Catherine M. Phillips

The metabolic syndrome: the crossroads of diet and genetics

The metabolic syndrome is a very common disease associated with an increased risk of type 2 diabetes mellitus (T2DM) and CVD. The clinical characteristics of the metabolic syndrome include insulin resistance, dyslipidaemia, abdominal obesity and hypertension. The diverse clinical characteristics illustrate the complexity of the disease process, which involves several dysregulated metabolic pathways. Thus, multiple genetic targets must be involved in the pathogenesis and progression of the metabolic syndrome. Nevertheless, the human genome has not changed markedly in the last decade but the prevalence of the metabolic syndrome has increased exponentially, which illustrates the importance of gene-environmental interactions. There is good evidence that nutrition plays an important role in the development and progression of the metabolic syndrome. Indeed, obesity is a key aetiological factor in the development of the metabolic syndrome. Understanding the biological impact of gene-nutrient interactions will provide a key insight into the pathogenesis and progression of diet-related polygenic disorders, including the metabolic syndrome. The present paper will explore the interactions between genetic background and dietary exposure or nutritional therapy, focusing on the role of dietary fatty acids within the context of nutrient regulation of gene expression and individual responsiveness to dietary therapy. Only with a full understanding of gene-gene, gene-nutrient and gene-nutrient-environment interactions can the molecular basis of the metabolic syndrome be solved to minimise the adverse health effects of obesity and reduce the risk of the metabolic syndrome, and subsequent T2DM and CVD.

Metabolically healthy obesity: Definitions, determinants and clinical implications

Obesity is associated with increased risk of developing metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) leading to higher all-cause mortality. However accumulating evidence suggests that not all obese subjects are at increased cardiometabolic risk and that the “metabolically healthy obese” (MHO) phenotype may exist in the absence of metabolic abnormalities. Despite the knowledge of the existence of obese metabolic phenotypes for some time now there is no standard set of criteria to define metabolic health, thus impacting on the accurate estimation of the prevalence of the MHO phenotype and making comparability between studies difficult. Furthermore prospective studies tracking the development of cardiometabolic disease and mortality in MHO have also produced conflicting results. Limited data regards the determinants of the MHO phenotype exist, particularly in relation to dietary and lifestyle behaviours. In light of the current obesity epidemic it is clear that current “one size fits all” approaches to tackle obesity are largely unsuccessful. Whether dietary, lifestyle and/or therapeutic interventions based on stratification of obese individuals according to their metabolic health phenotype are more effective remains to be seen, with limited and conflicting data available so far. This review will present the current state of the art including the epidemiology of MHO and its definitions, what factors may be important in determining metabolic health status and finally, some potential implications of the MHO phenotype in the context of obesity diagnosis, interventions and treatment.

Does Inflammation Determine Metabolic Health Status in Obese and Nonobese Adults

CONTEXT Inflammation is a potential mechanism linking obesity and cardiometabolic risk. Limited data on inflammatory markers in metabolically healthy obese and nonobese individuals exist. OBJECTIVE The aim of the study was to investigate the extent to which differences between metabolically healthy and unhealthy obese and nonobese adults, defined using a range of metabolic health definitions, are correlated with a range of inflammatory markers. DESIGN A cross-sectional sample of 2047 men and women aged 45-74 years participated in the study. Participants were classified as obese (body mass index ≥ 30 kg/m(2)) and nonobese (body mass index < 30 kg/m(2)). Metabolic health status was defined using 5 existing metabolic health definitions based on a range of cardiometabolic abnormalities. Serum acute-phase reactants, adipocytokines, proinflammatory cytokines, and white blood cell counts were determined. RESULTS According to most definitions, metabolically healthy obese and nonobese individuals presented with lower concentrations of complement component 3, C-reactive protein, TNF-α, IL-6, and plasminogen activator inhibitor-1; higher adiponectin levels; and reduced white blood cell count compared to their metabolically unhealthy counterparts. Logistic regression analysis identified greater likelihood of metabolically healthy obesity among individuals with lower levels of complement component 3 (odds ratios [ORs], 2-3.5), IL-6 (ORs, 1.7-2.9), plasminogen activator inhibitor-1 (ORs, 1.7-2.9), and white blood cells (ORs, 2.1-2.5) and higher adiponectin concentrations (ORs, 2.6-4.0). CONCLUSIONS Favorable inflammatory status is positively associated with metabolic health in obese and nonobese individuals. These findings are of public health and clinical significance in terms of screening and stratification based on metabolic health phenotype to identify those at greatest cardiometabolic risk for whom appropriate therapeutic or intervention strategies should be developed.

