肥胖治疗的研究进展

肥胖(obesity)为慢性代谢疾病,具有高发病率及世界流行趋势;能量摄入长期多于能量消耗,可导致机体脂肪过度蓄积,为肥胖的主要病因之一。肥胖高发于欧美发达国家。中国肥胖人口亦迅速增长,呈全国急速发展态势。肥胖并发症主要为冠心病、2型糖尿病、高血压、中风及癌症等。肥胖及其并发症不仅对健康构成严重威胁,亦对社会经济及医疗卫生体系造成沉重负担。肥胖的治疗是当前世界医学界面临的严峻挑战。因此,研究肥胖发病机理、对其实施有效预防与治疗,对提高人民健康水平具有重要意义。我们参考世界卫生组织、中国社科院及中国疾病控制中心的官方数据,并结合一系列重要医学期刊发表的研究成果,综述近五年来肥胖机制与药物应用研究进展,以期为肥胖防治及减肥药物研发提供新的参考信息。     

Obesity and cardiovascular disease

Available evidence clearly indicates a rapid progression in the prevalence of obesity worldwide. As a consequence, there has also been a marked increase in the prevalence of type 2 diabetes all over the world and this chronic metabolic disease is now considered as a coronary heart disease risk equivalent. However, even in the absence of the hyperglycaemic state which characterizes type 2 diabetic patients, non diabetic individuals with a specific form of obesity, named abdominal obesity, often show clustering metabolic abnormalities which include high triglyceride levels, increased apolipoprotein B, small dense low density lipoproteins and decreased high density lipoproteins-cholesterol levels, a hyperinsulinemic-insulin resistant state, alterations in coagulation factors as well as an inflammatory profile. This agglomeration of abnormalities has been referred to as the metabolic syndrome which can be identified by the presence of three of the five following variables: abdominal obesity, elevated triglyceride concentrations, low HDL-cholesterol levels, increased blood pressure and elevated fasting glucose. Post-mortem analyses of coronary arteries have indicated that obesity (associated with a high accumulation of abdominal fat measured at autopsy) was predictive of earlier and greater extent of large vessels atherosclerosis as well as increase of coronary fatty streaks. Metabolic syndrome linked to abdominal obesity is also predictive of recurrent coronary events both in post-myocardial infarction patients and among coronary artery disease men who underwent a revascularization procedures. It is suggested that until the epidemic progression of obesity is stopped and obesity prevented or at least properly managed, cardiologists will be confronted to an evolving contribution of risk factors where smoking, hypercholesterolemia and hypertension may be relatively less prevalent but at the expense of a much greater contribution of abdominal obesity and related features of the metabolic syndrome.     

Obesity and hypertension: It's about more than the numbers

Objective:

This editorial comments on the recent Obesity Society and American Society of Hypertension joint position paper, justified by the substantial link between obesity and hypertension (HTN).

Design and Methods:

The editorial reviews the expert opinions. Other relevant clinical research is highlighted, such as an obesity paradox. Evidence‐based lifestyle changes, drugs, and behavorial modification and newer agents are highlighted.

Results:

Areas of controversy are noted. Despite the importance of renin angiotensin system blockage, future federal guidelines may maintain thiazides as first choice, even with metabolic syndrome (MetS) and diabetes (DM). Chlorthalidone, 12.5‐25 mg, has shown cardiovascular benefit, including with MetS and DM.

Conclusion:

The conclusion calls for more research. However, the identification and elimination of racial/ethnic disparities should be addressed more explicitly. To better understand the obesity–hypertension linkage, curtail costs, and decrease premature disease and death, this excellent position paper is essential.     

Clinical Considerations Regarding the Use of Obesity Pharmacotherapy in Adolescents with Obesity

