine that is associated with inflammation and adipogenesis. However, it remains unclear whether chemerin is involved in patients with cardiovascular disease. We investigated whether the serum chemerin levels of Korean patients with coronary artery disease correlated with specific cardiometabolic parameters.MethodsIn total, 131 patients, all of whom had coronary artery stenosis exceeding 50%, participated in this study. Their serum chemerin levels and cardiometabolic parameters were measured. The serum chemerin levels of two groups of patients were compared; those with one stenotic vessel (n=68) and those with multiple stenotic vessels, including left main coronary artery disease (n=63).ResultsSerum chemerin levels correlated positively with the degree of coronary artery stenosis and fasting glucose, triglyceride, total cholesterol, low density lipoprotein cholesterol, and high sensitive C-reactive protein levels. The group with multiple stenotic vessels, including left main disease, had higher chemerin levels than the group with one stenotic vessel (t=-2.129, P=0.035). Multiple binary logistic regression showed chemerin was not an independent risk factor of multiple vessel disease (odds ratio, 1.018; confidence interval, 0.997 to 1.040; P=0.091).ConclusionSerum chemerin levels have a significant correlation with several cardiometabolic risk factors and the degree of coronary artery stenosis in Korean patients with coronary artery disease. However, multiple binary logistic regression showed chemerin was not an independent risk factor of multiple vessel disease. Additional investigations are necessary to fully elucidate the role of chemerin in cardiovascular disease

Acute effects of active breaks during prolonged sitting on subcutaneous adipose tissue gene expression: an ancillary analysis of a randomised controlled trial.

Active breaks in prolonged sitting has beneficial impacts on cardiometabolic risk biomarkers. The molecular mechanisms include regulation of skeletal muscle gene and protein expression controlling metabolic, inflammatory and cell development pathways. An active communication network exists between adipose and muscle tissue, but the effect of active breaks in prolonged sitting on adipose tissue have not been investigated. This study characterized the acute transcriptional events induced in adipose tissue by regular active breaks during prolonged sitting. We studied 8 overweight/obese adults participating in an acute randomized three-intervention crossover trial. Interventions were performed in the postprandial state and included: (i) prolonged uninterrupted sitting; or prolonged sitting interrupted with 2-minute bouts of (ii) light- or (iii) moderate-intensity treadmill walking every 20 minutes. Subcutaneous adipose tissue biopsies were obtained after each condition. Microarrays identified 36 differentially expressed genes between the three conditions (fold change ≥0.5 in either direction; p < 0.05). Pathway analysis indicated that breaking up of prolonged sitting led to differential regulation of adipose tissue metabolic networks and inflammatory pathways, increased insulin signaling, modulation of adipocyte cell cycle, and facilitated cross-talk between adipose tissue and other organs. This study provides preliminary insight into the adipose tissue regulatory systems that may contribute to the physiological effects of interrupting prolonged sitting

Chemerin and Adiponectin Contribute Reciprocally to Metabolic Syndrome

Obesity and metabolic syndrome (MetS) are considered chronic inflammatory states. Chemerin, a novel adipokine, may play an important role in linking MetS and inflammation. We investigated the association of chemerin with inflammatory markers and with characteristics of MetS in apparently healthy overweight and obese adults. We studied 92 adults; 59 men and 33 women whose average body mass index (BMI) was 28.15±5.08 kg/m2. Anthropometric parameters, insulin resistance indices, lipid profiles, and inflammatory markers including high sensitivity C-reactive protein (hsCRP), pentraxin 3 (PTX3), adiponectin, and chemerin were measured. Controlling for age, gender, and BMI, serum chemerin level was positively correlated with body fat and serum triglyceride, and negatively correlated with adiponectin and high density lipoprotein cholesterol (HDL- C), and was not correlated with altered hsCRP or PTX3 levels. Among the low, moderate and high chemerin groups, high chemerin individuals are more likely to have lower HDL-C. Conversely, individuals in the low adiponectin group are more likely to have lower HDL-C and show more MetS phenotypic traits than moderate and high adiponectin subjects. To determine the relationships of chemerin and adiponectin to MetS and its components, participants were stratified into four groups based on their chemerin and adiponectin levels (high chemerin/high adiponectin, high chemerin/low adiponectin, low chemerin/high adiponectin, or low chemerin/low adiponectin). Participants who were in the high chemerin/low adiponectin group more likely to have dyslipidemia and MetS (OR: 5.79, 95% CI:1.00–33.70) compared to the other three group. Our findings suggest that chemerin and adiponectin may reciprocally participate in the development of MetS