Defining Metabolically Healthy Obesity: Role of Dietary and Lifestyle Factors

Background There is a current lack of consensus on defining metabolically healthy obesity (MHO). Limited data on dietary and lifestyle factors and MHO exist. The aim of this study is to compare the prevalence, dietary factors and lifestyle behaviours of metabolically healthy and unhealthy obese and non-obese subjects according to different metabolic health criteria. Method Cross-sectional sample of 1,008 men and 1,039 women aged 45-74 years participated in the study. Participants were classified as obese (BMI ≥30kg/m2) and non-obese (BMI <30kg/m2). Metabolic health status was defined using five existing MH definitions based on a range of cardiometabolic abnormalities. Dietary composition and quality, food pyramid servings, physical activity, alcohol and smoking behaviours were examined. Results The prevalence of MHO varied considerably between definitions (2.2% to 11.9%), was higher among females and generally increased with age. Agreement between MHO classifications was poor. Among the obese, prevalence of MH was 6.8% to 36.6%. Among the non-obese, prevalence of metabolically unhealthy subjects was 21.8% to 87%. Calorie intake, dietary macronutrient composition, physical activity, alcohol and smoking behaviours were similar between the metabolically healthy and unhealthy regardless of BMI. Greater compliance with food pyramid recommendations and higher dietary quality were positively associated with metabolic health in obese (OR 1.45-1.53 unadjusted model) and non-obese subjects (OR 1.37-1.39 unadjusted model), respectively. Physical activity was associated with MHO defined by insulin resistance (OR 1.87, 95% CI 1.19-2.92, p = 0.006). Conclusion A standard MHO definition is required. Moderate and high levels of physical activity and compliance with food pyramid recommendations increase the likelihood of MHO. Stratification of obese individuals based on their metabolic health phenotype may be important in ascertaining the appropriate therapeutic or intervention strategy.

Genetic and nutrient determinants of the metabolic syndrome.

Purpose of review The metabolic syndrome is a very common condition that is associated with an increased risk of type 2 diabetes mellitus and cardiovascular disease. The diverse clinical characteristics illustrate the complexity of the disease, involving several dysregulated metabolic pathways and multiple genetic targets. The increasing prevalence of obesity heightens the requirement to reduce the risk of the metabolic syndrome. In order to understand the aetiology, it is critical to appreciate the nature of multiple gene–gene and gene–nutrient interactions relevant to the metabolic syndrome. Recent findings Research indicates a major role for genetic susceptibility to the metabolic syndrome. Nutrition clearly plays an important role in the development and progression of the condition. Genetic background can interact with habitual dietary fat composition, thereby affecting predisposition to the metabolic syndrome, and may also determine an individuals responsiveness to altered dietary fat intake. These studies indicate that therapeutic dietary therapy may require a ‘personalized nutrition’ approach, wherein a particular genetic profile may determine responsiveness of patients to specific dietary fatty acid interventions. Summary Understanding the biological impact of gene–nutrient interactions will provide a key insight into the pathogenesis and progression of diet-related polygenic disorders. This review explores the hypothesis that genetic components of the metabolic syndrome may be modified by dietary fatty acid composition.

Nutrigenetics and Metabolic Disease: Current Status and Implications for Personalised Nutrition

Obesity, particularly central adiposity, is the primary causal factor in the development of insulin resistance, the hallmark of the metabolic syndrome (MetS), a common condition characterized by dyslipidaemia and hypertension, which is associated with increased risk of cardiovascular disease (CVD) and type 2 diabetes (T2DM). Interactions between genetic and environmental factors such as diet and lifestyle, particularly over-nutrition and sedentary behavior, promote the progression and pathogenesis of these polygenic diet-related diseases. Their current prevalence is increasing dramatically to epidemic proportions. Nutrition is probably the most important environmental factor that modulates expression of genes involved in metabolic pathways and the variety of phenotypes associated with obesity, the MetS and T2DM. Furthermore, the health effects of nutrients may be modulated by genetic variants. Nutrigenomics and nutrigenetics require an understanding of nutrition, genetics, biochemistry and a range of “omic” technologies to investigate the complex interaction between genetic and environmental factors relevant to metabolic health and disease. These rapidly developing fields of nutritional science hold much promise in improving nutrition for optimal personal and public health. This review presents the current state of the art in nutrigenetic research illustrating the significance of gene-nutrient interactions in the context of metabolic disease.

Docosahexaenoic acid attenuates macrophage-induced inflammation and improves insulin sensitivity in adipocytes-specific differential effects between LC n-3 PUFA ☆

OBJECTIVE Adipose tissue inflammation with immune cell recruitment plays a key role in obesity-induced insulin resistance (IR). Long-chain (LC) n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have anti-inflammatory potential; however, their individual effects on adipose IR are ill defined. We hypothesized that EPA and DHA may differentially affect macrophage-induced IR in adipocytes. METHODS J774.2 macrophages pretreated with EPA or DHA (50 μM for 5 days) were stimulated with lipopolysaccharide (LPS, 100 ng/ml for 30 min-48 h). Cytokine secretion profiles and activation status of macrophages were assessed by enzyme-linked immunosorbent assay and flow cytometry. Pretreated macrophages were seeded onto transwell inserts and placed over 3T3-L1 adipocytes for 24-72 h; effects on adipocyte-macrophage cytokine cross-talk and insulin-stimulated ³H-glucose transport into adipocytes were monitored. RESULTS DHA had more potent anti-inflammatory effects relative to EPA, with marked attenuation of LPS-induced nuclear factor (NF)κB activation and tumor necrosis factor (TNF)α secretion in macrophages. DHA specifically enhanced anti-inflammatory interleukin (IL)-10 secretion and reduced the expression of proinflammatory M1 (F4/80⁺/CD11⁺) macrophages. Co-culture of DHA-enriched macrophages with adipocytes attenuated IL-6 and TNFα secretion while enhancing IL-10 secretion. Conditioned media (CM) from DHA-enriched macrophages attenuated adipocyte NFκB activation. Adipocytes co-cultured with DHA-enriched macrophages maintained insulin sensitivity with enhanced insulin-stimulated ³H-glucose transport, GLUT4 translocation and preservation of insulin-receptor substrate-1 expression compared to co-culture with untreated macrophages. We confirmed that IL-10 expressed by DHA-enriched macrophages attenuates the CM-induced proinflammatory IR phenotype in adipocytes. CONCLUSIONS We demonstrate an attenuated proinflammatory phenotype of DHA-pretreated macrophages, which when co-cultured with adipocytes partially preserved insulin sensitivity.

