肥胖不是你吃太多？科學家揭開能量平衡模型的真相！

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這篇觀點文章反駁「碳水化合物-胰島素模型」（CIM）對肥胖的解釋，強調「能量平衡模型」（EBM）才是以生物學為基礎的主流理論，認為大腦才是調控體重的關鍵器官，並指出飲食環境與神經調控才是肥胖流行的核心因素。

The energy balance model of obesity: beyond calories in, calories out

肥胖的能量平衡模型：超越卡路里攝入與消耗

Hall KD, Farooqi IS, Friedman JM, et al. 肥胖的能量平衡模型：超越卡路里攝入與消耗。美國臨床營養學雜誌。2022;115(5):1243-1254. doi:10.1093/ajcn/nqac031
Hall KD, Farooqi IS, Friedman JM, et al. The energy balance model of obesity: beyond calories in, calories out. Am J Clin Nutr. 2022;115(5):1243-1254. doi:10.1093/ajcn/nqac031

https://pmc.ncbi.nlm.nih.gov/articles/PMC9071483/

摘要 ABSTRACT

最近的一篇觀點文章描述了“碳水化合物-胰島素模型（CIM）”的肥胖理論，聲稱它“比所謂的主導能量平衡模型（EBM）更能反映體重控制的生物學知識”，而後者未能考慮“促進體重增加的生物機制”。不幸的是，該觀點混淆了能量平衡的原則，這是一條與肥胖機制無關的物理法則，與作為一個堅實基於生物學的肥胖理論模型的 EBM。這樣一來，作者在 CIM 和一個不反映現代肥胖科學的 EBM 的漫畫化版本之間提出了一個錯誤的選擇。在這裡，我們提供了對 EBM 更準確的描述，其中大腦是負責體重調節的主要器官，主要在我們的意識下運作，通過複雜的內分泌、代謝和神經系統信號來控制食物攝入，以響應身體的動態能量需求以及環境影響。 我們還描述了 CIM 的近期歷史，並展示了最新的“最全面的公式”如何放棄了以前要求脂肪在脂肪組織中積累作為正能量平衡主要驅動因素的中心特徵。因此，新的 CIM 可以被視為更全面的 EBM 的特例，但更專注於高升糖負荷飲食作為導致常見肥胖的主要因素。我們回顧了來自各種研究的數據，這些研究針對每個模型的有效性進行了探討，並證明 EBM 是一個比 CIM 更為穩健的肥胖理論。

A recent Perspective article described the “carbohydrate-insulin model (CIM)” of obesity, asserting that it “better reflects knowledge on the biology of weight control” as compared with what was described as the “dominant energy balance model (EBM),” which fails to consider “biological mechanisms that promote weight gain.” Unfortunately, the Perspective conflated and confused the principle of energy balance, a law of physics that is agnostic as to obesity mechanisms, with the EBM as a theoretical model of obesity that is firmly based on biology. In doing so, the authors presented a false choice between the CIM and a caricature of the EBM that does not reflect modern obesity science. Here, we present a more accurate description of the EBM where the brain is the primary organ responsible for body weight regulation operating mainly below our conscious awareness via complex endocrine, metabolic, and nervous system signals to control food intake in response to the body’s dynamic energy needs as well as environmental influences. We also describe the recent history of the CIM and show how the latest “most comprehensive formulation” abandons a formerly central feature that required fat accumulation in adipose tissue to be the primary driver of positive energy balance. As such, the new CIM can be considered a special case of the more comprehensive EBM but with a narrower focus on diets high in glycemic load as the primary factor responsible for common obesity. We review data from a wide variety of studies that address the validity of each model and demonstrate that the EBM is a more robust theory of obesity than the CIM.

