肥胖的研究进展

肥胖已经成为一种社会现象,其发病过程复杂,危害严重,近年来的研究表明,肥胖是一种由食欲和能量调节紊乱引起的疾病,与遗传、环境、膳食结构等多种因素有关,其中基因是主要的决定因素,肥胖与Ⅱ型糖尿病、心血管疾病、某些肿瘤等有明确的关系。目前对肥胖的治疗尚处于探索时期,１９９４年发现的苗条素（leptin)仍然是争论的一大焦点。本文综述介绍了肥胖的流行、病因、危害与治疗,并对苗条素进行了比较详细的介绍,以帮助读者了解肥胖的概貌、基础研究进展以及部分临床问题。     

Bariatric surgery to unload the stressed heart: a metabolic hypothesis

Obesity is an independent risk factor for cardiovascular disease. Data from the Framingham Study have reported a higher incidence of heart failure in obese individuals compared with a normal cohort. The body initially copes with the abundance of fuel present in an obese milieu by storing it in adipose tissue. However, when the storage capacity is exceeded, the excess energy is taken up and stored ectopically as fat in vital organs such as the heart. Indeed, intramyocardial lipid overload is present in hearts of obese patients, as well as in hearts of animal models of obesity, and is associated with a distinct gene expression profile and cardiac dysfunction. By imposing a metabolic stress on the heart, obesity causes it to hypertrophy and ultimately to fail. Conventional measures to treat obesity include diet, exercise, and drugs. More recently, weight loss surgery (WLS) has achieved increasing prominence because of its ability to reduce the neurohumoral load, normalize metabolic dysregulation, and improve overall survival. The effects of WLS on systemic metabolic, neurohumoral, and hemodynamic parameters are well described and include an early normalization of serum glucose and insulin levels as well as reduction in blood pressure. WLS is also associated with reverse cardiac remodeling, regression of left ventricular hypertrophy, and improved left ventricular and right ventricular function. By targeting the source of the excess energy, we hypothesize that WLS improves contractile function by limiting exogenous substrate availability to the metabolically overloaded heart. These changes have also been found to be associated with increased levels of adiponectin and improved insulin sensitivity. Taken together, the sustained beneficial effects of WLS on left ventricular mass and function highlight the need to better understand the mechanism by which obesity regulates cardiovascular physiology.     

The emergence of obesity among indigenous Siberians

Once considered a disease of affluence and confined to industrialized nations, obesity is currently emerging as a major health concern in nearly every country in the world. Available data suggest that the prevalence rate of obesity has reached unprecedented levels in most developing countries, and is increasing at a rate that far outpaces that of developed nations. This increase in obesity has also been documented among North American circumpolar populations and is associated with lifestyle changes related to economic development. While obesity has not been well studied among indigenous Siberians, recent anthropological studies indicate that obesity and its associated comorbidities are important health problems.The present study examines recent adult body composition data from four indigenous Siberian populations (Evenki, Ket, Buriat, and Yakut) with two main objectives: 1) to determine the prevalence of overweight and obesity among these groups, and 2) to assess the influence of lifestyle and socioeconomic factors on the development of excess body fat. The results of this study indicate that obesity has emerged as an important health issue among indigenous Siberians, and especially for women, whose obesity rates are considerably higher than those of men (12% vs. 7%). The present study investigated the association between lifestyle and body composition among the Yakut, and documented substantial sex differences in lifestyle correlates of obesity. Yakut men with higher incomes and who owned more luxury consumer goods were more likely to have excess body fat while, among Yakut women, affluence was not strongly associated with overweight and obesity.     

The role of apolipoprotein A5 in obesity and the metabolic syndrome

Apolipoprotein A5 (apoA5) has an important role in lipid metabolism, specifically for triglyceride‐rich lipoproteins. Recently, evidence has emerged for an association between genetic variability at the APOA5 locus and increased risk of obesity and metabolic syndrome. However, its mechanism of action remains to be fully elucidated. Importantly, an intracellular role of apoA5 has been indicated since apoA5 is associated with cytoplasmic lipid droplets and affects intrahepatic triglyceride accumulation, as well as affecting intravascular triglyceride metabolism. Given that adipocytes provide the largest storage depot for energy in the form of triglyceride within the lipid droplets, and play a crucial role in the development of obesity, we highlight recent findings discussing the interaction of apoA5 with adipocytes or adipose tissue, indicating that apoA5 may act as a novel regulator to modulate triglyceride storage in adipocytes. We review the association of APOA5 gene polymorphisms with obesity and metabolic syndrome, and propose potential mechanisms by which apoA5 may increase susceptibility to these conditions. This review provides new insights into the physiological role of apoA5 and identifies a potential therapeutic target for obesity and associated disorders.     