The role of inflammation and macrophage accumulation in the development of obesity-induced type 2 diabetes mellitus and the possible therapeutic effects of long-chain n-3 PUFA.

The WHO estimate that >1 x 10(6) deaths in Europe annually can be attributed to diseases related to excess body weight, and with the rising global obesity levels this death rate is set to drastically increase. Obesity plays a central role in the metabolic syndrome, a state of insulin resistance that predisposes patients to the development of CVD and type 2 diabetes mellitus. Obesity is associated with low-grade chronic inflammation characterised by inflamed adipose tissue with increased macrophage infiltration. This inflammation is now widely believed to be the key link between obesity and development of insulin resistance. In recent years it has been established that activation of pro-inflammatory pathways can cross talk with insulin signalling pathways via a number of mechanisms including (a) down-regulation of insulin signalling pathway proteins (e.g. GLUT4 and insulin receptor substrate (IRS)-1), (b) serine phosphorylation of IRS-1 blocking its tyrosine phosphorylation in response to insulin and (c) induction of cytokine signalling molecules that sterically hinder insulin signalling by blocking coupling of the insulin receptor to IRS-1. Long-chain (LC) n-3 PUFA regulate gene expression (a) through transcription factors such as PPAR and NF-kappaB and (b) via eicosanoid production, reducing pro-inflammatory cytokine production from many different cells including the macrophage. LC n-3 PUFA may therefore offer a useful anti-inflammatory strategy to decrease obesity-induced insulin resistance, which will be examined in the present review.

Gene-nutrient interactions in the metabolic syndrome: single nucleotide polymorphisms in ADIPOQ and ADIPOR1 interact with plasma saturated fatty acids to modulate insulin resistance

BACKGROUND Progression of the metabolic syndrome (MetS) is determined by genetic and environmental factors. Gene-environment interactions may be important in modulating the susceptibility to the development of MetS traits. OBJECTIVE Gene-nutrient interactions were examined in MetS subjects to determine interactions between single nucleotide polymorphisms (SNPs) in the adiponectin gene (ADIPOQ) and its receptors (ADIPOR1 and ADIPOR2) and plasma fatty acid composition and their effects on MetS characteristics. DESIGN Plasma fatty acid composition, insulin sensitivity, plasma adiponectin and lipid concentrations, and ADIPOQ, ADIPOR1, and ADIPOR2 SNP genotypes were determined in a cross-sectional analysis of 451 subjects with the MetS who participated in the LIPGENE (Diet, Genomics, and the Metabolic Syndrome: an Integrated Nutrition, Agro-food, Social, and Economic Analysis) dietary intervention study and were repeated in 1754 subjects from the LIPGENE-SU.VI.MAX (SUpplementation en VItamines et Minéraux AntioXydants) case-control study (http://www.ucd.ie/lipgene). RESULTS Single SNP effects were detected in the cohort. Triacylglycerols, nonesterified fatty acids, and waist circumference were significantly different between genotypes for 2 SNPs (rs266729 in ADIPOQ and rs10920533 in ADIPOR1). Minor allele homozygotes for both of these SNPs were identified as having degrees of insulin resistance, as measured by the homeostasis model assessment of insulin resistance, that were highly responsive to differences in plasma saturated fatty acids (SFAs). The SFA-dependent association between ADIPOR1 rs10920533 and insulin resistance was replicated in cases with MetS from a separate independent study, which was an association not present in controls. CONCLUSIONS A reduction in plasma SFAs could be expected to lower insulin resistance in MetS subjects who are minor allele carriers of rs266729 in ADIPOQ and rs10920533 in ADIPOR1. Personalized dietary advice to decrease SFA consumption in these individuals may be recommended as a possible therapeutic measure to improve insulin sensitivity. This trial was registered at clinicaltrials.gov as NCT00429195.

Obesity and body fat classification in the metabolic syndrome: Impact on cardiometabolic risk metabotype

Obesity is a key factor in the development of the metabolic syndrome (MetS), which is associated with increased cardiometabolic risk. We investigated whether obesity classification by BMI and body fat percentage (BF%) influences cardiometabolic profile and dietary responsiveness in 486 MetS subjects (LIPGENE dietary intervention study).