關鍵詞：肥胖，食物攝入，能量平衡，碳水化合物，胰島素
Keywords: obesity, food intake, energy balance, carbohydrates, insulin

引言 Introduction

肥胖病理發生的理論模型可以幫助組織和綜合觀察，形成實驗檢驗的假設。這些實驗的結果可以用來完善或駁斥模型，從而更好地理解導致常見肥胖的機制驅動因素。因此，一個基於證據的模型，能夠增進我們對肥胖原因的理解，可以用來設計更有效的肥胖預防和治療干預措施。

Theoretical models of the pathogenesis of obesity can help organize and synthesize observations to form hypotheses for experimental interrogation. The results of such experiments can be used to refine or refute models, thereby leading to a better understanding of the mechanistic drivers of common obesity. Therefore, an evidence-based model that increases our understanding of the factors responsible for obesity can be used to design more effective interventions for obesity prevention and therapy.

成功的模型應該解決有關人類肥胖的兩個重要問題。首先，什麼解釋了人群中脂肪量的個體差異？其次，什麼解釋了過去幾十年來肥胖在人群中的流行率的全球變化？作為第一個問題的部分答案，BMI 具有高度的遺傳性，基因差異解釋了個體之間約 75%的 BMI 變異（ 1 ， 2 ）。關於第二個問題，儘管職業體力活動和建成環境的變化可能通過減少整體體力活動來促進肥胖（ 3 ），但食品環境的變化可能是近幾十年肥胖流行率上升的主要驅動因素（ 4 ）。然而，食品環境中最“促進肥胖”的具體方面以及它們如何與易感個體的遺傳學相互作用以導致肥胖，都是熱烈辯論的主題，競爭性的理論模型涉及不同的機制。

Two important questions regarding human obesity should be addressed by a successful model. First, what explains between-person variability in adiposity in a population? Second, what explains the global shifts in the population prevalence of obesity over the past several decades? As a partial answer to the first question, BMI is highly heritable and genetic differences explain ∼75% of BMI variability among individuals (1, 2). Regarding the second question, although changes in occupational physical activity and the built environment might have contributed to obesity by reducing overall physical activity (3), changes in the food environment are likely the primary driver of the increased obesity prevalence in recent decades (4). However, the specific aspects of the food environment that are most “obesogenic” and how they interact with the genetics of susceptible individuals to cause obesity are topics that are hotly debated, and competing theoretical models implicate different mechanisms.

最近的一篇觀點文章描述了肥胖的理論“碳水化合物-胰島素模型（CIM）”，聲稱它“比作者所描述的‘主導能量平衡模型（EBM）’更能反映對體重控制生物學的認識”，而 EBM 被聲稱為一種“未考慮促進體重增加的生物機制”的肥胖理論（ 5 ）。在這樣做的過程中，作者在 CIM 和 EBM 的卡通化版本之間提出了一個錯誤的選擇，將 EBM 視為一種不反映現代肥胖科學的肥胖理論。

A recent Perspective article described the theoretical “carbohydrate-insulin model (CIM)” of obesity, asserting that it “better reflects knowledge on the biology of weight control” as compared with what the authors described as the “dominant energy balance model (EBM),” which was claimed to conceptualize obesity “without considering the biological mechanisms promoting weight gain” (5). In doing so, the authors presented a false choice between the CIM and a caricature of the EBM as a theory of obesity that does not reflect modern obesity science.

確實，最近的觀點混淆了能量平衡的原則，這是一條與肥胖機制無關的物理定律，與 EBM 作為肥胖的理論模型。該觀點將 EBM 描述為一種“固有的同義反覆”，認為“在所有實際目的上，所有卡路里在代謝上都是相似的”（ 5 ）。這些陳述更恰當地指的是物理定律，而不是 EBM 作為一個基於生物機制的理論模型。為了明確起見，所有的肥胖理論模型，包括 CIM，必須滿足能量平衡的原則，以避免違反物理定律。

Indeed, the recent Perspective conflated and confused the principle of energy balance, a law of physics that is agnostic to obesity mechanisms, with the EBM as a theoretical model of obesity. The Perspective described the EBM as an “inherent tautology” that “considers all calories to be metabolically alike for all practical purposes” (5). These statements more aptly refer to the law of physics and not the EBM as a theoretical model that is firmly based on biological mechanisms. To be clear, all theoretical models of obesity, including the CIM, must satisfy the principle of energy balance to avoid violating the laws of physics.