Mediterranean diet and metabolic diseases

PURPOSE OF REVIEW: The objective of this article is to present evidence illustrating the relationship between Mediterranean diets and metabolic diseases, including obesity, type 2 diabetes, and the metabolic syndrome, and to briefly discuss potential mechanisms by which these diets can help in disease prevention and treatment. RECENT FINDINGS: Although the Mediterranean diet has long been celebrated for its impact on cardiovascular health, mounting evidence indicates a favorable effect on obesity and type 2 diabetes, as well. While health promotion strategies aimed at preventing adult obesity are emphasizing components of Mediterranean dietary patterns, a role for Mediterranean diets in attenuating the inflammatory burden associated with type 2 diabetes is also emerging. Moreover, a lower prevalence of the metabolic syndrome is associated with dietary patterns rich in fruits, vegetables, whole grains, dairy products, and unsaturated fats. Both epidemiological and interventional studies have revealed a protective effect of the Mediterranean diet against mild chronic inflammation and its metabolic complications. SUMMARY: Mounting evidence suggests that Mediterranean diets could serve as an anti-inflammatory dietary pattern, which could help fighting diseases that are related to chronic inflammation, including visceral obesity, type 2 diabetes and the metabolic syndrome.     

Galanin and its receptors: a novel strategy for appetite control and obesity therapy

The rapid increase in the prevalence of overweight and obesity is becoming an important health problem. Overweight and obesity may cause several metabolic complications, including type 2 diabetes mellitus, hyperlipidemia, high cholesterol, coronary artery disease as well as hypertension. Prevention and treatment of obesity will benefit the treatment of these related diseases. Current strategies for treatment of obesity are not adequately effective and are frequently companied with many side effects. Thus, new ways to treat obesity are urgently needed. Galanin is undoubtedly involved in the regulation of food intake and body weight. The aim of this review is to provide up-to-date knowledge concerning the roles of central and peripheral galanin as well as its receptors in the regulation of metabolism, obesity and appetite. We also highlight the mechanisms of galanin and its receptors in experimental obesity, trying to establish a novel anti-obesity strategy.     

The adipose organ at a glance

The main parenchymal cells of the adipose organ are adipocytes. White adipocytes store energy, whereas brown adipocytes dissipate energy for thermogenesis. These two cell types with opposing functions can both originate from endothelial cells, and co-exist in the multiple fat depots of the adipose organ – a feature that I propose is crucial for this organ’s plasticity. This poster review provides an overview of the adipose organ, describing its anatomy, cytology, physiological function and histopathology in obesity. It also highlights the remarkable plasticity of the adipose organ, explaining theories of adipocyte transdifferentiation during chronic cold exposure, physical exercise or lactation, as well as in obesity. White-to-brown adipocyte transdifferentiation is of particular medical relevance, because animal data indicate that higher amounts of brown adipose tissue are positively associated with resistance to obesity and its co-morbidities, and that ‘browning’ of the adipose organ curbs these disorders.     

Bofu-Tsu-Shosan,an Oriental Herbal Medicine,Exerts a Combinatorial Favorable Metabolic Modulation Including Antihypertensive Effect on a Mouse Model of Human Metabolic Disorders with Visceral Obesity

