HSP70 as a biomarker of the thin threshold between benefit and injury due to physical exercise when exposed to air pollution

Physical exercise has acute and chronic effects on inflammatory balance, metabolic regulation, and redox status. Exercise-induced adaptations are mediated by enhanced 70-kDa heat shock protein (HSP70) levels and an improved heat shock response (HSR). Therefore, exercise could be useful against disease conditions [obesity, diabetes mellitus (DM), and exposure to atmospheric pollutants] marked by an impaired HSR. However, exercise performed by obese or diabetic subjects under pollution conditions might also be dangerous at certain intensities. Intensity correlates with an increase in HSP70 levels during physical exercise until a critical point at which the effort becomes harmful and impairs the HSR. Establishing a unique biomarker able to indicate the exercise intensity on metabolism and cellular fatigue is essential to ensure adequate and safe exercise recommendations for individuals with obesity or DM who require exercise to improve their metabolic status and live in polluted regions. In this review, we examined the available evidence supporting our hypothesis that HSP70 could serve as a biomarker for determining the optimal exercise intensity for subjects with obesity or diabetes when exposed to air pollution and establishing the fine threshold between anti-inflammatory and pro-inflammatory exercise effects.     

Obesity, attention deficit-hyperactivity disorder and the dopaminergic reward system

The obesity epidemic has focused attention on obesity's health consequences beyond cardio-vascular disease and diabetes. To evaluate the potential consequences of obesity for Attention Deficit-Hyperactivity Disorder (ADHD), we surveyed the literature. Current findings link both obesity and ADHD to the dopamine system and implicate dopamine genes in body weight, eating, and ADHD. Detailed consideration suggests that dopaminergic changes in the prefrontal cortex among individuals with the ADHD subtype Attention Deficit Disorder (ADD) may increase their risk for obesity. Thus, individuals and populations with a high prevalence of hyperdopaminergic genes may experience higher rates of obesity in the presence of abundant food. From an evolutionary perspective, alterations in the dopamine system appear to effect a wide range of behavioral phenotypes. We suggest that recent evolutionary changes in the dopamine receptor genes selected to increase cognitive and behavioral flexibility may now be associated with attention problems and increased food consumption in an obesogenic environment.     

Genes, exercise, growth, and the sedentary, obese child.

It is still not possible to provide an evidence-based answer to the question of whether regular exercise is essential for normal growth. It is also unclear whether very low levels of exercise result in growth deficits. Regular exposure to exercise is characterized by heterogeneity in responsiveness, with most individuals experiencing improvements in fitness traits but a significant proportion showing only very minor gains. Whether a sedentary mode of life during the growing years results in a permanent deficit in cardiorespiratory fitness or a diminished ability to respond favorably to regular exercise later in life remains to be investigated. Although several genes have been associated with fitness levels or response to regular exercise, the quality of the evidence is weak mainly because studies are statistically underpowered. The special case of the obese, sedentary child is discussed, and the importance of the "energy gap" in the excess weight gain during growth is highlighted. Obese, sedentary children have high blood pressure, dyslipidemia, elevated glycemia and type 2 diabetes, hepatic steatosis, respiratory problems, orthopedic complications, and other health disorders more frequently than normal weight, physically active children. The role of genetic differences in the inclination to be sedentary or physically active is reviewed. An understanding of the true role of genetic differences and regular exercise on the growth of children will require more elaborate paradigms incorporating not only DNA sequence variants and exercise exposure but also information on nutrition, programming, and epigenetic events during fetal life and early postnatal years.     

