Obesity and associated chronic inflammation initiate a state of insulin resistance (IR). The secretion of chemoattractants such as MCP-1 and MIF and of cytokines IL-6, TNF-α, and IL-1β, draw immune cells including dendritic cells, T cells, and macrophages into adipose tissue (AT). Dysfunctional AT lipid metabolism leads to increased circulating free fatty acids, initiating inflammatory signaling cascades in the population of infiltrating cells. A feedback loop of pro-inflammatory cytokines exacerbates this pathological state, driving further immune cell infiltration and cytokine secretion and disrupts the insulin signaling cascade. Disruption of normal AT function is causative of defects in hepatic and skeletal muscle glucose homeostasis, resulting in systemic IR and ultimately the development of type 2 diabetes. Pharmaceutical strategies that target the inflammatory milieu may have some potential; however there are a number of safety concerns surrounding such pharmaceutical approaches. Nutritional anti-inflammatory interventions could offer a more suitable long-term alternative; whilst they may be less potent than some pharmaceutical anti-inflammatory agents, this may be advantageous for long-term therapy. This review will investigate obese AT biology, initiation of the inflammatory, and insulin resistant environment; and the mechanisms through which dietary anti-inflammatory components/functional nutrients may be beneficial.

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Obesity-related metabolic conditions such as insulin resistance (IR), type 2 diabetes and CVD share a number of pathological features, one of which is metabolic-inflammation. Metabolic-inflammation results from the infiltration of immune cells into the adipose tissue, driving a pro-inflammatory environment, which can induce IR. Furthermore, resolution of inflammation, an active process wherein the immune system counteracts pro-inflammatory states, may be dysregulated in obesity. Anti-inflammatory nutritional interventions have focused on attenuating this pro-inflammatory environment. Furthermore, with inherent variability among individuals, establishing at-risk populations who respond favourably to nutritional intervention strategies is important. This review will focus on chronic low-grade metabolic-inflammation, resolution of inflammation and the putative role anti-inflammatory nutrients have as a potential therapy. Finally, in the context of personalised nutrition, the approaches used in defining individuals who respond favourably to nutritional interventions will be highlighted. With increasing prevalence of obesity in younger people, age-dependent biological processes, preventative strategies and therapeutic options are important to help protect against development of obesity-associated co-morbidities.

Evidence suggests that at a population level, childhood and adolescent obesity increase the long-term risk of chronic diseases such as type 2 diabetes and CVD. At an individual level, however, the metabolic consequences of obesity in youth vary immensely. Despite comparable BMI, some adolescents develop impaired glucose tolerance while others maintain normal glucose homeostasis. It has been proposed that the variation in the capacity to store lipid in the subcutaneous adipose tissue (SAT) may partially discriminate metabolically healthy from unhealthy obesity. In positive energy balance, a decreased capacity to expand SAT may drive lipid accumulation to visceral adipose tissue, liver and skeletal muscle. This state of lipotoxicity is associated with chronic low-grade inflammation, insulin resistance and dyslipidaemia. The present review examines the differential adipose tissue development and function in children and adolescents who exhibit metabolic dysregulation compared with those who are protected. Additionally, the role of manipulating dietary fat quality to potentially prevent and treat metabolic dysfunction in obesity will be discussed. The findings of the present review highlight the need for further randomised controlled trials to establish the effect of dietary n-3 PUFA on the metabolic phenotype of obese children and adolescents. Furthermore, using a personalised nutrition approach to target interventions to those at risk of, or those with established metabolic dysregulation may optimise the efficacy of modifying dietary fat quality.

BackgroundVisceral obesity has a strong association with both the incidence and mortality of esophageal adenocarcinoma (EAC). Alterations in mitochondrial function and energy metabolism is an emerging hallmark of cancer, however, the potential role that obesity plays in driving these alterations in EAC is currently unknown.MethodsAdipose conditioned media (ACM) was prepared from visceral adipose tissue taken from computed tomography-determined viscerally-obese and non-obese EAC patients. Mitochondrial function in EAC cell lines was assessed using fluorescent probes, mitochondrial gene expression was assessed using qPCR-based gene arrays and intracellular ATP levels were determined using a luminescence-based kit. Glycolysis and oxidative phosphophorylation was measured using Seahorse XF technology and metabolomic analysis was performed using 1H NMR. Expression of metabolic markers was assessed in EAC tumor biopsies by qPCR.ResultsACM from obese EAC patients significantly increased mitochondrial mass and mitochondrial membrane potential in EAC cells, which was significantly associated with visceral fat area, and was coupled with a significant decrease in reactive oxygen species. This mitochondrial dysfunction was accompanied by altered expression of 19 mitochondrial-associated genes and significantly reduced intracellular ATP levels. ACM from obese EAC patients induced a metabolic shift to glycolysis in EAC cells, which was coupled with significantly increased sensitivity to the glycolytic inhibitor 2-deoxyglucose. Metabolomic profiling demonstrated an altered glycolysis and amino acid-related signature in ACM from obese patients. In EAC tumors, expression of the glycolytic marker PKM2 was significantly positively associated with obesity.ConclusionThis study demonstrates for the first time that ACM from viscerally-obese EAC patients elicits an altered metabolic profile and can drive mitochondrial dysfunction and altered energy metabolism in EAC cells in vitro. In vivo, in EAC patient tumors, expression of the glycolytic enzyme PKM2 is positively associated with obesity.