Coexpression Network Analysis in Abdominal and Gluteal Adipose Tissue Reveals Regulatory Genetic Loci for Metabolic Syndrome and Related Phenotypes

Metabolic Syndrome (MetS) is highly prevalent and has considerable public health impact, but its underlying genetic factors remain elusive. To identify gene networks involved in MetS, we conducted whole-genome expression and genotype profiling on abdominal (ABD) and gluteal (GLU) adipose tissue, and whole blood (WB), from 29 MetS cases and 44 controls. Co-expression network analysis for each tissue independently identified nine, six, and zero MetS–associated modules of coexpressed genes in ABD, GLU, and WB, respectively. Of 8,992 probesets expressed in ABD or GLU, 685 (7.6%) were expressed in ABD and 51 (0.6%) in GLU only. Differential eigengene network analysis of 8,256 shared probesets detected 22 shared modules with high preservation across adipose depots (DABD-GLU = 0.89), seven of which were associated with MetS (FDR P<0.01). The strongest associated module, significantly enriched for immune response–related processes, contained 94/620 (15%) genes with inter-depot differences. In an independent cohort of 145/141 twins with ABD and WB longitudinal expression data, median variability in ABD due to familiality was greater for MetS–associated versus un-associated modules (ABD: 0.48 versus 0.18, P = 0.08; GLU: 0.54 versus 0.20, P = 7.8×10−4). Cis-eQTL analysis of probesets associated with MetS (FDR P<0.01) and/or inter-depot differences (FDR P<0.01) provided evidence for 32 eQTLs. Corresponding eSNPs were tested for association with MetS–related phenotypes in two GWAS of >100,000 individuals; rs10282458, affecting expression of RARRES2 (encoding chemerin), was associated with body mass index (BMI) (P = 6.0×10−4); and rs2395185, affecting inter-depot differences of HLA-DRB1 expression, was associated with high-density lipoprotein (P = 8.7×10−4) and BMI–adjusted waist-to-hip ratio (P = 2.4×10−4). Since many genes and their interactions influence complex traits such as MetS, integrated analysis of genotypes and coexpression networks across multiple tissues relevant to clinical traits is an efficient strategy to identify novel associations

The Chemerin/ChemR23 System Does Not Affect the Pro-Inflammatory Response of Mouse and Human Macrophages Ex Vivo

Macrophages constitute a major component of innate immunity and play an essential role in defense mechanisms against external aggressions and in inflammatory responses. Chemerin, a chemoattractant protein, is generated in inflammatory conditions, and recruits cells expressing the G protein-coupled receptor ChemR23, including macrophages. Chemerin was initially expected to behave as a pro-inflammatory agent. However, recent data described more complex activities that are either pro- or anti-inflammatory, according to the disease model investigated. In the present study, peritoneal macrophages were generated from WT or ChemR23−/− mice, stimulated with lipopolyssaccharide in combination or not with IFN-γ and the production of pro- (TNF-α, IL-1β and IL-6) and anti-inflammatory (IL-10) cytokines was evaluated using qRT-PCR and ELISA. Human macrophages generated from peripheral blood monocytes were also tested in parallel. Peritoneal macrophages from WT mice, recruited by thioglycolate or polyacrylamide beads, functionally expressed ChemR23, as assessed by flow cytometry, binding and chemotaxis assays. However, chemerin had no effect on the strong upregulation of cytokine release by these cells upon stimulation by LPS or LPS/IFN-γ, whatever the concentration tested. Similar data were obtained with human macrophages. In conclusion, our results rule out the direct anti-inflammatory effect of chemerin on macrophages ex vivo, described previously in the literature, despite the expression of a functional ChemR23 receptor in these cells