這篇觀點還描述了一個理論能量平衡模型（EBM）的稻草人版本，假設“能量密集、美味的現代加工食品通過增加攝入量驅動正能量平衡”，在“意識控制”之下（ 5 ）。然而，這對 EBM 的描述並不準確，我們在下面進行澄清。我們還描述了 CIM 的近期歷史，並展示其最新的“最全面的公式”（ 5 ）如何放棄其以前的核心特徵（ 6–9 ），並且可以被視為 EBM 的一個特例，專注於高升糖負荷飲食作為導致肥胖的主要因素。我們回顧了來自各種研究的數據，這些研究針對每個模型的有效性進行了探討，並證明 EBM 是一個比 CIM 更為穩健的肥胖理論。

The Perspective also described a straw-man version of the theoretical EBM postulating that “energy-dense, tasty, modern processed foods drive a positive energy balance through increased intake” under “conscious control” (5). However, this is an inaccurate description of the EBM, which we clarify below. We also describe the recent history of the CIM and show how its latest “most comprehensive formulation” (5) constitutes abandonment of its formerly central feature (6–9) and can be considered as a special case of the EBM that focuses on diets with high glycemic load as the primary factor responsible for obesity. We review data from a wide variety of studies that address the validity of each model and demonstrate that the EBM is a more robust theory of obesity than the CIM.

肥胖的能量平衡模型
The EBM of Obesity

EBM 提出大腦是負責體重調節的主要器官，通過整合來自食物環境的外部信號以及來自周邊器官的內部信號來控制食物攝入（ Figure 1 ）（ 10 ）。特定的大腦區域，如下丘腦、基底神經節和腦幹，通過複雜的內分泌、代謝和神經系統信號在我們的意識下調節食物攝入（ 11–13 ），這些信號是對身體動態能量需求以及環境影響的反應（ 14 ， 15 ）。能量穩態的協調是通過短期信號（例如，胃餓素、肽 YY、類胰高血糖素肽 1（GLP-1）、迷走神經傳入）控制進餐模式（即進食的開始和停止）以及長期信號（例如，瘦素）來調節短期系統的活動，從而增加或減少整體能量攝入。因此，儘管個體的日常能量攝入和能量平衡可能高度變化，但能量平衡的神經調節通常是在較長的時間尺度上實現的（ 16–19 ）。

The EBM proposes that the brain is the primary organ responsible for body weight regulation via integration of external signals from the food environment along with internal signals from peripheral organs to control food intake (Figure 1) (10). Specific brain regions, such as the hypothalamus, basal ganglia, and the brainstem modulate food intake below our conscious awareness via complex endocrine, metabolic, and nervous system signals (11–13) acting in response to the body’s dynamic energy needs as well as environmental influences (14, 15). The orchestration of energy homeostasis occurs through short-term signals [e.g., ghrelin, peptide YY, glucagon-like peptide 1 (GLP-1), vagal afferents] controlling meal patterns (i.e., the initiation and cessation of feeding) and long-term signals (e.g., leptin) that modulate the activity of the short-term system thereby increasing or decreasing overall energy intake. Thus, whereas day-to-day energy intake and energy balance of an individual can be highly variable, neural regulation of energy balance is generally achieved over prolonged time scales (16–19).

