Genetics of obesity: gene x nutrient interactions

Obesity results from a long-term positive energy balance, in which gene-related differences may account for some of the disparities found in weight gain among populations. However, the rising prevalence of obesity in developed and developing societies must reflect lifestyle changes. Despite that the genetic background remains stable over many generations, obesity may be derived from a failure on the homeostasis systems, as a consequence of a dysfunction at the genetic level, which may be affected by changing environmental exposure (dietary habits, sedentarism, etc). In practice, obesity risk at least depends on two important factors, which mutually interact: 1) genetic variants and gene expression changes in candidate genes and 2) exposure to environmental risk factors. Disagreements among studies involving gene-nutrient interactions may reflect the difficulty of accurate measurement of specific types of dietary macro and micronutrients intake as well of phenotype assessment rather than a discrepancy in biological relevance. Identification of individuals who are genetically more likely to respond to particular dietary changes may be important for successful intervention in obesity treatment, since gene screening will allow health professionals to tailor-design weight management and dietary guidance in individuals with a genetic predisposition to become obese

Interaction between genes and lifestyle factors on obesity.

Obesity originates from a failure of the body-weight control systems, which may be affected by changing environmental influences. Basically, the obesity risk depends on two important mutually-interacting factors: (1) genetic variants (single-nucleotide polymorphisms, haplotypes); (2) exposure to environmental risks (diet, physical activity etc.). Common single-nucleotide polymorphisms at candidate genes for obesity may act as effect modifiers for environmental factors. More than 127 candidate genes for obesity have been reported and there is evidence to support the role of twenty-two genes in at least five different populations. Gene-environment interactions imply that the synergy between genotype and environment deviates from either the additive or multiplicative effect (the underlying model needs to be specified to appraise the nature of the interaction). Unravelling the details of these interactions is a complex task. Emphasis should be placed on the accuracy of the assessment methods for both genotype and lifestyle factors. Appropriate study design (sample size) is crucial in avoiding false positives and ensuring that studies have enough power to detect significant interactions, the ideal design being a nested case-control study within a cohort. A growing number of studies are examining the influence of gene-environmental interactions on obesity in either epidemiological observational or intervention studies. Positive evidence has been obtained for genes involved in adiposity, lipid metabolism or energy regulation such as PPARgamma2 (Pro12Ala), beta-adrenoceptor 2 (Gln27Glu) or uncoupling proteins 1, 2 and 3. Variants on other genes relating to appetite regulation such as melanocortin and leptin receptors have also been investigated. Examples of some recently-identified interactions are discussed

Obesity and immunocompetence

The increasing worldwide prevalence of obesity is a major health problem since excessive body weight constitutes a risk factor in a number of chronic diseases. It has been reported that obese individuals are more susceptible to infection than lean subjects; however, the underlying factors are not fully understood. Limited and often controversial information exists comparing immunocompetence in obese and nonobese subjects as well as the cellular and molecular mechanisms involved, although much evidence supports a link between adipose tissue metabolism and immunocompetent cell functions. The complexity and heterogeneity of nutritional status and immune system interactions require an integral study of the immunocompetent cells, their subsets and products, as well as specific and non-specific inducer/regulatory systems in situations of human obesity. Additional research is needed to determine the clinical implications of these alterations on immunity and whether various interventions such as weight loss, exercise or nutrient supplementation could help to ameliorate them

Changes in UCP mRNA expression levels in brown adipose tissue and skeletal muscle after feeding a high-energy diet and relationships with leptin, glucose and PPARgamma

Brown adipose tissue and skeletal muscle are known to be important sites for nonshivering thermogenesis. In this context, it is accepted that uncoupling proteins (UCPs) are involved in such process, but little is known about the physiological regulation of these proteins as affected by the intake of a high-energy (cafeteria) diet inducing fat deposition. In this study, the UCP messenger RNA (mRNA) expression in interscapular brown adipose tissue (iBAT) and skeletal muscle was assessed to evaluate the influence of a dietary manipulation on energy homeostasis regulation. We report a statistically significant increase in mRNA levels of iBAT UCP1 and UCP3 and a statistical marginal rise in skeletal muscle UCP3 mRNA expression after feeding a high-energy diet, whereas no changes in UCP2 expression were found in either tissue. Furthermore, significant positive associations between iBAT UCP1 and UCP3 mRNA levels with serum leptin were found. Although the expression of the b3 adrenoceptor (b3AR) was about 50% in the lean controls compared with the obese group in iBAT, no statistically significant changes were observed concerning peroxisome proliferator-activated receptor g2 (PPARg2) mRNA levels in muscle or iBAT. We conclude that feeding a diet inducing weight and fat gain produces different outcomes on iBAT and skeletal muscle UCP mRNA expression, revealing a tissue-dependent response for the three UCPs. Results suggest that the regulation of UCP expression in both tissues under these specific dietary conditions may be related to leptin circulating levels

Evidences on three relevant obesogenes: MC4R, FTO and PPARγ. Approaches for personalized nutrition.