Accumulating evidence indicates that metabolic dysfunction with visceral obesity is a major medical problem associated with the development of hypertension, type 2 diabetes (T2DM) and dyslipidemia, and ultimately severe cardiovascular and renal disease. Therefore, an effective anti-obesity treatment with a concomitant improvement in metabolic profile is important for the treatment of metabolic dysfunction with visceral obesity. Bofu-tsu-shosan (BOF) is one of oriental herbal medicine and is clinically available to treat obesity in Japan. Although BOF is a candidate as a novel therapeutic strategy to improve metabolic dysfunction with obesity, the mechanism of its beneficial effect is not fully elucidated. Here, we investigated mechanism of therapeutic effects of BOF on KKAy mice, a model of human metabolic disorders with obesity. Chronic treatment of KKAy mice with BOF persistently decreased food intake, body weight gain, low-density lipoprotein cholesterol and systolic blood pressure. In addition, both tissue weight and cell size of white adipose tissue (WAT) were decreased, with concomitant increases in the expression of adiponectin and peroxisome proliferator-activated receptors genes in WAT as well as the circulating adiponectin level by BOF treatment. Furthermore, gene expression of uncoupling protein-1, a thermogenesis factor, in brown adipose tissue and rectal temperature were both elevated by BOF. Intriguingly, plasma acylated-ghrelin, an active form of orexigenic hormone, and short-term food intake were significantly decreased by single bolus administration of BOF. These results indicate that BOF exerts a combinatorial favorable metabolic modulation including antihypertensive effect, at least partially, via its beneficial effect on adipose tissue function and its appetite-inhibitory property through suppression on the ghrelin system.     

MicroRNAs: Emerging roles in adipogenesis and obesity

Obesity is a serious health problem worldwide associated with an increased risk of life-threatening diseases such as type 2 diabetes, atherosclerosis, and certain types of cancer. Understanding the molecular basis of adipogenesis and fat cell development in obesity is essential to identify new biomarkers and therapeutic targets for the development of anti-obesity drugs. Recent computational and experimental studies have shown that microRNAs (miRNAs) appear to play regulatory roles in many biological processes associated with obesity, including adipocyte differentiation and lipid metabolism. In addition, many miRNAs are dysregulated in metabolic tissues from obese animals and humans, which potentially contributes to the pathogenesis of obesity-associated complications. The discovery of circulating miRNAs has highlighted their potential as both endocrine signaling molecules and disease markers. The potential of miRNA based therapeutics targeting obesity is highlighted as well as recommendations for future research which could lead to a breakthrough in the treatment of obesity.     

Adipose tissue as an endocrine organ: role of leptin and adiponectin in the pathogenesis of cardiovascular diseases

Obesity, the most common nutritional disorder in industrial countries, is associated with increased cardiovascular mortality and morbidity. Nevertheless, the molecular basis linking obesity with cardiovascular disturbances have not yet been fully clarified. Recent advances in the biology of adipose tissue indicate that it is not simply an energy storage organ, but also a secretory organ, producing a variety of bioactive substances, including leptin and adiponectin, that may influence the function as well as the structural integrity of the cardiovascular system. Leptin, besides being a satiety signal for the central nervous system and to be related to insulin and glucose metabolism, may also play an important role in regulating vascular tone because of the widespread distribution of functional receptors in the vascular cells. On the other hand, the more recently discovered protein, adiponectin, seems to play a protective role in experimental models of vascular injury, in probable relation to its ability to suppress the attachment of monocytes to endothelial cells, which is an early event in the atherosclerotic process. There is already considerable evidence linking altered production of some adipocyte hormones with the cardiovascular complications of obesity. Therefore, the knowledge of alterations in the endocrine function of adipose tissue may help to further understand the high cardiovascular risk associated with obesity.     

microRNAs in the regulation of adipogenesis and obesity

Worldwide obesity is a growing health problem, associated with increased risk of chronic disease. Understanding the molecular basis of adipogenesis and fat cell development in obesity is essential to identify new biomarkers and therapeutic targets for the development of anti-obesity drugs. microRNAs (miRNAs) appear to play regulatory roles in many biological processes associated with obesity, including adipocyte differentiation, insulin action and fat metabolism. Recent studies show miRNAs are dysregulated in obese adipose tissue. During adipogenesis miRNAs can accelerate or inhibit adipocyte differentiation and hence regulate fat cell development. In addition miRNAs may regulate adipogenic lineage commitment in multipotent stem cells and hence govern fat cell numbers. Recent findings suggest miR-519d may be associated with human obesity, but larger case-control studies are needed. Few miRNA targets have been experimentally validated in adipocytes but interestingly both miR-27 and miR-519d target PPAR family members, which are well established regulators of fat cell development. In this review recent advances in our understanding of the role of miRNAs in fat cell development and obesity are discussed. The potential of miRNA based therapeutics targeting obesity is highlighted as well as recommendations for future research which could lead to a breakthrough in the treatment of obesity.     

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.     