Genetic aspects of susceptibility to obesity and related dyslipidemias

Obesity has a multifactorial origin. However, although environmental variables undoubtedly play a role in the development of obesity, it is now clear that genetic variation is also involved in the determination of an individual's susceptibility to body fat accumulation. In addition, it is also widely accepted that obesity is not a single homogeneous phenotype. It is also heterogeneous regarding its causes and metabolic complications. The regional distribution of body fat appears to be an important correlate of the metabolic complications that have been related to obesity. Due to their higher accumulation of abdominal fat, men are generally more at risk for the metabolic complications of obesity than women whereas some obese women, with large gluteal-femoral adipose depots may have a cosmetic problem which may not necessarily require medical intervention. Several studies have been conducted to understand the mechanisms by which abdominal obesity is related to diabetes, hypertension and cardiovascular disease. It appears that the increased risk of abdominal obesity is the result of complex hormonal and metabolic interactions. Studies in genetic epidemiology have shown that both total body fatness and the regional distribution of body fat have a significant genetic component. Standardized intervention studies using an identical twin design have shown that individuals that have the same genetic background tend to show similar changes in body fat and in plasma lipoprotein levels when exposed to standardized caloric excess or energy restriction. Finally, although abdominal obesity is a significant risk factor for cardiovascular disease, not every abdominal obese subject will experience metabolic complications, suggesting that some obese individuals may be more susceptible than others. Variation in several genes relevant to lipid and lipoprotein metabolism may alter the relation of abdominal obesity to dyslipoproteinemias. Abdominal obesity should therefore be considered as a factor that exacerbates an individual's susceptibility to cardiovascular disease.     

Genetic predisposition for Type 2 diabetes, but not for overweight/obesity, is associated with a restricted adipogenesis

Background

Development of Type 2 diabetes, like obesity, is promoted by a genetic predisposition. Although several genetic variants have been identified they only account for a small proportion of risk. We have asked if genetic risk is associated with abnormalities in storing excess lipids in the abdominal subcutaneous adipose tissue.

Methodology/Principal Findings

We recruited 164 lean and 500 overweight/obese individuals with or without a genetic predisposition for Type 2 diabetes or obesity. Adipose cell size was measured in biopsies from the abdominal adipose tissue as well as insulin sensitivity (HOMA index), HDL-cholesterol and Apo AI and Apo B. 166 additional non-obese individuals with a genetic predisposition for Type 2 diabetes underwent a euglycemic hyperinsulinemic clamp to measure insulin sensitivity. Genetic predisposition for Type 2 diabetes, but not for overweight/obesity, was associated with inappropriate expansion of the adipose cells, reduced insulin sensitivity and a more proatherogenic lipid profile in non-obese individuals. However, obesity per se induced a similar expansion of adipose cells and dysmetabolic state irrespective of genetic predisposition.

Conclusions/Significance

Genetic predisposition for Type 2 diabetes, but not obesity, is associated with an impaired ability to recruit new adipose cells to store excess lipids in the subcutaneous adipose tissue, thereby promoting ectopic lipid deposition. This becomes particularly evident in non-obese individuals since obesity per se promotes a dysmetabolic state irrespective of genetic predisposition. These results identify a novel susceptibility factor making individuals with a genetic predisposition for Type 2 diabetes particularly sensitive to the environment and caloric excess.     

Glucose Induces Sensitivity to Oxygen Deprivation and Modulates Insulin/IGF-1 Signaling and Lipid Biosynthesis in Caenorhabditis elegans

Diet is a central environmental factor that contributes to the phenotype and physiology of individuals. At the root of many human health issues is the excess of calorie intake relative to calorie expenditure. For example, the increasing amount of dietary sugars in the human diet is contributing to the rise of obesity and type 2 diabetes. Individuals with obesity and type 2 diabetes have compromised oxygen delivery, and thus it is of interest to investigate the impact a high-sugar diet has on oxygen deprivation responses. By utilizing the Caenorhabditis elegans genetic model system, which is anoxia tolerant, we determined that a glucose-supplemented diet negatively impacts responses to anoxia and that the insulin-like signaling pathway, through fatty acid and ceramide synthesis, modulates anoxia survival. Additionally, a glucose-supplemented diet alters lipid localization and initiates a positive chemotaxis response. Use of RNA-sequencing analysis to compare gene expression responses in animals fed either a standard or glucose-supplemented diet revealed that glucose impacts the expression of genes involved with multiple cellular processes including lipid and carbohydrate metabolism, stress responses, cell division, and extracellular functions. Several of the genes we identified show homology to human genes that are differentially regulated in response to obesity or type 2 diabetes, suggesting that there may be conserved gene expression responses between C. elegans fed a glucose-supplemented diet and a diabetic and/or obesity state observed in humans. These findings support the utility of the C. elegans model for understanding the molecular mechanisms regulating dietary-induced metabolic diseases.     

