Abstract 摘要
To tackle the burden of obesity-induced cardiometabolic disease, the scientific community relies on accurate and reproducible adiposity measurements in the clinic. These measurements guide our understanding of underlying biological mechanisms and clinical outcomes of human trials. However, measuring adiposity and adipose tissue distribution in a clinical setting can be challenging, and different measurement methods pose important limitations. BMI is a simple and high-throughput measurement, but it is associated relatively poorly with clinical outcomes when compared with waist-to-hip and sagittal abdominal diameter measurements. Body composition measurements by dual energy X-ray absorptiometry or MRI scans would be ideal due to their high accuracy, but are not high-throughput. Another important consideration is that adiposity measurements vary between men and women, between adults and children, and between people of different ethnic backgrounds.
为应对肥胖引发的心脏代谢疾病负担,科学界依赖于临床中准确且可重复的肥胖测量。这些测量指导我们理解基础生物学机制及人体试验的临床结果。然而,在临床环境中测量肥胖及脂肪组织分布颇具挑战,不同测量方法存在显著局限性。BMI 作为一种简单且高通量的测量手段,与腰臀比及矢状腹径测量相比,其与临床结果的相关性相对较弱。双能 X 线吸收法或 MRI 扫描进行的身体成分测量因其高精度而理想,但并非高通量。另一重要考量是,肥胖测量在男女之间、成人与儿童之间以及不同种族背景的人群中存在差异。
In this Perspective article, we discuss how these critical challenges can affect our interpretation of research data in the field of obesity and the design and implementation of clinical guidelines.
在这篇观点文章中,我们讨论了这些关键挑战如何影响我们对肥胖领域研究数据的解读以及临床指南的设计与实施。
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Introduction 引言
Obesity increases the risks of developing cardiometabolic disease, and reduces life expectancy by approximately 5 to 20 years1. However, increased adiposity might not be the only driver of this increased risk of disease, as body adipose tissue distribution, specifically elevated visceral adipose tissue (VAT) mass, influences disease risk independently of total weight2. Although initially regarded as a homogeneous tissue, adipose is now recognized as an important endocrine organ with depot-specific differences (Box 1). It is particularly noteworthy that subcutaneous and visceral white adipose tissues respond differently to metabolic challenges, with variations in endothelial function, lipid turnover and susceptibility to vasculature inflammation3,4,5. Furthermore, increased VAT mass, relative to subcutaneous adipose tissue (SAT) mass, is associated with an elevated risk of developing cardiometabolic conditions, such as type 2 diabetes mellitus (T2DM), hypertension and cardiovascular disease6. Understanding the individual patient’s adipose tissue distribution can thus provide critical insight into obesity-related pathophysiology and aid therapeutic approaches, but this endeavour requires accurate clinical measurements of body adipose tissue and its distribution.
肥胖增加了患心血管代谢疾病的风险,并使预期寿命减少约 5 至 20 年 1 。然而,体脂增加可能并非疾病风险增加的唯一驱动因素,因为身体脂肪组织分布,特别是内脏脂肪组织(VAT)质量的增加,独立于总体重影响疾病风险 2 。尽管最初被视为同质组织,脂肪现在被认识到是一个重要的内分泌器官,具有部位特异性差异(见框 1)。特别值得注意的是,皮下和内脏白色脂肪组织对代谢挑战的反应不同,表现在内皮功能、脂质周转和对血管炎症的易感性上的差异 3,4,5 。此外,相对于皮下脂肪组织(SAT)质量,VAT 质量的增加与患心血管代谢疾病(如 2 型糖尿病(T2DM)、高血压和心血管疾病)的风险升高相关 6 。 了解个体患者的脂肪组织分布因此能为肥胖相关病理生理学提供关键见解,并辅助治疗方法,但这一努力需要准确临床测量身体脂肪组织及其分布。
However, performing accurate adiposity measurements is challenging, particularly in a clinical research setting. There is no one-size-fits-all method that accurately captures an individual’s total body adiposity and adipose tissue distribution. Various measurement techniques, such as BMI, bioelectrical impedance analysis (BIA), dual-energy X-ray absorptiometry (DXA) and MRI, all provide different insights7 (Tables 1,2), making it difficult to choose a single, universally applicable method. Many measurements are influenced by hydration, muscle mass or bone density, leading to potential inaccuracies, while cost and accessibility can limit the use of advanced imaging techniques in resource-constrained clinical settings. The accuracy of each measurement method is also a critical concern8, as treatment plans and weight loss tracking rely heavily on precision. This Perspective article discusses the importance of carefully selecting and interpreting adiposity and adipose tissue distribution measurements, the strengths and weaknesses of the respective approaches, and how these challenges can influence our understanding and interpretation of research data.