Obesity‐related hypertension: Pathogenesis,cardiovascular risk,and treatment—A position paper of the The Obesity Society and the American Society of Hypertension

In light of the worldwide epidemic of obesity, and in recognition of hypertension as a major factor in the cardiovascular morbidity and mortality associated with obesity, The Obesity Society and The American Society of Hypertension agreed to jointly sponsor a position paper on obesity‐related hypertension to be published jointly in the journals of each society. The purpose is to inform the members of both societies, as well as practicing clinicians, with a timely review of the association between obesity and high blood pressure, the risk that this association entails, and the options for rational, evidenced‐based treatment. The position paper is divided into six sections plus a summary as follows: pathophysiology, epidemiology and cardiovascular risk, the metabolic syndrome, lifestyle management in prevention and treatment, pharmacologic treatment of hypertension in the obese, and the medical and surgical treatment of obesity in obese hypertensive patients. Obesity (2012)     

Fetal programming of adipose tissue function: an evolutionary perspective

Obesity is an escalating threat of pandemic proportions and has risen to such unrivaled prominence in such a short period of time that it has come to define a whole generation in many countries around the globe. The burden of obesity, however, is not equally shared among the population, with certain ethnicities being more prone to obesity than others, while some appear to be resistant to obesity altogether. The reasons behind this ethnic basis for obesity resistance and susceptibility, however, have remained largely elusive. In recent years, much evidence has shown that the level of brown adipose tissue thermogenesis, which augments energy expenditure and is negatively associated with obesity in both rodents and humans, varies greatly between ethnicities. Interestingly, the incidence of low birth weight, which is associated with an increased propensity for obesity and cardiovascular disease in later life, has also been shown to vary by ethnic background. This review serves to reconcile ethnic variations in BAT development and function with ethnic differences in birth weight outcomes to argue that the variation in obesity susceptibility between ethnic groups may have its origins in the in utero programming of BAT development and function as a result of evolutionary adaptation to cold environments.     

Target identification of the novel antiobesity agent tungstate in adipose tissue from obese rats

Adipose tissue plays an active role in the development of obesity, and thus characterization of the molecular changes related to obesity in this tissue is a priority. Recently, we identified tungstate as a potent body weight reducing agent in obese animals, adipose tissue being one of the targets of its action. In this study a proteomics approach combining 2-DE and MS was used to identify proteins associated with obesity and targets of tungstate in white adipose tissue. Twenty-nine proteins were found differentially expressed between lean and diet-induced obese rats. Expression changes in transferrin, vimentin, vinculin, peroxiredoxins, Rho-GTP dissociation inhibitor, grifin, guanine deaminase and 3-phosphoglycerate dehydrogenase were associated here for the first time with obesity. Furthermore, tungstate treatment of obese rats reverted expression changes of 70% of the proteins modulated by obesity and another ten proteins were regulated by tungstate independently of the body weight reduction. The results suggest that the tungstate antiobesity effect can be mediated by the modulation of cellular structure, metabolism, redox state and signalling processes in adipose tissue. These findings open new avenues for the study of the aetiology of obesity and its treatment.     

Association of the FTO rs9939609 polymorphism with obesity in Roma/Gypsy population

The rs9939609 SNP located in the first intron of the fat mass and obesity associated gene (FTO) has been found to be associated with common obesity mainly in populations of European descent. The Roma/Gypsy population as an ethnic minority of Asian Indian origin is well known for its adverse health status with a high prevalence of obesity. The main aim of this study was to examine the contribution of the rs9939609 FTO polymorphism to the high prevalence of obesity in the Roma/Gypsy population. Following a number of anthropometric measurements, the FTO rs9939609 polymorphism was genotyped in 312 Roma/Gypsy individuals. We observed significant differences in body mass index (BMI), waist circumference, and waist-to-hip ratio between different genotypes (P = 0.003, P = 0.012, and P = 0.03, respectively). The waist circumference in the subjects with AA genotype was about 7.1 cm larger than in those with TT genotypes (P = 0.005). However, the strongest association of minor allele A of the rs9939609 FTO polymorphism was found with BMI (odds ratio, 1.55; 95% confidence interval, 1.129-2.128; P = 0.007), even after adjusting for age, sex, and smoking status. This study provides the first report of allele and genotype frequencies for the rs9939609 polymorphism and also the first evidence of the association of the FTO variant with obesity in the Roma/Gypsy population.     