Obesity is a complex disease that results from the interaction between lifestyle (dietary patterns and sedentary habits) and genetic factors. The recognition of a genetic basis for human obesity have driven to identify putative causal genes to understand the pathways that control body mass and fat deposition in humans as well as to provide personalized treatments and prevention strategies to fight against obesity. More than 120 candidate genes have been associated with obesity-related traits. GWAS (genome-wide association study) have so far identified over 20 novel loci convincingly associated with adiposity. This review is specifically focused on the study of the effects of MC4R, PPARγ and FTO gene variants and their interactions with dietary intake, physical activity or drug administration on body weight control. The advances in this field are expected to open new ways in genome-customized diets for obesity prevention and therapy following personalized approaches.

Up-regulation of a thermogenesis-related gene (UCP1) and down-regulation of PPARgamma and aP2 genes in adipose tissue: possible features of the antiobesity effects of a beta3-adrenergic agonist.

A number of experiments have demonstrated the antiobesity effects of beta(3)-adrenergic receptor stimulation by promoting thermogenesis and/or lipolysis. While many studies have been performed in order to develop beta(3)-adrenergic agonists as a novel strategy in the management of obesity, more information is needed about the mechanisms involved in thermogenesis and the actions of these drugs on adipocyte differentiation. To address this, the possible thermogenic and antiadipogenic properties of Tertatolol, a beta(3)-adrenergic agonist, in a diet-induced obesity model has been tested. Animals fed on a high-fat diet gained more weight and fat mass as compared with control and high-fat fed animals treated with Tertatolol. A RT-PCR was carried out in white adipose tissue specific genes involved in thermogenesis such as uncoupling proteins (UCPs) and adipogenesis such as peroxisome proliferator-activated receptor (PPARgamma2), retinoid receptors (RXRalpha/RARalpha), and fatty acid binding protein (aP2). Levels of UCP1 mRNA were augmented in the Tertatolol-treated group as compared to non-treated high-fat fed animals, while the beta(3)-adrenergic agonist treatment significantly decreased the expression levels of aP2 and transcription factors such as PPARgamma2 and the ratio RXRalpha/RARalpha as compared to obese rats. Altogether these data suggest that the antiobesity effects of beta(3)-adrenergic agonists are not limited to the promotion of thermogenesis and/or lipolysis and support the implication that these beta(3)-adrenergic agonists also affect fat deposition by impairing adipogenesis in white adipose tissue (WAT)

Obesity risk is associated with carbohydrate intake in women carrying the Gln27Glu beta2-adrenoceptor polymorphism.

Interindividual differences in the response to dietary intake are, in some cases, genotype dependent. Moreover, genotype-environment interactions may appear when the impact of lifestyle factors (e.g., diet) on a phenotype (e.g., BMI > 30 kg/m2) differs by genotype. A case-control study (obese subjects vs. normal weight controls) was conducted to assess a possible effect modification on obesity risk of the Gln27Glu polymorphism for the ß2-adrenoceptor gene depending on dietary intake. The sample included 159 subjects with BMI > 30 kg/m2 and 154 controls with BMI 49% energy (E)] had a higher obesity risk (OR = 2.56, P = 0.051). The product-term introduced in the logistic model to assess effect modification revealed a marginally significant interaction (P = 0.058) between both factors. Furthermore, a high intake of CHO (E > 49%) was associated with higher insulin levels among women carrying the Gln27Glu polymorphism (P < 0.01). This gene-nutrient interaction emphasizes the importance of examining the outcome of some obesity-related mutations depending on lifestyle (including diet) and may explain the heterogeneity of findings from previous studies

Dietary total antioxidant capacity is associated with leukocyte telomere length in a children and adolescent population

Background & Aims: Oxidative stress and inflammation seem to be potential underlying mechanisms for telomere attrition. A lack of specific antioxidants is believed to increase free radical damage and a greater risk for telomere shortening. Our aim was to evaluate the relationship between diet and leukocyte telomere length in a cross-sectional study of children and adolescents. We hypothesized that dietary total antioxidant capacity would be positively associated with telomere length. Methods: Telomere length was measured by quantitative real-time polymerase chain reaction in 287 participants (55% males, 6–18 years), who were randomly selected from the GENOI study. Results: A positive correlation between dietary total antioxidant capacity and telomere length (r=0.157, p=0.007) was found after adjustment for age and energy intake. However, higher white bread consumption was associated with shorter telomeres (β=-0.204, p=0.002) in fully-adjusted models. Interestingly, those individuals who had simultaneously higher dietary total antioxidant capacity and lower white bread consumption significantly presented the longest telomeres. Moreover, the multivariable-adjusted odds ratio for very short telomeres was 0.30 for dietary total antioxidant capacity (p=0.023) and 1.37 for white bread (p=0.025). Conclusion: It was concluded that longer telomeres were associated with higher dietary total antioxidant capacity and lower white bread consumption in S2panish children and adolescents. These findings might open a new line of investigation about the potential role of an antioxidant diet in maintaining telomere length