Do genetic variations alter the effects of exercise training on cardiovascular disease and can we identify the candidate variants now or in the future?

Cardiovascular disease (CVD) and CVD risk factors are highly heritable, and numerous lines of evidence indicate they have a strong genetic basis. While there is nothing known about the interactive effects of genetics and exercise training on CVD itself, there is at least some literature addressing their interactive effect on CVD risk factors. There is some evidence indicating that CVD risk factor responses to exercise training are also heritable and, thus, may have a genetic basis. While roughly 100 studies have reported significant effects of genetic variants on CVD risk factor responses to exercise training, no definitive conclusions can be generated at the present time, because of the lack of consistent and replicated results and the small sample sizes evident in most studies. There is some evidence supporting "possible" candidate genes that may affect these responses to exercise training: APO E and CETP for plasma lipoprotein-lipid profiles; eNOS, ACE, EDN1, and GNB3 for blood pressure; PPARG for type 2 diabetes phenotypes; and FTO and BAR genes for obesity-related phenotypes. However, while genotyping technologies and statistical methods are advancing rapidly, the primary limitation in this field is the need to generate what in terms of exercise intervention studies would be almost incomprehensible sample sizes. Most recent diabetes, obesity, and blood pressure genetic studies have utilized populations of 10,000-250,000 subjects, which result in the necessary statistical power to detect the magnitude of effects that would probably be expected for the impact of an individual gene on CVD risk factor responses to exercise training. Thus at this time it is difficult to see how this field will advance in the future to the point where robust, consistent, and replicated data are available to address these issues. However, the results of recent large-scale genomewide association studies for baseline CVD risk factors may drive future hypothesis-driven exercise training intervention studies in smaller populations addressing the impact of specific genetic variants on well-defined physiological phenotypes.     

Obesity and genetics regulate microRNAs in islets, liver, and adipose of diabetic mice

Type 2 diabetes results from severe insulin resistance coupled with a failure of β cells to compensate by secreting sufficient insulin. Multiple genetic loci are involved in the development of diabetes, although the effect of each gene on diabetes susceptibility is thought to be small. MicroRNAs (miRNAs) are noncoding 19–22-nucleotide RNA molecules that potentially regulate the expression of thousands of genes. To understand the relationship between miRNA regulation and obesity-induced diabetes, we quantitatively profiled approximately 220 miRNAs in pancreatic islets, adipose tissue, and liver from diabetes-resistant (B6) and diabetes-susceptible (BTBR) mice. More than half of the miRNAs profiled were expressed in all three tissues, with many miRNAs in each tissue showing significant changes in response to genetic obesity. Furthermore, several miRNAs in each tissue were differentially responsive to obesity in B6 versus BTBR mice, suggesting that they may be involved in the pathogenesis of diabetes. In liver there were approximately 40 miRNAs that were downregulated in response to obesity in B6 but not BTBR mice, indicating that genetic differences between the mouse strains play a critical role in miRNA regulation. In order to elucidate the genetic architecture of hepatic miRNA expression, we measured the expression of miRNAs in genetically obese F2 mice. Approximately 10% of the miRNAs measured showed significant linkage (miR-eQTLs), identifying loci that control miRNA abundance. Understanding the influence that obesity and genetics exert on the regulation of miRNA expression will reveal the role miRNAs play in the context of obesity-induced type 2 diabetes.     