A growing number of youth suffer from obesity and in particular severe obesity for which intensive lifestyle intervention does not adequately reduce excess adiposity. A treatment gap exists wherein effective treatment options for an adolescent with severe obesity include intensive lifestyle modification or metabolic and bariatric surgery while the application of obesity pharmacotherapy remains largely underutilized. These youth often present with numerous obesity‐related comorbid diseases, including hypertension, dyslipidemia, prediabetes/type 2 diabetes, obstructive sleep apnea, nonalcoholic fatty liver disease, musculoskeletal problems, and psychosocial issues such as depression, anxiety, and social stigmatization. Current pediatric obesity treatment algorithms for pediatric primary care providers focus primarily on intensive lifestyle intervention with escalation of treatment intensity through four stages of intervention. Although a recent surge in the number of Food and Drug Administration‐approved medications for obesity treatment has emerged in adults, pharmacotherapy options for youth remain limited. Recognizing treatment and knowledge gaps related to pharmacological agents and the urgent need for more effective treatment strategies in this population, discussed here are the efficacy, safety, and clinical application of obesity pharmacotherapy in youth with obesity based on current literature. Legal ramifications, informed consent regulations, and appropriate off‐label use of these medications in pediatrics are included, focusing on prescribing practices and prescriber limits.     

Obesity disease management opportunities and barriers

Disease management, a system of coordinated health care interventions and communications for chronically ill populations, relies on patient education and case management to engage individuals in the management of their condition. Disease management also aims to enhance the quality of interactions between doctors and patients and advance evidence-based medicine. Because these programs' interventions frequently include helping individuals who suffer comorbidities associated with obesity to reduce their BMI, adaptation of disease management to populations with obesity seems a viable option. A major barrier for implementing disease management for obesity, however, is the lack of proven return on investment, which limits health plan and disease management organization interest. Purchaser demand may overcome this reluctance. Further research is needed to objectively test whether disease management interventions would be clinically effective for obese populations, produce positive financial outcomes for insurers, and enhance workplace productivity.     

Obesity and inflammation

The prevalence of obesity has recently increased dramatically and has contributed to the increasing prevalence of various pathological conditions, including type 2 diabetes mellitus, nonalcoholic fatty liver disease, asthma, various types of cancer, cardiovascular and neurodegenerative diseases, and others. Accumulating evidence points to localized inflammation in adipose tissue, which, in turn, promotes systemic low-grade inflammation as a primary force contributing to the development of these pathologies. A better understanding of the underlying mechanisms behind obesity-induced adipose tissue inflammation is required to develop effective therapeutic or prophylactic strategies. This review is aimed to present the current knowledge of adipose tissue inflammation associated with obesity.     

Obesity in Europe

Obesity, defined as a body mass index > 30 kg/m² is relatively common in Europe, particularly among women, and especially in Southern and Eastern European countries. Among men the distribution of body mass index values is surprisingly similar in most countries of Europe. Educational level is strongly inversely associated with the prevalence of obesity. Although differences in body mass index cannot entirely explain the large variation in risk factors and mortality from coronary heart disease, it can be shown that within populations an increased body mass index is associated with less favorable risk patterns. More research is needed to elucidate the reasons for the large variation in the prevalence of obesity among European women and to the health risks associated with obesity in different European countries.     

Attitudes,Perceptions, and Practices Among Endocrinologists Managing Obesity

ObjectiveObesity has been globally recognized as a critically important disease by professional medical organizations, in addition to the World Health Organization and American Medical Association, but health care systems, medical teams, and the public have been slow to embrace this concept.MethodsThe American Association of Clinical Endocrinology staff drafted a survey, and 2 endocrinologists independently reviewed the survey’s questions and modified the survey instrument. The survey included questions related to practice and patient demographics, awareness about obesity, treatment of obesity, barriers to improving obesity outcomes, digital health, cognitive behavioral therapy, lifestyle medicine, antiobesity medications, weight stigma, and social determinants of health. The survey was emailed to 493 endocrinologists, with 305 (62%) completing the study.ResultsOf the responders, 98% agreed that obesity is a disease, whereas 2% neither agreed nor disagreed. Of the respondents, 53% were familiar with the term “adiposity-based chronic disease” and 13% were certified by the American Board of Obesity Medicine. Of the respondents, 57% used published obesity guidelines as a resource for treating patients with obesity. Most endocrinologists recommended dietary and lifestyle changes, but fewer prescribed an antiobesity medication or recommended bariatric surgery. American Board of Obesity Medicine-certified endocrinologists were more likely to use a multidisciplinary approach.ConclusionSelf-reported knowledge and practices in the management of obesity highlight the importance of a multimodal approach to obesity and foster collaboration among health care professionals. It is necessary to raise awareness about obesity among clinicians, identify knowledge gaps, and create educational tools to address those gaps.     