圖1

肥胖的能量平衡模型假設，體重是由大腦根據來自食物環境的外部信號進行調節，這些信號與內部信號相結合，以控制食物攝入，低於我們的意識。肥胖的普遍性增加是由於食物環境的變化，導致食物攝入和循環燃料的增加。包括胰島素在內的荷爾蒙對營養攝入和吸收作出反應，以指導代謝流向各個器官的進出，並向大腦提供控制食物攝入的信號。供應給肝臟和肌肉等器官的能量增加，這支持了它們在肥胖發展過程中的增長，並可能導致異位脂質積累。指示各個器官能量狀態的信號被大腦感知，以通過尚未完全闡明的機制控制食物攝入。碳水化合物、脂肪和蛋白質的氧化為身體提供其能量需求，隨著肥胖的發展而增加。 代謝燃料選擇的適應以及內分泌環境的變化確保了整體能量失衡的分配主要反映為脂肪組織三酸甘油脂儲存的變化，無論飲食成分如何。這些過程的遺傳變異，特別是大腦中的變異，對於在特定環境中對肥胖的易感性或抵抗力的個體差異負有相當大的責任。厚藍色箭頭表示能量的流動。GI，腸胃道。

The energy balance model of obesity posits that body weight is regulated by the brain in response to external signals from the food environment that are integrated with internal signals to control food intake below our conscious awareness. Increased prevalence of obesity has resulted from changes in the food environment leading to increased food intake and circulating fuels. Hormones, including insulin, respond to nutrient intake and absorption to direct the flow of metabolic fluxes into and out of various organs and provide signals to the brain that control food intake. Energy supply to organs such as liver and muscle increases, which supports their increased growth during the development of obesity and can result in ectopic lipid accumulation. Signals indicating the energy status of various organs are sensed by the brain to control food intake by mechanisms that remain to be fully elucidated. Oxidation of carbohydrate, fat, and protein provides the body with its energy needs, which increase as obesity develops. Adaptations of metabolic fuel selection as well as changes in the endocrine milieu ensure that partitioning of overall energy imbalances are primarily reflected as changes in adipose tissue triglyceride storage regardless of diet composition. Inherited variation in the operation of these processes, particularly those in the brain, are responsible for a substantial proportion of the interindividual difference in susceptibility or resistance to developing obesity in a particular environment. Thick blue arrows indicate the flow of energy. GI, gastrointestinal.

EBM 提出，近幾十年來肥胖的普遍性增加主要是由於食品環境的變化，包括各種便宜、方便、高能量密度的超加工食品的可獲得性和市場推廣增加，這些食品的份量大、脂肪和糖含量高，而蛋白質和纖維含量低。CIM 觀點淡化了食物的“喜好”或可口性在驅動肥胖方面的潛在作用（ 5 ）。然而，可口性只是食物獎勵這一多面向概念的一個維度，涉及激勵顯著性、渴望和動機，這些主要在我們的意識下運作（ 11 ）。

The EBM proposes that the increasing population prevalence of obesity in recent decades is primarily due to changes in the food environment, including increased availability and marketing of a wide variety of inexpensive, convenient, energy-dense, ultraprocessed foods that are high in portion size, fat, and sugar, and low in protein and fiber. The CIM Perspective downplayed the potential role of conscious “liking” or palatability of food in driving obesity (5). However, palatability is only 1 dimension of the multifaceted concept of food reward that involves incentive salience, wanting, and motivation that primarily operate below our conscious awareness (11).

控制能量攝入的腦迴路以開始被闡明的方式對變化的食物環境作出反應，特別是在小鼠模型中（ 20 ， 21 ）。例如，最近在控制恆定性飢餓的表達 agouti 相關肽（AgRP）的下丘腦神經元與影響食物獎勵的中腦多巴胺系統之間識別出一個雙向迴路（ 22 ）。接觸高脂飲食改變了這個雙向迴路的活動，導致過量能量攝入、肥胖的發展，以及對不會引起肥胖的低脂飲食的貶值（ 23 ）。已經識別出不同的腸-腦通路用於感知膳食脂肪和碳水化合物，從而調節下丘腦 AgRP 神經元的活動（ 24 ）和紋狀體多巴胺的釋放（ 11 ）。因此，能量平衡模型與這一觀點一致，即飲食成分，而不僅僅是其熱量含量，可能是中樞神經系統控制食物攝入的重要因素。

