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

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

Nutritional status and nutritional treatment are related to outcomes and mortality in older adults with hip fracture

Malnutrition is very prevalent in geriatric patients with hip fracture. Nevertheless, its importance is not fully recognized. The objective of this paper is to review the impact of malnutrition and of nutritional treatment upon outcomes and mortality in older people with hip fracture. We searched the PubMed database for studies evaluating nutritional aspects in people aged 70 years and over with hip fracture. The total number of studies included in the review was 44, which analyzed 26,281 subjects (73.5% women, 83.6 ± 7.2 years old). Older people with hip fracture presented an inadequate nutrient intake for their requirements, which caused deterioration in their already compromised nutritional status. The prevalence of malnutrition was approximately 18.7% using the Mini-Nutritional Assessment (MNA) (large or short form) as a diagnostic tool, but the prevalence was greater (45.7%) if different criteria were used (such as Body Mass Index (BMI), weight loss, or albumin concentration). Low scores in anthropometric indices were associated with a higher prevalence of complications during hospitalization and with a worse functional recovery. Despite improvements in the treatment of geriatric patients with hip fracture, mortality was still unacceptably high (30% within 1 year and up to 40% within 3 years). Malnutrition was associated with an increase in mortality. Nutritional intervention was cost effective and was associated with an improvement in nutritional status and a greater functional recovery. To conclude, in older people, the prevention of malnutrition and an early nutritional intervention can improve recovery following a hip fracture

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.

Oxygen in metabolic dysfunction and its therapeutic relevance

Significance: In recent years, a number of studies have shown altered oxygen partial pressure at a tissue level in metabolic disorders, and some researchers have considered oxygen to be a (macro) nutrient. Oxygen availability may be compromised in obesity and several other metabolism-related pathological conditions, including sleep apnea-hypopnea syndrome, the metabolic syndrome (which is a set of conditions), type 2 diabetes, cardiovascular disease, and cancer. Recent Advances: Strategies designed to reduce adiposity and its accompanying disorders have been mainly centered on nutritional interventions and physical activity programs. However, novel therapies are needed since these approaches have not been sufficient to counteract the worldwide increasing rates of metabolic disorders. In this regard, intermittent hypoxia training and hyperoxia could be potential treatments through oxygen-related adaptations. Moreover, living at a high altitude may have a protective effect against the development of abnormal metabolic conditions. In addition, oxygen delivery systems may be of therapeutic value for supplying the tissue-specific oxygen requirements. Critical Issues: Precise in vivo methods to measure oxygenation are vital to disentangle some of the controversies related to this research area. Further, it is evident that there is a growing need for novel in vitro models to study the potential pathways involved in metabolic dysfunction to find appropriate therapeutic targets. Future Directions: Based on the existing evidence, it is suggested that oxygen availability has a key role in obesity and its related comorbidities. Oxygen should be considered in relation to potential therapeutic strategies in the treatment and prevention of metabolic disorders

Position guidelines and evidence base concerning determinants of childhood obesity with a European perspective

Childhood obesity is one of the most pressing global public health issues, with rates increasing fastest in countries at low levels of income. Obesity occurring during childhood is likely to persist throughout the life course, and it is a cause of increased disease risk from the early years of life. This supplement is the result of collaborations involving a large and multidisciplinary group of researchers that were established in the context of the ongoing European Horizon 2020 project Science and Technology in childhood Obesity Policy (STOP). The aim, as in the entire STOP project, is to generate evidence that can support better policies to tackle the problem of childhood obesity in Europe and elsewhere. Quality of life and health well-being concerning children needs to consider personalized, population, and planetary facets to tackle childhood obesity at early stages of life, for in-deep phenotyping, integrating personalized medicine and precision public health interventions at global levels. This supplement contributes to this aim. © 2021 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation