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

Nutrición en el enfermo con fibrosis quística

La fibrosis quística es una enfermedad que se asocia a una mutación de un gen localizado en el brazo largo del cromosoma 7. Esta enfermedad multisistémica afecta especialmente a los pulmones y al páncreas exocrino, lo cual supone el trastorno más influyente en la nutrición de estos pacientes. Generalmente, la suplementación con enzimas pancreáticas es necesaria como elemento terapéutico. La prevalencia de diabetes en esta enfermedad aumenta con la edad, mientras que la afectación hepática clínica es menos frecuente y otras complicaciones intestinales como el ileomeconial, el reflujo gastroesofágico o la obstrucción del intestino distal pueden condicionar también la malnutrición. La prevalencia de la desnutrición en los pacientes con fibrosis quística es elevada, aunque variable, y se asocia directamente con el estado pulmonar y la supervivencia. La terapia nutricional ha adquirido gran importancia ya que se asocia con un mejor crecimiento y mejora o estabilización de la función pulmonar, por lo que debe ser una parte integral del tratamiento de estos pacientes

Central urocortin activation of sympathetic-regulated energy metabolism in Wistar rats

The corticotropin-releasing hormone (CRH) system, including CRH and urocortin (UCN), is implicated in the central control of appetite and energy metabolism. Urocortin, a recently isolated neuropeptide closely related to CRH is involved in the central signaling cascade that inhibits energy intake. When administered intracerebroventricularly and intra-hypothalamically, UCN potently decreases food intake. Receptors for UCN, while widely distributed, are expressed in hypothalamic nuclei. As the hypothalamus is involved in modulating autonomic outflow, UCN may also act as a catabolic neuropeptide to facilitate energy expenditure through sympathetic-regulated thermogenesis. To test the hypothesis that UCN also enhances regulatory energy expenditure via the activation of the sympathetic nervous system, we examined whole body oxygen consumption (VO2) and colonic temperature in male Wistar rats in response to central UCN administration. That is, the intracerebroventricular injection of 1.0 μg of UCN in male Wistar rats (n=10) significantly increased whole body oxygen consumption compared to PBS control. In addition, colonic temperature was significantly increased (Δ0.7±0.08 °C) in UCN- vs. PBS-administered rats, which was prevented by pretreatment with the ganglionic blocker chlorisondamine. These studies suggest that UCN acutely increased whole body oxygen consumption and body temperature via central activation of sympathetic outflow

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.

Energy-restricted diets based on a distinct food selection affecting the glycemic index induce different weight loss and oxidative response

Background and aims: Low glycemic index (GI) based diets could influence the accompanying physiological adaptations to energy restriction in the treatment of obesity. It was aimed to investigate the effects of two energy-restricted diets with different food distribution and GI values on weight loss and energy metabolism in the nutritional treatment of obesity. Subjects and Methods: Participants (n=32;BMI:32.5±4.3kg/m2) were randomly assigned to follow two energy-restricted diets with higher-GI or lower-GI for 8 weeks. The energy restriction was -30% in relation to energy expenditure. Anthropometry, energy expenditure and mitochondrial oxidation were assessed at baseline and at the endpoint of the intervention. Body weight was also measured one year after the treatment. The work was approved by the ethical committees of the University of Navarra (54/2006).Results: Volunteers consuming the lower-GI diet showed a significantly higher weight loss than their counterparts (-5.3±2.6% vs -7.5±2.9%;p=0.032), although the decrease in resting energy expenditure (REE) was similar between groups (p=0.783). Mitochondrial oxidation was significantly affected by the type of diet (p=0.001), being activated after the lower-GI treatment (p=0.022). Interestingly, one year after the nutritional intervention weight regain was only statistically significant in the higher-GI group (p=0.033).Conclusions: Lower-GI energy-restricted diets achieved through a specific differential food selection can improve the energy adaptations during obesity treatment, favouring weight loss and probably weight maintenance compared with higher-GI hypocaloric diets

Thermogenesis induced by a high-carbohydrate meal in fasted lean and overweight young men: insulin, body fat, and sympathetic nervous system involvement

Objective This dietary trial was designed to evaluate the effect of an experimental short-term fasting period followed by a high-carbohydrate meal on energy expenditure, thermogenesis, and sympathetic nervous system activity in normal (body mass index 27 kg/m2) men who were healthy, non-diabetic or with no other endocrine disease, non-smokers, not taking oral prescription medications, and with a stable body weight for the previous 3 mo. Methods Fasting and fed energy expenditures and diet-induced thermogenesis were measured after a high-carbohydrate meal in seven overweight and six lean young male subjects by indirect calorimetry. Heart rate, urinary excretion of catecholamines, serum glucose, and insulin were also measured over the experimental fasting (7.5 h) and postprandial (4 h) periods. Results After carbohydrate intake, overweight men showed a significantly higher energy production (kJ/kg of fat-free mass) than did lean individuals, and the diet-induced thermogenesis (percentage of energy intake) was positively correlated with body fat (kg), percentage of body fat, fat-free mass (kg), and fasting pre-meal serum insulin levels. Postprandial cumulative energy expenditure was directly associated with postprandial insulin response and with mean postprandial heart rate values. No significant differences in urinary catecholamines were found between lean and overweight men at basal conditions or during the study period. Conclusions Overweight individuals showed similar short-term sympathetic nervous system responses induced by an experimental fasting period. Although diet-induced thermogenesis after carbohydrate intake was not statistically different between lean and overweight men, the postprandial insulin response and body fat content seemed to be involved in sympathetic nervous system activity

Effects of leptin resistance on acute fuel metabolism after a high carbohydrate load in lean and overweight young men

Objective: Six lean (BMI = 20.8 ± 0.7) and seven overweight (BMI = 30.8 ± 1.7) young men (18–27 years old) were studied to investigate the acute effect of a high-carbohydrate meal on leptin levels and its relation to energy expenditure as well as to protein, carbohydrate and fat oxidation. Methods: Study participants were given a high-carbohydrate meal (17% as protein, 80% as carbohydrates and 3% as lipids) covering 40% of their estimated daily energy requirements. Serum leptin, insulin, glucose, free fatty acids and triglycerides levels were measured before meal intake and during the four postprandial hours. Furthermore, energy expenditure (EE), protein, carbohydrate and lipid oxidation were measured in fasted and fed conditions. Results: Fasting leptin was found to be positively correlated with circulating insulin concentrations (r = .748; p = 0.011) and body fat in kg (r = .827; p = 0.001). During the measured postprandial period no statistically significant changes were found in leptin levels as compared with pre-meal values in either lean or overweight men, nor differences in leptin changes between both groups. After load intake, carbohydrate oxidation was lower in overweight individuals (p < 0.05), while no significant differences were observed in protein oxidation. Cumulative lipid oxidation was found to be negatively associated with post-meal leptin values, being significantly lower in the overweight as compared with lean men (p < 0.05). This study demonstrates that the acute postprandial fuel substrate utilization is altered in overweight men with a lower carbohydrate oxidation and a strong inhibition of lipid oxidation, which could be attributed to some leptin resistance. Conclusion: These data also suggest that short-term meal-related metabolic responses may explain the long-term body adiposity if they are sustained over long intervals