Aoibheann M. McMorrow

Mechanisms of Obesity-Induced Inflammation and Insulin Resistance: Insights into the Emerging Role of Nutritional Strategies

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.

Fatty acids and chronic low grade inflammation associated with obesity and the metabolic syndrome

The metabolic syndrome is a group of obesity associated metabolic conditions that result in increased risk of cardiovascular disease and type 2 diabetes. Global increases in obesity rates have led to an increase in metabolic syndrome resulting in a demand for increased understanding of the mechanisms involved. This review examines the relationship between adipose tissue biology, lipid metabolism and chronic low grade inflammation relating to obesity and insulin resistance.

High-Density Lipoprotein Proteomic Composition, and not Efflux Capacity, Reflects Differential Modulation of Reverse Cholesterol Transport by Saturated and Monounsaturated Fat Diets

Background— Acute inflammation impairs reverse cholesterol transport (RCT) and reduces high-density lipoprotein (HDL) function in vivo. This study hypothesized that obesity-induced inflammation impedes RCT and alters HDL composition, and investigated if dietary replacement of saturated (SFA) for monounsaturated (MUFA) fatty acids modulates RCT. Methods and Results— Macrophage-to-feces RCT, HDL efflux capacity, and HDL proteomic profiling was determined in C57BL/6j mice following 24 weeks on SFA- or MUFA-enriched high-fat diets (HFDs) or low-fat diet. The impact of dietary SFA consumption and insulin resistance on HDL efflux function was also assessed in humans. Both HFDs increased plasma 3H-cholesterol counts during RCT in vivo and ATP-binding cassette, subfamily A, member 1–independent efflux to plasma ex vivo, effects that were attributable to elevated HDL cholesterol. By contrast, ATP-binding cassette, subfamily A, member 1–dependent efflux was reduced after both HFDs, an effect that was also observed with insulin resistance and high SFA consumption in humans. SFA-HFD impaired liver-to-feces RCT, increased hepatic inflammation, and reduced ABC subfamily G member 5/8 and ABC subfamily B member 11 transporter expression in comparison with low-fat diet, whereas liver-to-feces RCT was preserved after MUFA-HFD. HDL particles were enriched with acute-phase proteins (serum amyloid A, haptoglobin, and hemopexin) and depleted of paraoxonase-1 after SFA-HFD in comparison with MUFA-HFD. Conclusions— Ex vivo efflux assays validated increased macrophage-to-plasma RCT in vivo after both HFDs but failed to capture differential modulation of hepatic cholesterol trafficking. By contrast, proteomics revealed the association of hepatic-derived inflammatory proteins on HDL after SFA-HFD in comparison with MUFA-HFD, which reflected differential hepatic cholesterol trafficking between groups. Acute-phase protein levels on HDL may serve as novel biomarkers of impaired liver-to-feces RCT in vivo.

Dietary quality in a sample of adults with type 2 diabetes mellitus in Ireland; a cross-sectional case control study

BackgroundA number of dietary quality indices (DQIs) have been developed to assess the quality of dietary intake. Analysis of the intake of individual nutrients does not reflect the complexity of dietary behaviours and their association with health and disease. The aim of this study was to determine the dietary quality of individuals with type 2 diabetes mellitus (T2DM) using a variety of validated DQIs.MethodsIn this cross-sectional analysis of 111 Caucasian adults, 65 cases with T2DM were recruited from the Diabetes Day Care Services of St. Columcille’s and St. Vincent’s Hospitals, Dublin, Ireland. Forty-six controls did not have T2DM and were recruited from the general population. Data from 3-day estimated diet diaries were used to calculate 4 DQIs.ResultsParticipants with T2DM had a significantly lower score for consumption of a Mediterranean dietary pattern compared to the control group, measured using the Mediterranean Diet Score (Range 0–9) and the Alternate Mediterranean Diet Score (Range 0–9) (mean ± SD) (3.4 ± 1.3 vs 4.8 ± 1.8, P < 0.001 and 3.3 ± 1.5 vs 4.2 ± 1.8, P = 0.02 respectively). Participants with T2DM also had lower dietary quality than the control population as assessed by the Healthy Diet Indicator (Range 0–9) (T2DM; 2.6 ± 2.3, control; 3.3 ± 1.1, P = 0.001). No differences between the two groups were found when dietary quality was assessed using the Alternate Healthy Eating Index. Micronutrient intake was assessed using the Micronutrient Adequacy Score (Range 0–8) and participants with T2DM had a significantly lower score than the control group (T2DM; 1.6 ± 1.4, control; 2.3 ± 1.4, P = 0.009). When individual nutrient intakes were assessed, no significant differences were observed in macronutrient intake.ConclusionOverall, these findings demonstrate that T2DM was associated with a lower score when dietary quality was assessed using a number of validated indices.

Adipose tissue dysregulation and metabolic consequences in childhood and adolescent obesity: potential impact of dietary fat quality

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.

Impact of anti-inflammatory nutrients on obesity-associated metabolic-inflammation from childhood through to adulthood.

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.

Personalized Cardio-Metabolic Responses to an Anti-Inflammatory Nutrition Intervention in Obese Adolescents: A Randomized Controlled Crossover Trial

Scope Chronic 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 results Seventy 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. Conclusion The 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.