ScopeChronic inflammation and hypoadiponectinemia are characteristics of obesity‐induced insulin resistance (IR). The effect of an anti‐inflammatory nutrition supplement (AINS) on IR and adiponectin biology in overweight adolescents was investigated. The secondary objective was to examine the extent to which individuals’ biomarker profiles, derived from baseline phenotypes, predicted response or not to the AINS. Additionally, the impact of DNA methylation on intervention efficacy was assessed.Methods and resultsSeventy overweight adolescents (13–18 years) were recruited to this randomized controlled crossover trial. Participants received an AINS (long chain n‐3 PUFA, vitamin C, α‐tocopherol, green tea extract, and lycopene) and placebo for 8 weeks each. Homeostatic model assessment (HOMA)‐IR, adiponectin, inflammatory profiles, and DNA methylation were assessed. HOMA‐IR was unchanged in the total cohort. High‐molecular‐weight (HMW) adiponectin was maintained following the AINS while it decreased over time following the placebo intervention. HOMA‐IR decreased in 40% of subjects (responders) following the AINS. Responders’ pretreatment phenotype was characterized by higher HOMA‐IR, total and LDL cholesterol, but similar BMI in comparison to nonresponders. HMW adiponectin response to the AINS was associated with bidirectional modulation of adipogenic gene methylation.ConclusionThe AINS modulated adiponectin biology, an early predictor of type 2 diabetes risk, was associated with bidirectional modulation of adipogenic gene methylation in weight‐stable overweight adolescents. HOMA‐IR decreased in a sub‐cohort of adolescents with an adverse metabolic phenotype. Thus, suggesting that more stratified or personalized nutrition approaches may enhance efficacy of dietary interventions.

The OLTT induced some gender-specific correlations of gene coexpression network modules. In females, biological processes relating to energy metabolism and inflammation pathways were evident. This suggests a gender specific link between inflammation and energy metabolism in response to lipids. In contrast, G-protein coupled receptor protein signaling pathway was common to both genders.

This abstract was presented as the Cellular and Molecular Theme highlight.Obese youth are at increased risk of developing cardiovascular disease in adulthood (1) . High density lipoprotein (HDL) particles facilitate efflux of cholesterol from lipid-laden arterial macrophages in atherosclerotic lesions, and deliver acquired lipid back to the liver for excretion (2) . This study aimed to characterise the impact of weight status and dietary fat on cholesterol efflux capacity in adolescents, which has not previously been described.Cholesterol efflux from macrophages was determined as a metric of HDL function in a cross-sectional cohort of lean, overweight and obese adolescents (n = 82). Cholesterol efflux was assessed by incubating plasma HDL with 3 H-cholesterol labelled J774 macrophages for 4 h, from which ABCA1-dependent and ABCA1-independent efflux capacities were quantified. The effects of long chain (LC) n-3 polyunsaturated fatty acid (PUFA)-rich anti-inflammatory supplementation and a monounsaturated fatty acid (MUFA)-rich control supplement on efflux capacity were examined after an 8-wk randomised controlled crossover trial in overweight and obese adolescents (n = 52). Cholesteryl ester fatty acid composition was assessed as a biomarker of dietary fat intake.Cross-sectional analysis demonstrated impaired total cholesterol efflux capacity in obese adolescents. Relative to lean adolescents, ABCA1-dependent efflux was impaired in overweight and obese adolescents with low cholesteryl ester n-3 PUFA status. However, HDL function was preserved in overweight and obese adolescents with high cholesteryl ester n-3 PUFA status, despite reduced HDL cholesterol concentration. Both LC n-3 PUFA-rich and MUFA-rich supplementation increased ABCA1-mediated cholesterol efflux in overweight and obese adolescents with impaired HDL function at baseline, independently of changes in HDL cholesterol or apolipoprotein A1 concentrations. Improved inflammatory profile, characterised by increased high molecular weight adiponectin and decreased complement component C3, was demonstrated in response to LC n-3 PUFA supplementation in adolescents with reduced baseline HDL function.We demonstrate for the first time, impaired cholesterol efflux capacity in obese adolescents. However, both LC n-3 PUFA-rich anti-inflammatory supplementation and iso-energetic MUFA-rich supplementation partially rescued HDL function despite obesity. These novel findings illustrate the potential to attenuate cardiovascular disease risk in overweight and obese adolescents through dietary modification.