Lipotoxicity and cardiac dysfunction in mammals and Drosophila

The lipotoxic effects of obesity are important contributing factors in cancer, diabetes, and cardiovascular disease (CVD), but the genetic mechanisms, by which lipotoxicity influences the initiation and progression of CVD are poorly understood. Hearts, of obese and diabetic individuals, exhibit several phenotypes in common, including ventricular remodeling, prolonged QT intervals, enhanced frequency of diastolic and/or systolic dysfunction, and decreased fractional shortening. High systemic lipid concentrations are thought to be the leading cause of lipid-related CVD in obese or diabetic individuals. However, an alternative possibility is that obesity leads to cardiac-specific steatosis, in which lipids and their metabolites accumulate within the myocardial cells themselves and thereby disrupt normal cardiovascular function. Drosophila has recently emerged as an excellent model to study the fundamental genetic mechanisms of metabolic control, as well as their relationship to heart function. Two recent studies of genetic and diet-induced cardiac lipotoxicity illustrate this. One study found that alterations in genes associated with membrane phospholipid metabolism may play a role in the abnormal lipid accumulation associated with cardiomyopathies. The second study showed that Drosophila fed a diet high in saturated fats, developed obesity, dysregulated insulin and glucose homeostasis, and severe cardiac dysfunction. Here, we review the current understanding of the mechanisms that contribute to the detrimental effects of dysregulated lipid metabolism on cardiovascular function. We also discuss how the Drosophila model could help elucidate the basic genetic mechanisms of lipotoxicity- and metabolic syndrome-related cardiomyopathies in mammals.     

Lipotoxicity and cardiac dysfunction in mammals and Drosophila

The lipotoxic effects of obesity are important contributing factors in cancer, diabetes, and cardiovascular disease (CVD), but the genetic mechanisms, by which lipotoxicity influences the initiation and progression of CVD are poorly understood. Hearts, of obese and diabetic individuals, exhibit several phenotypes in common, including ventricular remodeling, prolonged QT intervals, enhanced frequency of diastolic and/or systolic dysfunction, and decreased fractional shortening. High systemic lipid concentrations are thought to be the leading cause of lipid-related CVD in obese or diabetic individuals. However, an alternative possibility is that obesity leads to cardiac-specific steatosis, in which lipids and their metabolites accumulate within the myocardial cells themselves and thereby disrupt normal cardiovascular function. Drosophila has recently emerged as an excellent model to study the fundamental genetic mechanisms of metabolic control, as well as their relationship to heart function. Two recent studies of genetic and diet-induced cardiac lipotoxicity illustrate this. One study found that alterations in genes associated with membrane phospholipid metabolism may play a role in the abnormal lipid accumulation associated with cardiomyopathies. The second study showed that Drosophila fed a diet high in saturated fats, developed obesity, dysregulated insulin and glucose homeostasis, and severe cardiac dysfunction. Here, we review the current understanding of the mechanisms that contribute to the detrimental effects of dysregulated lipid metabolism on cardiovascular function. We also discuss how the Drosophila model could help elucidate the basic genetic mechanisms of lipotoxicity- and metabolic syndrome-related cardiomyopathies in mammals.     

Shared genetic risk factors for obstructive sleep apnea and obesity.

Both obesity and obstructive sleep apnea (OSA) are complex disorders with multiple risk factors, which interact in a complicated fashion to determine the overall phenotype. In addition to environmental risk factors, each disorder has a strong genetic basis that is likely due to the summation of small to moderate effects from a large number of genetic loci. Obesity is a strong risk factor for sleep apnea, and there are some data to suggest sleep apnea may influence obesity. It is therefore not surprising that many susceptibility genes for obesity and OSA should be shared. Current research suggests that approximately half of the genetic variance in the apnea hypopnea index is shared with obesity phenotypes. Genetic polymorphisms that increase weight will also be risk factors for apnea. In addition, given the interrelated pathways regulating both weight and other intermediate phenotypes for sleep apnea such as ventilatory control, upper airway muscle function, and sleep characteristics, it is likely that there are genes with pleiotropic effects independently impacting obesity and OSA traits. Other genetic loci likely interact with obesity to influence development of OSA in a gene-by-environment type of effect. Conversely, environmental stressors such as intermittent hypoxia and sleep fragmentation produced by OSA may interact with obesity susceptibility genes to modulate the importance that these loci have on defining obesity-related traits.     