Obesity in Eastern Europe: An overview of its health and economic implications

AIMS: To assess the evolution and patterns of obesity in countries of the WHO European Region with a particular focus on the Eastern European countries, and to discuss the health and economic implications of obesity for those countries. METHODS: The available data on overweight and obesity in children and adults for the countries of the WHO European countries were collated from the International Obesity TaskForce database and considered in the light of estimates for the costs of obesity-related ill health. RESULTS: Overweight and obesity in most countries of Europe show rising secular trends, and are predicted to continue rising if not addressed. Estimates of the costs to the health services and to economic productivity indicate that some countries may find it hard to cope with the burden of obesity: up to 6% of total health care costs and as much in indirect costs of lost productivity could be attributed to obesity and its associated illnesses. CONCLUSIONS: Transition, despite the many benefits it has undoubtedly conferred to the population living in the Region, has also entailed the collateral damage of a fast growing obesity challenge. Policy-makers in the new and candidate EU countries as well as other countries of the European Region can learn from the negative Western European and global experience, act now to stem the obesity epidemic from further developing and in so doing, reduce the substantial economic losses associated with obesity. Local, national and international strategies will be needed to combat the problem.     

Insulin and insulin resistance

As obesity and diabetes reach epidemic proportions in the developed world, the role of insulin resistance and its consequences are gaining prominence. Understanding the role of insulin in wide-ranging physiological processes and the influences on its synthesis and secretion, alongside its actions from the molecular to the whole body level, has significant implications for much chronic disease seen in Westernised populations today. This review provides an overview of insulin, its history, structure, synthesis, secretion, actions and interactions followed by a discussion of insulin resistance and its associated clinical manifestations. Specific areas of focus include the actions of insulin and manifestations of insulin resistance in specific organs and tissues, physiological, environmental and pharmacological influences on insulin action and insulin resistance as well as clinical syndromes associated with insulin resistance. Clinical and functional measures of insulin resistance are also covered. Despite our incomplete understanding of the complex biological mechanisms of insulin action and insulin resistance, we need to consider the dramatic social changes of the past century with respect to physical activity, diet, work, socialisation and sleep patterns. Rapid globalization, urbanisation and industrialization have spawned epidemics of obesity, diabetes and their attendant co-morbidities, as physical inactivity and dietary imbalance unmask latent predisposing genetic traits.     

Obesity in rhesus and cynomolgus macaques: a comparative review of the condition and its implications for research

Obesity is an increasingly important health issue in both humans and animals and has been highly correlated as a risk factor for hyperglycemic conditions in humans. Naturally occurring obesity has been extensively studied in nonhuman primates with a focus on the development of biomarkers for characterizing overweight individuals and tracking the progression of obesity to conditions such as type 2 diabetes mellitus. Animal models have provided a basic understanding of metabolism and carbohydrate physiology, and continue to contribute to ongoing research of obesity and its adverse health effects. This review focuses on spontaneous obesity in rhesus and cynomolgus macaques as a model for human obesity and type 2 diabetes mellitus, including associated risk factors for the development of obesity and obesity-related health conditions. Little is known about preventive measures to minimize obesity while maintaining a healthy colony of macaques, and numerous complexities such as social status, feeding behaviors, timing of feeding, food distribution, and stress have been identified as contributing factors to overweight body condition in both single and group housed nonhuman primates. As in humans, increased body weight and obesity in macaques affect their overall health status. These conditions may interfere with the suitability of some animals in various studies unrelated to obesity.     

Focus: Microbiome: Treating Obesity and Metabolic Syndrome with Fecal Microbiota Transplantation

The worldwide prevalence of metabolic syndrome, which includes obesity and its associated diseases, is rising rapidly. The human gut microbiome is recognized as an independent environmental modulator of host metabolic health and disease. Research in animal models has demonstrated that the gut microbiome has the functional capacity to induce or relieve metabolic syndrome. One way to modify the human gut microbiome is by transplanting fecal matter, which contains an abundance of live microorganisms, from a healthy individual to a diseased one in the hopes of alleviating illness. Here we review recent evidence suggesting efficacy of fecal microbiota transplant (FMT) in animal models and humans for the treatment of obesity and its associated metabolic disorders.