Brain circuits controlling energy intake respond to a changing food environment in ways that are beginning to be elucidated, especially in mouse models (20, 21). For example, a bidirectional circuit was recently identified between hypothalamic neurons expressing agouti-related peptide (AgRP) that control homeostatic hunger and the midbrain dopamine system influencing food reward (22). Exposure to a high-fat diet alters the activity of this bidirectional circuit and results in excess energy intake, development of obesity, and devaluation of a low-fat diet that does not induce obesity (23). Distinct gut-brain pathways have been identified for sensing dietary fat and carbohydrate thereby modulating hypothalamic AgRP neuronal activity (24) and striatal dopamine release (11). Therefore, the EBM is consistent with the idea that diet composition, not simply its caloric content, could be an important factor in the central nervous system control of food intake.

能量平衡的物理原則並未明確說明決定能量不平衡如何在體內分配的生物機制，以致主要導致脂肪組織脂肪儲存的變化，與其他身體區域儲存或利用的能量變化相比——這一事實最近被誤解為是能量平衡模型的缺陷（ 25 ）。然而，基於對人類宏量營養素平衡在各種飲食干預下的廣泛研究（ 26–34 ），能量平衡模型納入了能量分配的生理機制，其中飲食成分和數量影響整體的碳水化合物、脂肪和蛋白質的淨氧化速率，使得整體能量不平衡主要反映為脂肪不平衡，無論飲食的成分如何（ 35–37 ）。這種宏量營養素代謝的調節是多種激素協調控制多器官代謝流的結果，包括但不限於胰島素，因此整體脂肪不平衡最終主要反映為脂肪組織脂肪儲存的變化（ 38–40 ）。 因此，能量平衡模型將脂肪組織概念化為一個活躍的內分泌器官，旨在動態協調對能量盈餘和赤字的有效儲存和動員能量（即三酸甘油脂）。

The physical principle of energy balance does not specify the biological mechanisms determining how energy imbalances are partitioned within the body to result primarily in changes in adipose tissue fat stores compared with changes in energy stored or utilized in other body compartments—a fact that has been recently misinterpreted as being a deficiency in the EBM (25). However, based on extensive studies of human macronutrient balance in response to various dietary interventions (26–34), the EBM incorporates physiological mechanisms underlying energy partitioning whereby diet composition and amount affect whole-body net oxidation rates of carbohydrate, fat, and protein such that overall energy imbalances are primarily reflected as fat imbalances regardless of the composition of the diet (35–37). This regulation of macronutrient metabolism is the consequence of coordinated control of multiorgan metabolic fluxes by a variety of hormones, including but not limited to insulin, such that whole-body fat imbalances end up primarily reflected as changes in adipose tissue fat storage (38–40). The EBM therefore conceptualizes adipose tissue as an active endocrine organ evolved to dynamically coordinate the efficient storage and mobilization of energy (i.e., triglycerides) in response to energy surplus and deficit, respectively.

能量平衡模型（EBM）承認，個體在能量分配上的差異可能導致不同程度的肥胖，即使能量攝入沒有差異（ 41 ， 42 ）。這部分是因為瘦體重的增加導致的能量消耗大於脂肪質量的積累。事實上，能量分配的差異解釋了為什麼女性在生長和發展過程中儘管攝入的總卡路里較少，卻比男性積累更多的體脂肪（ 43 ）。此外，在快速生長期間，當正能量平衡與瘦體重的增加相對應時，體脂肪質量可能相對穩定甚至減少（ 44 ）。此外，脂肪組織動態的微妙差異可能影響能量分配和燃料利用，從而在長期內影響身體組成（ 45–49 ），但這些影響對於常見肥胖的程度目前尚不清楚。