人Leptin和肥胖的研究进展

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。最近人和小鼠的肥胖基因被相继克隆,发现它能在脂肪组织特异表达,其编码的蛋白Leptin可作用于下丘脑,产生抑制摄食、减轻肥胖、减少体重的作用。此外,它还对生殖系统、造血系统等有调节作用。     

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)     

The Case for Medical Management of Obesity: A Call for Increased Physician Involvement

The United States is in the midst of an escalating epidemic of obesity. Over one-third of the adult population in the United States is currently obese and the prevalence of obesity is growing rapidly. By any criteria, obesity represents a chronic disease which is associated with a wide range of comorbidities, including coronary heart disease (CHD), Type 2 diabetes, hypertension and dyslipidemias. The comorbidities of obesity are common, occurring in over 70% of individuals with a BMI of ≥ 27. In addition to obesity itself, excessive accumulation of visceral abdominal fat and significant adult weight gain also represent health risks. Physicians have an important role to play in the treatment of obesity. Unfortunately, the medical community has not been involved actively enough to help stem the major epidemic of obesity occurring in the United States. This article puts forth a proposed model for the treatment of obesity in clinical practice, including obtaining the “vital signs” of obesity, recommending lifestyle measures, and instituting pharmacologic therapy when appropriate. By utilizing a chronic disease treatment model, physicians can join other health care professionals to effectively treat the chronic disease of obesity. Relatively modest weight loss, on the order of 510% of initial body weight can result in significant health improvements for many patients and represent an achievable goal for most obese patients.     

Dealing With Obesity as a Chronic Disease

There are major efforts underway to educate the primary care physician about the health risks of obesity. Obesity is a chronic disease that requires chronic management. We must establish models that allow primary care physicians to participate in the chronic management of obesity, while recognizing that the interest and ability of primary care physicians to participate in obesity management will vary. Three general models of obesity management are proposed for the primary care physician, ranging from minimal evaluation to complete evaluation and treatment. In order for the models to be implemented, we must consider establishing a category of obesity specialists who can develop comprehensive treatment programs to which patients with obesity can be referred, and who can provide leadership and guidance for primary care physicians who are involved in obesity management. The North American Association for the Study of Obesity (NAASO) could help establish obesity specialists and provide a structure to allow them to provide leadership for obesity treatment.     

Obesity epidemic: origins and consequences

Obesity is a chronic disease with serious health consequences. Initial weight gain is related to behavioural and environmental factors acting on a biological (mainly genetic) predisposition. The evolution of the disease is characterized by the development of an inflammatory organ disease that involves the adipocytes and other adipose tissue components. These alterations lead to various clinical complications and to a progressive resistance to diet effects. The treatment of obesity must be adapted to the stage of development of the disease and to the prevalent complications.     

蛋白质组学在肥胖症研究中的应用

在世界范围内,肥胖及其相关代谢性疾病的发生率逐年增加,尤其是儿童肥胖症的普遍存在引起了广泛关注。过度肥胖是2型糖尿病、心血管疾病和一些肿瘤的重要危险因素。有关肥胖症的研究过去主要集中在脂肪组织功能改变,脂肪细胞分化,棕色脂肪转化,线粒体功能失调,以及肠道营养物质吸收这些方面的分子生物学研究。肥胖作为一种复杂的代谢紊乱性疾病,基因层面的探索并不能全面体现肥胖的机体内各种参与能量代谢的蛋白质功能的变化。高通量蛋白质组学的应用为研究肥胖的机体蛋白质表达和功能变化提供了可能,并为进一步理解肥胖症的发病机理,寻找疾病相关干预靶点提供了重要的帮助。本综述,总结了近年来关于蛋白质组学在肥胖症病理生理变化中的相关研究,并讨论参与肥胖症发生的可能机制和干预作用靶点。     

Evaluation of Drugs for Treating Obesity

Criteria for the evaluation of new drugs to treat obesity are important as guides for designing clinical trials to test these agents. These criteria must be developed in relation to the realities of obesity, which is a chronic disease associated with morbidity and mortality that is increased by visceral fat deposits. The observation that patients regain weight after stopping drug treatment for obesity argues for the proposition that drugs work only when taken and NOT that the drugs are ineffective. The analogy between the development of treatments for obesity to those for the treatment of hypertension is used to highlight potential areas for new developments. Several features of an ideal drug for the treatment of obesity are suggested. Criteria for evaluating new drugs include both primary and secondary endpoints. The primary endpoint for an anti-obesity drug should be weight loss, possibly by category of success. Losses of total body fat or visceral fat might be alternative primary endpoints. Secondary endpoints include reduction in risk factors for associated diseases and improvement in the quality of life. In trials where vigorous placebo designs including highly aggressive behavior modification or very-low-calorie diets were used, it may be difficult or impossible to detect a response to a drug.     