然而,进行准确的肥胖测量具有挑战性,特别是在临床研究环境中。没有一种放之四海而皆准的方法能够精确捕捉个体的总体肥胖程度和脂肪组织分布。多种测量技术,如 BMI、生物电阻抗分析(BIA)、双能 X 射线吸收法(DXA)和 MRI,各自提供了不同的见解 7 (表 1、2),这使得选择一种普遍适用的单一方法变得困难。许多测量结果受水分、肌肉量或骨密度的影响,可能导致不准确,而成本和可及性则限制了在资源有限的临床环境中使用先进的成像技术。每种测量方法的准确性也是一个关键问题 8 ,因为治疗计划和减重追踪高度依赖于精确性。本文讨论了精心选择和解释肥胖及脂肪组织分布测量的重要性、各自方法的优缺点,以及这些挑战如何影响我们对研究数据的理解和解释。
Adiposity in different populations
不同人群中的肥胖
The function of adipose tissue differs depending on its anatomical location (Box 1; Fig. 1). In addition, adipose tissue function and distribution can vary between children and adults, people of different ethnic backgrounds, and women and men. This variation calls for a need to apply age-specific, ethnicity-specific and sex-specific standards when analysing body composition, as these parameters can influence clinical interpretation and the risk of developing obesity-related diseases and comorbidities.
脂肪组织的功能因其解剖位置而异(框 1;图 1)。此外,脂肪组织的功能和分布在儿童与成人、不同种族背景的人群以及女性和男性之间可能存在差异。这种差异要求在分析身体成分时应用年龄特定、种族特定和性别特定的标准,因为这些参数可能影响临床解释以及发展肥胖相关疾病和合并症的风险。
Adiposity differences in children versus adults
儿童与成人之间的肥胖差异
The prevalence of childhood obesity remains substantial9,10,11, and as mothers can genetically ‘imprint’ the risk of developing obesity onto their children, the disease burden can span generations12,13.
儿童肥胖的患病率仍然居高不下 9,10,11 ,由于母亲能够通过基因将肥胖风险“印记”给子女,这种疾病负担可能跨越数代 12,13 。
Historically, infant size and shape are quantified by standard anthropometry, beginning with birthweight14. However, relatively little is understood about body composition during infancy. Importantly, the first 1,000 days (that is, from conception to the age of 2 years) represent a ‘critical window’ that can affect growth and development, and potentially also body composition15. A global consensus on definitions and protocols for body composition assessment in infancy would thus be most valuable to the field16. Indeed, recent attempts to assemble growth and body composition trajectories in infants have been made (for example, in a 2022 study using air displacement plethysmography17). Nonetheless, more research is needed to determine how infant weight and adipose tissue distribution affects long-term trends and predictive outcomes of an individual’s risk of developing cardiometabolic disease.
历史上,婴儿的体型和形态通过标准人体测量学进行量化,始于出生体重 14 。然而,对于婴儿期的身体组成了解相对较少。重要的是,最初的 1000 天(即从受孕到 2 岁)代表了一个“关键窗口”,可以影响生长和发育,并可能影响身体组成 15 。因此,关于婴儿身体组成评估的定义和协议的全球共识对该领域将极为宝贵 16 。事实上,最近已经尝试汇编婴儿的生长和身体组成轨迹(例如,在 2022 年的一项使用空气置换体积描记法的研究 17 )。尽管如此,还需要更多的研究来确定婴儿体重和脂肪组织分布如何影响长期趋势以及个体发展心脏代谢疾病风险的预测结果。
In children, weight gain is usually based on fat-free mass, rather than fat mass, as the proportion of adipose tissue mass declines during childhood, at least until puberty. It is challenging to assess body composition alterations related to children’s growth as it occurs in spurts18, but in adolescence, a higher BMI is associated with increased risk of disease development later in life (for example, T2DM and cardiometabolic disease)19,20,21. Similar to the findings in adults, ethnicity and sex affect both obesity prevalence22 and adiposity distribution23 in children.