Genes, environment, and interactions in prevention of type 2 diabetes: a focus on physical activity and lifestyle changes

Type 2 diabetes is one of the fastest growing public health problems worldwide. Both environmental (e.g. physical activity, obesity, and diet) and genetic factors are involved in the development of type 2 diabetes. The associations between physical activity and diabetes risk have been assessed by a number of prospective studies and clinical trials. The results from these studies consistently indicate that the regular physical activity during occupation, commuting, leisure time or daily life reduces the risk of type 2 diabetes by 15-60%; and lifestyle intervention, including counselling for physical activity, nutrition, and body weight, can reduce the risk of type 2 diabetes by 40-60% among adults with impaired glucose tolerance and by about 20% among general individuals. In the past decade, studies using traditional linkage analysis and candidate-gene association approach have found dozens of genes harboring common variants that were related to the common-form type 2 diabetes. However, most reported associations are lack of reproducibility, except TCF7L2, PPARG, CAPN10, and KCNJ11. Since 2007, seven genome-wide association (GWA) studies emerged to generate a list of new diabetes genes. The genetic effects are largely of moderate size. These findings provide novel insight into the diabetes etiology and pave new avenue for predicting the disease risk using genetic information. In addition, data especially those from intervention trials display preliminary but promising evidence that the genetic variants might interact with physical activity in predisposing to type 2 diabetes. The gene-environment interactions merit extensive exploration in large, prospective studies.     

高强度间歇训练改善认知功能及其机制研究进展

高强度间歇训练(high-intensity interval training,HIIT)己被证明是一种省时、高效的运动策略.与传统的中、低强度有氧运动相比,它可以提供类似甚至更好的健康效益.近年来一些研究表明,HIIT可作为一种有前途的运动康复疗法来改善肥胖、糖尿病、中风、痴呆等疾病引起的认知功能受损.因此,本文综...     

Diabetes, lipids, and adipocyte secretagogues.

That obesity is associated with insulin resistance and type II diabetes mellitus is well accepted. Overloading of white adipose tissue beyond its storage capacity leads to lipid disorders in non-adipose tissues, namely skeletal and cardiac muscles, pancreas, and liver, effects that are often mediated through increased non-esterified fatty acid fluxes. This in turn leads to a tissue-specific disordered insulin response and increased lipid deposition and lipotoxicity, coupled to abnormal plasma metabolic and (or) lipoprotein profiles. Thus, the importance of functional adipocytes is crucial, as highlighted by the disorders seen in both "too much" (obesity) and "too little" (lipodystrophy) white adipose tissue. However, beyond its capacity for fat storage, white adipose tissue is now well recognised as an endocrine tissue producing multiple hormones whose plasma levels are altered in obese, insulin-resistant, and diabetic subjects. The consequence of these hormonal alterations with respect to both glucose and lipid metabolism in insulin target tissues is just beginning to be understood. The present review will focus on a number of these hormones: acylation-stimulating protein, leptin, adiponectin, tumour necrosis factor alpha, interleukin-6, and resistin, defining their changes induced in obesity and diabetes mellitus and highlighting their functional properties that may protect or worsen lipid metabolism.     

Physical activity, cardiorespiratory fitness and insulin resistance: a short update

PURPOSE OF REVIEW: High levels of cardiorespiratory fitness and/or habitual physical activity are associated with reduced risk of cardiovascular disease. The responsible mechanisms are multifarious, but effects on insulin sensitivity are likely to play an important role. The purpose of this review is to highlight some recent evidence on the interrelationships between physical activity, fitness, obesity, genotype and insulin resistance. RECENT FINDINGS: Effects on cardiorespiratory fitness and abdominal obesity are both likely to contribute to the insulin-sensitizing effects of regular physical activity. Recent data suggest that at least in older adults, the intensity of an exercise intervention may influence the magnitude of changes in insulin sensitivity, and emerging data suggest that individual changes in insulin sensitivity following an exercise programme may, in part, be influenced by genotype. SUMMARY: Increasing physical activity reduces insulin resistance. As both intensity of exercise and genetic factors may modulate the magnitude of this effect, current physical activity for health guidelines that emphasize engagement in moderate-intensity physical activity in a 'one-size-fits-all' approach may need revision in the future to optimize the potential benefits accrued from individuals becoming more active.     