Addictive Genes and the Relationship to Obesity and Inflammation

There is increasing evidence that the same brain reward circuits involved in perpetuating drug abuse are involved in the hedonic urges and food cravings observed clinically in overweight and obese subjects. A polymorphism of the D2 dopamine receptor which renders it less sensitive to dopamine stimulation has been proposed to promote self-stimulatory behavior such as consuming alcohol, abusing drugs, or binging on foods. It is important to determine how this polymorphism may interact with other well-known candidate genes for obesity including polymorphisms of the leptin receptor gene and the opiomelanocortin gene. Leptin is a proinflammatory cytokine as well as a long-term signal maintaining body fat. Upper-body obesity stimulates systemic inflammation through the action of multiple cytokines including leptin throughout many organs including the brain. The association of numerous diseases including diabetes mellitus, heart disease, as well as depression with chronic low-grade inflammation due to abdominal obesity has raised the possibility that obesity-associated inflammation affecting the brain may promote addictive behaviors leading to a self-perpetuating cycle that may affect not only foods but addictions to drugs, alcohol, and gambling. This new area of interdisciplinary research holds the promise of developing new approaches to treating drug abuse and obesity.     

Analysis of the regulatory motifs in eukaryotic initiation factor 4E-binding protein 1

Mammalian target of rapamycin complex 1 (mTORC1) phosphorylates proteins such as eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and the S6 kinases. These substrates contain short sequences, termed TOR signalling (TOS) motifs, which interact with the mTORC1 component raptor. Phosphorylation of 4E-BP1 requires an additional feature, termed the RAIP motif (Arg-Ala-Ile-Pro). We have analysed the interaction of 4E-BP1 with raptor and the amino acid residues required for functional RAIP and TOS motifs, as assessed by raptor binding and the phosphorylation of 4E-BP1 in human cells. Binding of 4E-BP1 to raptor strongly depends on an intact TOS motif, but the RAIP motif and additional C-terminal features of 4E-BP1 also contribute to this interaction. Mutational analysis of 4E-BP1 reveals that isoleucine is a key feature of the RAIP motif, that proline is also very important and that there is greater tolerance for substitution of the first two residues. Within the TOS motif, the first position (phenylalanine in the known motifs) is most critical, whereas a wider range of residues function in other positions (although an uncharged aliphatic residue is preferred at position three). These data provide important information on the structural requirements for efficient signalling downstream of mTORC1.     

Covid-19 & Obesity: Beyond Bmi

The pandemic of novel coronavirus disease 2019 (COVID-19) has triggered an international crisis resulting in excess morbidity and mortality with adverse societal, economic, and geopolitical consequences. Like other disease states, there are patient characteristics that impact clinical risk and determine the spectrum of severity. Obesity, or adiposity-based chronic disease, has emerged as an important risk factor for morbidity and mortality due to COVID-19. It is imperative to further stratify risk in patients with obesity to determine optimal mitigation and perhaps therapeutic preparedness strategies. We suspect that insulin resistance is an important pathophysiologic cause of poor outcomes in patients with obesity and COVID-19 independent of body mass index. This explains the association of type 2 diabetes mellitus (T2DM), hypertension (HTN), and cardiovascular disease with poor outcomes since insulin resistance is the main driver of both dysglycemia-based chronic disease and cardiometabolic-based chronic disease towards end-stage disease manifestations. Staging the severity of adiposity-related disease in a “complication-centric” manner (HTN, dyslipidemia, metabolic syndrome, T2DM, obstructive sleep apnea, etc.) among different ethnic groups in patients with COVID-19 should help predict the adverse risk of adiposity on patient health in a pragmatic and actionable manner during this pandemic.     