在儿童中,体重增加通常基于无脂肪质量,而非脂肪质量,因为儿童期脂肪组织质量的比例下降,至少直到青春期。评估与儿童生长相关的身体成分变化具有挑战性,因为这种变化是间歇性的 18 ,但在青春期,较高的 BMI 与日后疾病(如 2 型糖尿病和心脏代谢疾病)发展风险增加相关 19,20,21 。与成人的研究结果相似,种族和性别影响儿童的肥胖率 22 和脂肪分布 23 。
Unfortunately, obesity research is poorly validated in children, and it remains unclear how the scientific community should handle this issue. For instance, what clinical guidelines are appropriate for weight-loss interventions in children? It is known that gastric bypass causes nutritional deficits in ;vitamin B12, folic acid, iron, calcium and thiamine due to rearrangement of the gastrointestinal tract24. Although bariatric surgery appears to be low-risk in adolescents25,26, how a lifelong nutritional deficit and supplementation therapy affects an individual’s physiology and cardiometabolic status remains poorly understood, and more research in this field would be welcome.
遗憾的是,儿童肥胖研究的验证不足,科学界应如何处理这一问题仍不明确。例如,针对儿童减重干预的临床指南应如何制定?已知胃旁路手术因胃肠道重组会导致维生素 B 12 、叶酸、铁、钙和硫胺素的营养缺乏 24 。尽管减重手术在青少年中似乎风险较低 25,26 ,但终身营养缺乏及补充疗法如何影响个体的生理和心脏代谢状态仍知之甚少,该领域亟需更多研究。
Ethnicity-related differences in adiposity and adipose tissue distribution
与种族相关的肥胖和脂肪组织分布差异
The prevalence of obesity-induced T2DM varies across different ethnic groups27, with some of the most high-risk groups being Hispanic people, African people and some Asian subpopulations28. Furthermore, T2DM onset occurs at a younger age and at lower BMI thresholds in African and Asian populations compared with European populations29,30.
肥胖诱发的 2 型糖尿病(T2DM)的患病率在不同种族群体中存在差异 27 ,其中一些高风险群体包括西班牙裔人群、非洲裔人群以及某些亚洲亚群体 28 。此外,与欧洲人群相比,非洲和亚洲人群的 T2DM 发病年龄更早,且 BMI 阈值更低 29,30 。
Body adipose tissue distribution patterns vary between ethnicities, and this variation might partly explain ethnic differences in obesity-associated disease risks. The underlying mechanisms are still not understood, but probably involve genetic traits that influence body adipose tissue distribution30. Within the same obesity category, Asian individuals typically present with more VAT than African or European individuals, which might explain the higher risk of developing T2DM in some Asian populations compared with other ethnic groups28,31,32. This could indicate that the SAT expansion capacity in individuals of Asian ethnicity is insufficient to support a high-calorie intake. Genome-wide association studies have identified loci that might genetically predispose ethnic differences in adipose tissue distribution and contribute to understanding ethnicity-dependent adipose tissue distribution diversity31. Interestingly, it is speculated that the ethnicity-specific differences in adipose tissue distribution and function could also be related to adipose tissue-induced systemic oxidative stress, and thus oxidative stress could contribute to the elevated susceptibility to metabolic diseases specifically in African women33.