Nutritional State Affects the Expression of the Obesity‐Associated Genes Etv5, Faim2, Fto,and Negr1

Obesity is a risk factor for type II diabetes, atherosclerosis, and some forms of cancer. Variation in common measures of obesity (e.g., BMI, waist/hip ratio) is largely explained by heritability. The advent of genome‐wide association studies (GWAS) has made it possible to identify several genetic variants that associate with measures of obesity, but how exactly these genetic variants contribute to overweight has remained largely unresolved. One first hint is given by the fact that many of the associated variants reside in or near genes that act in the central nervous system, which implicates neuronal signaling in the etiology of obesity. Although the brain controls both energy intake and expenditure, it has more capacity to regulate energy intake rather than energy expenditure. In environments where food is abundant, this renders the body prone to weight increases. To gain more insight into the neurobiological mechanisms involved, we set out to investigate the effect of dietary exposure on the expression levels of obesity‐associated genes in the ventro‐medial hypothalamus (VMH)/arcuate nucleus (ARC) and the substantia nigra (SN)/ventral tegmental area (VTA), two brain regions that are implicated in feeding behavior. We show that the expression of Etv5, Faim2, Fto, Negr1 but not Sh2b1 is affected by nutritional state in these two areas, thereby providing insight into the relationship between nutritional state and expression levels of obesity‐associated genes in two brain areas relevant to feeding.     

Sex differences in heritability of BMI: a comparative study of results from twin studies in eight countries.

Body mass index (BMI), a simple anthropometric measure, is the most frequently used measure of adiposity and has been instrumental in documenting the worldwide increase in the prevalence of obesity witnessed during the last decades. Although this increase in overweight and obesity is thought to be mainly due to environmental changes, i.e., sedentary lifestyles and high caloric diets, consistent evidence from twin studies demonstrates high heritability and the importance of genetic differences for normal variation in BMI. We analysed self-reported data on BMI from approximately 37,000 complete twin pairs (including opposite sex pairs) aged 20-29 and 30-39 from eight different twin registries participating in the GenomEUtwin project. Quantitative genetic analyses were conducted and sex differences were explored. Variation in BMI was greater for women than for men, and in both sexes was primarily explained by additive genetic variance in all countries. Sex differences in the variance components were consistently significant. Results from analyses of opposite sex pairs also showed evidence of sex-specific genetic effects suggesting there may be some differences between men and women in the genetic factors that influence variation in BMI. These results encourage the continued search for genes of importance to the body composition and the development of obesity. Furthermore, they suggest that strategies to identify predisposing genes may benefit from taking into account potential sex specific effects.     

Leveraging eQTLs to identify individual-level tissue of interest for a complex trait

Genetic predisposition for complex traits often acts through multiple tissues at different time points during development. As a simple example, the genetic predisposition for obesity could be manifested either through inherited variants that control metabolism through regulation of genes expressed in the brain, or that control fat storage through dysregulation of genes expressed in adipose tissue, or both. Here we describe a statistical approach that leverages tissue-specific expression quantitative trait loci (eQTLs) corresponding to tissue-specific genes to prioritize a relevant tissue underlying the genetic predisposition of a given individual for a complex trait. Unlike existing approaches that prioritize relevant tissues for the trait in the population, our approach probabilistically quantifies the tissue-wise genetic contribution to the trait for a given individual. We hypothesize that for a subgroup of individuals the genetic contribution to the trait can be mediated primarily through a specific tissue. Through simulations using the UK Biobank, we show that our approach can predict the relevant tissue accurately and can cluster individuals according to their tissue-specific genetic architecture. We analyze body mass index (BMI) and waist to hip ratio adjusted for BMI (WHRadjBMI) in the UK Biobank to identify subgroups of individuals whose genetic predisposition act primarily through brain versus adipose tissue, and adipose versus muscle tissue, respectively. Notably, we find that these individuals have specific phenotypic features beyond BMI and WHRadjBMI that distinguish them from random individuals in the data, suggesting biological effects of tissue-specific genetic contribution for these traits.