The Obesity Epidemic and Its Impact on Urologic Care

Although heart disease and cancer are the number one and two causes of death in the United States, respectively, obesity is gaining speed as a contributing cause to both of those conditions, along with diabetes, arthritis, dyslipidemia, coronary heart disease, gallbladder disease, and certain malignancies. Nearly one-third of the adults in the United States is overweight with a body mass index (BMI) greater than 25 kg/m², and another third of the adult population is obese, with a BMI greater than 30 kg/m². This article reviews the root causes of obesity, the societal implications, and the implications of obesity on various urologic diseases.Key words: Obesity, Morbid obesity, Body mass index, Exercise, Weight loss, Diet, EpidemicMore than 20% of adults in the United States are clinically obese, defined by a body mass index (BMI) of 30 kg/m² or higher, and an additional 30% are overweight, with a BMI between 25 and 30 kg/m².¹ An environment that promotes excessive food intake and discourages physical activity lies at the root of the current obesity epidemic. Although humans have excellent physiologic mechanisms to defend against body weight loss, they have only weak physiologic mechanisms to defend against body weight gain when food is abundant. So much has been discussed about the obesity epidemic that it’s easy to think the issue is being blown out of proportion. After all, people putting on a few pounds may not seem to warrant the proclamation of a national emergency. Although obesity may not attract the degree of attention that heart disease and cancer do, it is a serious public health issue. Experts agree that, as more and more obese children become obese adults, the diseases associated with obesity, such as heart disease, cancer, and particularly diabetes, will surge.The obesity epidemic in the United States is an unintended consequence of the economic, social, and technologic advances realized during the past several decades. The food supply is abundant and low in cost, and palatable foods with high caloric density are readily available in prepackaged forms and at fast-food restaurants. Laborsaving technologies have greatly reduced the amount of physical activity that used to be part of everyday life, and the widespread availability of electronic devices in the home, school, and office has promoted a sedentary lifestyle, particularly among children.A recent study estimated that medical expenditures attributed to overweight and obesity accounted for 9.1% of total US medical expenditures in 1998, and might have reached $78.5 billion dollars.² Today, the healthcare costs attributed to obesity are estimated to be $190 billion—nearly 21% of total US healthcare costs.³ Expenditures will continue to rise, particularly due to increases in the prevalence of obesity and the cost of related healthcare.Total healthcare costs attributable to this obesity epidemic are expected to double every decade, reaching $860.7 to $956.9 billion by 2030, accounting for 16% to 18% of total US healthcare costs, or 1 in every 6 dollars spent on healthcare. ⁴ In addition, obesity is likely to result in a decreased life expectancy for our population. Current US generations may have a shorter life expectancy than their parents if this obesity epidemic cannot be controlled.⁵ Based on nationally representative data and the assumptions of a future of increased obesity rates, along with increased healthcare costs, this paints an alarming picture of the future obesity epidemic. Projections show that if the trends continue, in 15 years, 80% of all American adults will be overweight or obese.⁶     

Multiple Dimensions of Socioeconomic Position and Obesity among Employees: The Helsinki Health Study

Objective: To examine socioeconomic differences in obesity using several different socioeconomic indicators, ranging from childhood socioeconomic environment and adult socioeconomic status to material resources and economic satisfaction. Research Methods and Procedures: The data derived from the Helsinki Health Study baseline surveys in 2000 and 2001. Respondents to postal surveys were middle‐aged employees of the City of Helsinki (4, 975 women and 1, 252 men, response rate 68%). Associations between eight socioeconomic indicators and obesity (BMI ≥ 30 kg/m²), calculated from self‐reported data, were examined by fitting a series of logistic regression models. Results: In women, all socioeconomic indicators except household income and economic satisfaction were associated with obesity. Parental education and childhood economic difficulties, i.e., socioeconomic conditions in childhood, remained associated with obesity after adjusting for all indicators of current socioeconomic position. Indicators of adult socioeconomic status, own education and occupational class, were no longer associated with obesity when childhood socioeconomic conditions were adjusted for. Home ownership and economic difficulties were associated with obesity after full adjustments. In men, the findings paralleled those among women, but few associations reached statistical significance. Discussion: Obesity was associated with several dimensions of socioeconomic position. Childhood socioeconomic disadvantage was associated with obesity independently of the various indicators of current socioeconomic position. Associations between obesity and both educational level and occupational class disappeared after adjustment for other indicators of socioeconomic position. This suggests that the variation observed in the prevalence of obesity by these key socioeconomic indicators may reflect differences in the related material resources.