身体脂肪组织分布模式在不同种族之间存在差异,这种差异可能部分解释了与肥胖相关疾病风险的种族差异。其潜在机制尚不清楚,但可能涉及影响身体脂肪组织分布的遗传特征 30 。在同一肥胖类别中,亚洲个体通常比非洲或欧洲个体拥有更多的内脏脂肪组织(VAT),这可能解释了某些亚洲人群相比其他种族群体发展 2 型糖尿病(T2DM)风险更高的原因 28,31,32 。这可能表明亚洲种族个体的皮下脂肪组织(SAT)扩展能力不足以支持高热量摄入。全基因组关联研究已经识别出可能遗传性地导致脂肪组织分布种族差异的基因位点,并有助于理解依赖于种族的脂肪组织分布多样性 31 。 有趣的是,据推测,脂肪组织分布和功能的种族特异性差异也可能与脂肪组织诱导的全身氧化应激有关,因此氧化应激可能特别增加了非洲女性对代谢疾病的易感性 33 。
Importantly, randomized trials have shown that all ethnic groups benefit from weight loss; for example, the UK-based DiRECT trial including predominantly Europeans34, the Qatar-based DIADEM-I trial including participants of Middle Eastern descent35, and the STANDby trial including South Asian people with obesity36. However, despite progress in the past decade, there is the prevailing problem of unreported race and/or ethnicity data of participants enrolled in studies, and the over-representation of white people in many risk-association studies and clinical trials37.
重要的是,随机试验表明所有种族群体都能从减重中获益;例如,以欧洲人为主的英国 DiRECT 试验 34 ,包含中东裔参与者的卡塔尔 DIADEM-I 试验 35 ,以及针对南亚肥胖人群的 STANDby 试验 36 。然而,尽管过去十年有所进展,研究中参与者种族和/或民族数据未报告的问题普遍存在,且许多风险关联研究和临床试验中白人比例过高 37 。
To conclude, we highlight the fact that some ethnic groups are under-represented in body-composition investigations. Due to the relative lack of comparable data, it remains uncertain what methodology is the most appropriate for comparing adiposity across different ethnic groups38.
综上所述,我们强调指出,某些族群在身体成分研究中的代表性不足。由于相对缺乏可比数据,目前尚不确定哪种方法最适合用于比较不同族群间的肥胖程度 38 。
Sex differences in adipose tissue distribution and function
脂肪组织分布和功能的性别差异
Clinical observation and epidemiological evidence shows that women, at a population level, can live longer with overweight and obesity without developing T2DM than men39,40. This finding is largely attributed to differences in adipose tissue distribution, as women have more subcutaneous and gluteal adipose tissue and a ‘pear-shaped’ adipose tissue distribution, while men have more VAT and an ‘apple-shaped’ adipose tissue distribution, which is associated with cardiometabolic risk factors41,42. The underlying mechanisms behind altered adipose distribution in men and women are still not entirely understood but are probably multifactorial. Important contributors are sex hormones, cell-intrinsic factors, adipose depot microenvironments and tissue-specific genetic and epigenetic influences43.
临床观察和流行病学证据表明,在群体水平上,女性在超重和肥胖状态下比男性更长寿且不易发展为 2 型糖尿病(T2DM) 39,40 。这一发现主要归因于脂肪组织分布的差异,女性拥有更多的皮下和臀部脂肪组织,呈现“梨形”脂肪分布,而男性则更多内脏脂肪组织(VAT),呈现“苹果形”脂肪分布,后者与心脏代谢风险因素相关 41,42 。男女脂肪分布差异背后的机制尚未完全明了,但可能是多因素共同作用的结果,包括性激素、细胞内在因素、脂肪库微环境以及组织特异性遗传和表观遗传影响 43 。
Sex differences in adiposity emerge during puberty and diminish at the onset of menopause. Indeed, menopause shifts the female adipose tissue function (increased adipocyte hypertrophy, immune cell infiltration and fibrosis) and adipose tissue distribution towards a more central obesity pattern resembling that of men44, thereby demonstrating the importance that sex hormones play in adipose tissue distribution. Thus, biological actions of oestrogen and its receptor are a key component to sex differences in adipose distribution, and women with high testosterone levels (due to polycystic ovary syndrome) are at an increased risk of developing T2DM, compared with women with normal levels of testosterone, irrespective of age and BMI45. However, androgen hormones are not necessarily responsible for poor metabolic outcomes, as testosterone deficiency due to hypogonadism increases men’s risk of developing T2DM and cardiovascular disease46. Importantly, sex also has an effect on the overall ‘health’ of adipose tissues, which is not necessarily related to the depot-specific distribution differences between men and women. For instance, male adipose tissues are more likely to be inflamed and have increased fibrosis relative to female adipose tissues, regardless of distribution42, which, importantly, increases susceptibility to T2DM47.