The EBM recognizes that individual differences in energy partitioning can result in different degrees of adiposity, even when energy intake is not different (41, 42). This can happen, in part, because accretion of lean body mass results in greater energy expenditure as compared with accumulation of body fat mass. Indeed, energy partitioning differences explain why females accumulate greater body fat than males during growth and development despite consuming fewer total calories (43). Also, body fat mass can be relatively constant or even decrease during periods of rapid growth when positive energy balance corresponds to increasing lean body mass (44). Furthermore, subtle differences in adipose tissue dynamics may affect energy partitioning and fuel utilization thereby influencing body composition over the long term (45–49), but the extent of such influences on common obesity are currently unclear.

EBM 允許在肥胖發展中考慮到身體活動減少的角色，儘管這不一定是因為能量消耗本身的減少，而是因為能量攝入控制的精確度降低（ 3 ， 50 ， 51 ）。此外，其他因素也可以在 EBM 框架內對肥胖的發展起到作用（ 52 ）。

The EBM allows for a role of decreased physical activity in the development of obesity, although not necessarily because of decreased energy expenditure per se but rather due to decreased precision of energy intake control (3, 50, 51). Furthermore, other factors can also play a role in the development of obesity within the EBM framework (52).

上述對能量平衡模型的描述與 Ludwig 等人（ 5 ）在其觀點及其他地方（ 7 ）的特徵化不一致，後者將其視為一種“基本上忽視了對脂肪儲存的生物影響的知識”的理論模型，並提出肥胖是由“對影響能量攝入或支出的行為的有意控制”所導致的。事實上，能量平衡模型強調強大的內部和外部信號影響著我們意識下的能量平衡的神經調節，並解釋了為什麼簡單的建議“少吃多動”對於持續減重是無效的。

The above description of the EBM is inconsistent with the characterization by Ludwig et al. (5) in their Perspective and elsewhere (7) as a theoretical model that “essentially disregards knowledge about the biological influences on fat storage,” proposing that obesity results from “conscious control” of behaviors affecting energy intake or expenditure. Indeed, the EBM emphasizes that powerful internal and external signals influence the neural regulation of energy balance below our conscious awareness and explains why simple advice to “eat less and move more” is ineffective for sustained weight loss.

肥胖的 CIM
The CIM of Obesity

最近的觀點中提出的 CIM（ 5 ）與其之前的版本有著實質性的不同（ 6–9 ）。 Box 1 提供了與此相關的理論概念的簡要歷史，這些概念導致了 Taubes 在 2007 年提出的以脂肪為中心的 CIM（ 9 ），該模型認為肥胖是由於飲食中碳水化合物的增加驅動過量的胰島素分泌，導致脂肪組織積累和囤積脂肪，從而使非脂肪組織缺乏燃料。因此，“通過驅動脂肪積累，碳水化合物也增加了飢餓感，並減少了我們在新陳代謝和身體活動中消耗的能量”（ 9 ），從而導致正能量平衡，能量攝入超過支出。

The CIM presented in the recent Perspective (5) is substantially different from its previous iterations (6–9). Box 1 provides a brief history of related theoretical concepts leading to Taubes’ 2007 proposal (9) of the adipocentric CIM whereby obesity results from increased dietary carbohydrates driving excess insulin secretion causing adipose tissue to accumulate and trap fat thereby starving nonadipose tissues of fuel. Thus, “by driving fat accumulation, carbohydrates also increase hunger and decrease the amount of energy we expend in metabolism and physical activity” (9) thereby resulting in positive energy balance with energy intake exceeding expenditure.

