BackgroundIn recent years an individual’s ability to respond to an acute dietary challenge has emerged as a measure of their biological flexibility. Analysis of such responses has been proposed to be an indicator of health status. However, for this to be fully realised further work on differential responses to nutritional challenge is needed. This study examined whether metabolic phenotyping could identify differential responders to an oral glucose tolerance test (OGTT) and examined the phenotypic basis of the response.Methods and ResultsA total of 214 individuals were recruited and underwent challenge tests in the form of an OGTT and an oral lipid tolerance test (OLTT). Detailed biochemical parameters, body composition and fitness tests were recorded. Mixed model clustering was employed to define 4 metabotypes consisting of 4 different responses to an OGTT. Cluster 1 was of particular interest, with this metabotype having the highest BMI, triacylglycerol, hsCRP, c-peptide, insulin and HOMA- IR score and lowest VO2max. Cluster 1 had a reduced beta cell function and a differential response to insulin and c-peptide during an OGTT. Additionally, cluster 1 displayed a differential response to the OLTT.ConclusionsThis work demonstrated that there were four distinct metabolic responses to the OGTT. Classification of subjects based on their response curves revealed an “at risk” metabolic phenotype.

The role of metabolomics in the field of nutrition is continuing to grow and it has the potential to assist in the understanding of metabolic regulation and explain how minor perturbations can have a multitude of biochemical endpoints. It is this development, which creates the potential to provide the knowledge necessary to facilitate a more targeted approach to nutrition. In recent years, there has been interest in applying metabolomics to examine alterations in the metabolic profile according to weight gain/obesity. Emerging from these studies is the strong evidence that alterations in the amino acid (AA) profiles are associated with obesity. Several other studies have also shown a relationship between branched-chain amino acids (BCAA), obesity and insulin resistance. The present review focuses on the proposed link between AA and in particular BCAA, obesity and insulin resistance. In conclusion, a wealth of information is accumulating to support the role of AA, and in particular of the BCAA, in obesity. Metabolomics: Amino acids: BMI: Branched-chain amino acidsObesity is now considered as a major global health problem, and the WHO has demonstrated that obesity levels have reached epidemic proportions worldwide with approximately 2 . 3 billion adults predicted to be overweight or obese by the year 2015(1) . It is well recognised that obesity plays a central role in insulin resistance, the metabolic syndrome and type-2 diabetes mellitus. Despite many years of research the exact mechanisms underlying the role of obesity in the development of these disorders and diseases are still not fully elucidated. However, in recent years, the application of 'omic' technologies to studies comparing lean and obese subjects has enhanced our understanding of this research area. This review will focus on the literature, which has utilised metabolomic techniques to investigate the altered metabolic profile in obesity and the subsequent effect on insulin resistance. MetabolomicsMetabolomics is the comprehensive study of metabolites in biofluids, tissues or cellular extracts. The metabolic profile of a sample may be assessed using a variety of techniques including Proton NMR spectroscopy, LC-MS and GC-MS. The role of metabolomics in the field of nutrition is continuing to grow and its utility in a number of studies has been demonstrated (2,3) . Earlier applications of metabolomics in this field compared metabolic profiles of lean and obese subjects (Table 1). Pietiläinen et al.(4) investigated whether acquired obesity was associated with changes in global serum lipid profiles independent of genetic factors in young adult monozygotic twins. In this study, fourteen healthy monozygotic pairs discordant for obesity (10-25 kg weight Abbreviations: AA, amino acid; BCAA, branched-chain amino acid; GBP, gastric bypass surgery; HF, high fat.

The objectives of the present study were to (1) examine the effects of the phenotypic factors age, gender and BMI on the lipidomic profile and (2) investigate the relationship between the lipidome, inflammatory markers and insulin resistance. Specific ceramide, phosphatidylcholine and phosphatidylethanolamine lipids were increased in females relative to males and specific lysophosphatidylcholine, lysophosphatidylethanolamine, phosphatidylcholine and phosphatidylethanolamine lipids decreased as BMI increased. However, age had a minimal effect on the lipid profile with significant differences found in only two lipid species. Network analysis revealed strong negative correlations between the inflammatory markers CRP, TNF-α, resistin and MCP-1 and lipids in the LPC, PC and PE classes, whereas IL-8 formed positive correlations with lipids from the CER and SM classes. Further analysis revealed that LPC a C18:1 and PE ae C40:6 were highly associated with insulin resistance as indicated by HOMA-IR score. The present study identified lipids that are affected by BMI and gender and identified a series of lipids which had significant relationships with inflammatory markers. LPC a C18:1 and PE ae C40:6 were found to be highly associated with insulin resistance pointing to the possibility that the alterations in these specific lipids may play a role in the development of insulin resistance.

The PBMC transcriptome may therefore provide a unique insight into the inflammatory component of metabolic health, as opposed to directly reflecting the metabolic component of the adipose tissue transcriptome.