青春期期间,性别差异在脂肪分布上显现,并在更年期开始时减弱。实际上,更年期使女性脂肪组织功能(脂肪细胞肥大、免疫细胞浸润和纤维化增加)及脂肪分布向更类似于男性的中心性肥胖模式转变 44 ,这证明了性激素在脂肪分布中的重要性。因此,雌激素及其受体的生物学作用是脂肪分布性别差异的关键因素,且与睾酮水平正常的女性相比,睾酮水平高的女性(由于多囊卵巢综合征)不论年龄和 BMI 如何,患 2 型糖尿病(T2DM)的风险增加 45 。然而,雄激素并不必然导致不良代谢结果,因为性腺功能减退导致的睾酮缺乏会增加男性患 T2DM 和心血管疾病的风险 46 。重要的是,性别也影响脂肪组织的整体“健康”,这并不一定与男女之间特定脂肪库分布的差异相关。 例如,相对于女性脂肪组织,男性脂肪组织更容易发生炎症并增加纤维化,无论其分布如何 42 ,这一点显著增加了对 2 型糖尿病(T2DM)的易感性 47 。
Understanding the mechanisms that govern adipose distribution and sex differences in humans presents opportunities to advance the field of precision medicine. Such advances would be particularly useful for the early identification of at-risk individuals and the development of novel therapeutic strategies that alleviate central obesity and related cardiometabolic disorders43. However, our understanding of mechanisms and underlying sex-dependent differences in adiposity and cardiometabolic disease risk is still developing. A prominent example is the finding that, although women with obesity live longer without developing hyperglycaemia than men, they are at a higher risk of exhibiting subclinical atherosclerosis if they progress to T2DM39,40. Indeed, women with obesity who also have T2DM present more rapidly with cardiovascular risk factors than men, regardless of age or race48,49,50,51. The greater impact of T2DM in women cannot be understated, particularly as the general awareness about the extent of cardiovascular disease in women remains underappreciated. We argue that sex differences should be a factor to consider when studying an individual’s risk of obesity and metabolic dysfunction. Sex is important for determining treatment strategies and clinical guidelines, as well as for providing opportunities for precision medicine.
理解调控人体脂肪分布及性别差异的机制,为精准医学领域的发展提供了契机。这些进展尤其有助于早期识别高危个体,并开发缓解中心性肥胖及相关心脏代谢疾病的新型治疗策略 43 。然而,我们对于脂肪堆积及心脏代谢疾病风险中性别依赖性差异的机制理解仍在发展中。一个显著的例子是,尽管肥胖女性在未发展为高血糖的情况下比男性寿命更长,但若进展至 2 型糖尿病(T2DM),她们表现出亚临床动脉粥样硬化的风险更高 39,40 。事实上,患有 T2DM 的肥胖女性,无论年龄或种族,比男性更快出现心血管风险因素 48,49,50,51 。T2DM 对女性的更大影响不容忽视,尤其是考虑到公众对女性心血管疾病程度的认识仍显不足。 我们认为,在研究个体肥胖和代谢功能障碍风险时,性别差异应作为一个考虑因素。性别对于确定治疗策略和临床指南至关重要,同时也为精准医学提供了机会。
Measuring adiposity in the clinic
在诊所测量肥胖程度
A range of tools and methods have been developed to quantify adiposity and body composition (Fig. 2; Tables 1,2). Each method has advantages and limitations, and their appropriateness depends on factors such as the level of accuracy required, accessibility, and the specific population being studied. Although practical to implement, BMI and other anthropometric surrogate measures are relatively poor predictors of an individual’s adipose tissue distribution and metabolic risk; therefore, body composition measurements that assess the relative proportion and placement of adipose tissue, muscle and bone are often considered more valuable. The choice usually comes down to a trade-off between cost and availability. To choose the most adequate method, and importantly, to interpret data correctly, it is essential to discuss the strengths and weaknesses of the respective methods (Tables 1,2). This can be particularly relevant for large clinical trials and weight-loss interventions (Supplementary Box 1). Indeed, large clinical trials are often unable to implement the use of accurate but expensive diagnostic imaging methods, such as DXA or MRI. In addition, substantial weight loss can alter body composition to the extent that certain measurements become less accurate (for example, due to belly and skin displacement), as outlined in this section.