脂肪中心的 CIM 的歷史先例
Historical antecedents of the adipocentric CIM

在 20 世紀初，“脂肪親和性”的概念提出脂肪組織是肥胖中調節失常的主要部位，儘管飲食中的碳水化合物驅動的胰島素分泌並未被牽涉到這一病理生理中（ 143 ）。在 1950 年代初，Pennington（ 144–148 ）提出肥胖者在氧化碳水化合物的能力上存在細胞缺陷，這導致了新生脂肪生成的增加、脂肪組織脂解的抑制，從而導致體脂肪的積累以及能量消耗的減少和食慾的增加。儘管從未發現這種細胞缺陷，Pennington 推測飲食中的碳水化合物驅動的胰島素分泌加劇了這一問題，這有助於解釋他低碳水化合物飲食方案在治療肥胖方面的明顯有效性。1962 年，Astwood（ 149 ）擴展了脂肪親和性的概念，假設某些肥胖者的食慾增加可能是由於胰島素、皮質醇或其他激素的異常作用，這些激素要麼將脂肪困住在脂肪組織中，要麼防止周邊組織中的脂肪氧化。 從 1970 年代中期開始，延續到 1990 年代末，馬克·弗里德曼（ 150–153 ）提出，外周組織，特別是肝臟中的能量感知，提供了控制能量攝入的主要信號給大腦，並指出高脂肪和高碳水化合物的飲食可能導致肥胖，因為燃料分配異常到脂肪組織，導致肝臟能量狀態下降（ 150 ）。

In the early 20th century, the idea of “lipophilia” proposed adipose tissue was the primary site of dysregulation in obesity, although dietary carbohydrate-driven insulin secretion was not implicated in this pathophysiology (143). In the early 1950s, Pennington (144–148) proposed that people with obesity have a cellular defect in their ability to oxidize carbohydrate that resulted in increased de novo lipogenesis, suppression of adipose lipolysis, and thereby resulted in body fat accumulation along with reduced energy expenditure and increased appetite. Although such a cellular defect was never found, Pennington speculated that dietary carbohydrate-driven insulin secretion exacerbated the problem, which helped explain the apparent effectiveness of his low-carbohydrate diet regimen for treating obesity. In 1962, Astwood (149) expanded on the lipophilia concept by hypothesizing that increased appetite in some people with obesity could be due to aberrant action of insulin, cortisol, or other hormones to either trap fat in adipose tissue or prevent fat oxidation in peripheral tissues. Beginning in the mid-1970s and extending into the late 1990s, Mark Friedman (150–153) proposed that energy sensing in peripheral tissues, especially the liver, provides the primary signals to the brain controlling energy intake and noted that diets high in both fat and carbohydrate could be responsible for obesity due to aberrant fuel partitioning to adipose tissue leading to a decrement in liver energy status (150).

在 2000 年代初期，路德維希（ 75 ， 154 ）假設過度飲食是由於攝取高升糖指數的食物，這些食物迅速增加血漿葡萄糖和胰島素，導致在胰島素反應性組織中吸收營養，並在餐後晚期導致循環燃料的減少，這些變化被大腦感知以促進飢餓。2006 年，拉斯蒂格（ 155 ）將日益增加的人口肥胖率與“我們當前的西方飲食[這]是高度促胰島素的，這一點通過其增加的能量密度、高脂肪含量、高升糖指數、增加的果糖成分、減少的纖維和減少的乳製品含量得以證明”聯繫起來。拉斯蒂格提出，自主神經功能障礙加劇了飲食引起的高胰島素血症，這被假設為通過拮抗瘦素信號並增加大腦中的多巴胺來增加能量攝入。路德維希和拉斯蒂格在他們的肥胖模型中都沒有強調脂肪組織胰島素信號的主要作用。 相反，胰島素被認為是同時作用於多個器官，而大腦在控制能量攝入方面扮演了直接角色，無論是通過感知循環燃料的低濃度（ 75 ）還是由於高胰島素血症導致的中樞瘦素和多巴胺信號的改變（ 155 ）。