一系列工具和方法已被开发用于量化肥胖和身体成分(图 2;表 1、2)。每种方法都有其优势和局限性,其适用性取决于所需精度水平、可及性以及研究的具体人群等因素。尽管 BMI 和其他人体测量替代指标实施起来较为方便,但在预测个体脂肪组织分布和代谢风险方面相对较差;因此,评估脂肪组织、肌肉和骨骼相对比例及分布的身体成分测量通常被认为更具价值。选择通常归结为成本与可用性之间的权衡。为了选择最合适的方法,并正确解读数据,讨论各自方法的优缺点至关重要(表 1、2)。这对于大型临床试验和减重干预尤其相关(补充框 1)。实际上,大型临床试验往往无法采用准确但昂贵的诊断成像方法,如 DXA 或 MRI。 此外,如本节所述,显著的体重减轻可能会改变身体成分,以至于某些测量结果变得不太准确(例如,由于腹部和皮肤位移)。
Anthropometric indices 人体测量指标
Anthropometric measurements are quantitative measurements of the body used to assess various physical characteristics. These measurements include parameters such as height, weight, circumference of different body parts (such as waist, hip and limbs), skinfold thickness and BMI, which are routinely used to quantify the level of obesity and body composition.
人体测量学测量是用于评估各种身体特征的定量测量。这些测量包括身高、体重、不同身体部位(如腰围、臀围和四肢)的围度、皮褶厚度和 BMI 等参数,这些参数通常用于量化肥胖水平和身体成分。
BMI is a numerical value calculated from an individual’s weight and height. The major benefit of BMI is that it is easy to calculate. Thus, it has been used extensively in clinical practice and obesity research, and is the basis for WHO’s definition of overweight (BMI 25.0–29.9 kg/m2) and obesity (BMI ≥30 kg/m2)52. In epidemiological studies, BMI is helpful when investigating the prevalence of obesity in large populations, tracking trends over time and assessing the effect of obesity on health. Clinically, BMI is used to categorize patients; for example, an individual must typically fall within obesity class III (BMI ≥40 kg/m2) to qualify for gastric bypass surgery. Although BMI has been a cornerstone of obesity research and clinical practice for decades, relying solely on BMI has several limitations and can lead to an incomplete or even misleading understanding of the complexities of obesity. For instance, BMI does not consider factors such as muscle mass, meaning that individuals with a high muscle mass might be classified as having overweight or obesity, even though they have low body fat content. For a given BMI, an individual’s body adipose tissue percentage also changes with age, and the rate of this change differs depending on sex, ethnicity and individual differences53,54,55,56. Most importantly, although BMI is associated with lipid accumulation and metabolic health in large populations, it is insensitive to the actual distribution of body lipids and adipose tissue, which is critically important for assessing an individual’s metabolic health. As a result, BMI has a relatively poor association with cardiometabolic outcomes, and the community is discussing if the BMI measurement has ‘missed the target’ and should be revised57,58. At the very least, we argue that BMI should only be used in conjunction with other measurements to provide a more comprehensive understanding of the relationship between body weight and health.
BMI 是根据个体的体重和身高计算得出的数值。BMI 的主要优点在于其易于计算。因此,它被广泛应用于临床实践和肥胖研究中,并且是世界卫生组织(WHO)定义超重(BMI 25.0–29.9 kg/m²)和肥胖(BMI ≥30 kg/m²)的基础。在流行病学研究中,BMI 有助于调查大规模人群中肥胖的患病率、追踪时间趋势以及评估肥胖对健康的影响。临床上,BMI 用于对患者进行分类;例如,个体通常必须达到肥胖 III 级(BMI ≥40 kg/m²)才有资格接受胃旁路手术。尽管几十年来 BMI 一直是肥胖研究和临床实践的基石,但仅依赖 BMI 存在一些局限性,可能导致对肥胖复杂性的理解不完整甚至误导。例如,BMI 未考虑肌肉质量等因素,这意味着肌肉质量高的个体可能被归类为超重或肥胖,即使他们的体脂含