In the early 2000s, Ludwig (75, 154) hypothesized that overeating is the result of consuming high-glycemic-index foods that rapidly increase plasma glucose and insulin, resulting in uptake of nutrients in insulin-responsive tissues and subsequent decreases in circulating fuels in the late postprandial period that are sensed by the brain to promote hunger. In 2006, Lustig (155) linked increasing population obesity prevalence to “our current Western diet [that] is highly insulinogenic, as demonstrated by its increased energy density, high fat content, high glycemic index, increased fructose composition, decreased fiber, and decreased dairy content.” Lustig proposed that autonomic dysfunction potentiates diet-induced hyperinsulinemia, which was hypothesized to increase energy intake by antagonizing leptin signaling and increasing dopamine in the brain. Neither Ludwig nor Lustig emphasized a primary role of adipose tissue insulin signaling in their models of obesity. Rather, insulin was presumed to act on multiple organs in parallel, and the brain played a direct role in controlling energy intake either by sensing low concentrations of circulating fuels (75) or by altered central leptin and dopamine signaling as a result of hyperinsulinemia (155).

塔布斯通過聲稱“到 1960 年代中期，四個事實已經毫無疑問地確立：1）碳水化合物是促使胰島素分泌的唯一原因；2）胰島素是誘導脂肪積累的唯一原因；3）飲食中的碳水化合物是過量脂肪積累所必需的；4）2 型糖尿病患者和肥胖者的循環胰島素濃度異常升高”來為他的脂肪中心 CIM 辯護[強調添加]（ 9 ）。為了解釋“最近西化人口中肥胖的出現”的流行病學觀察，塔布斯表示，“碳水化合物，特別是精製碳水化合物——也許還有果糖含量，因此消耗的糖量——是胰島素慢性升高的主要嫌疑犯；因此，它們是常見肥胖的最終原因”（ 9 ）。

Taubes justified his adipocentric CIM by asserting that “by the mid-1960s four facts had been established beyond reasonable doubt: 1) carbohydrates are singularly responsible for prompting insulin secretion; 2) insulin is singularly responsible for inducing fat accumulation; 3) dietary carbohydrates are required for excess fat accumulation; and 4) both type 2 diabetics and the obese have abnormally elevated concentrations of circulating insulin” [emphasis added] (9). To explain the epidemiological observations of “the emergence of obesity in recently Westernized populations” Taubes stated that, “carbohydrates, and particularly refined carbohydrates – and perhaps the fructose content as well, and thus the amount of sugars consumed – are the prime suspects in chronic elevation of insulin; hence, they are the ultimate cause of common obesity” (9).

不幸的是，脂肪中心的 CIM 的基本“事實”是錯誤的，特別是關於胰島素和膳食碳水化合物在脂肪組織脂肪代謝中角色的單一性和必要性的主張。相反，脂肪儲存可以在沒有膳食碳水化合物或胰島素濃度高於基線的情況下發生（ 38 ， 53 ， 54 ）。因此，替代的生理機制允許身體脂肪在不需要膳食碳水化合物的情況下儲存——這是脂肪組織的一個特徵，可能對雜食性物種具有進化優勢。此外，胰島素分泌受到多種因素的影響，而不僅僅是膳食碳水化合物（ 55–57 ）。事實上，基礎胰島素濃度同樣受到整體能量失衡的影響，無論這種失衡是通過操控膳食碳水化合物還是脂肪來實現的（ 58 ）。因此，儘管塔布斯認為“通過刺激胰島素分泌，碳水化合物使我們變胖並導致肥胖”是不可避免的結論，但實際上可能有許多途徑導致脂肪積累（ 9 ）。

Unfortunately, the foundational “facts” of the adipocentric CIM are in error, particularly the claims of singularity and necessity about the roles of insulin and dietary carbohydrates on adipose tissue fat metabolism. Rather, adipose fat storage can occur in the absence of either dietary carbohydrate or an increase in insulin above basal concentrations (38, 53, 54). Thus, alternative physiological mechanisms allow body fat to be stored without the necessity of dietary carbohydrates—a feature of adipose tissue that likely had evolutionary advantages for omnivorous species. Furthermore, insulin secretion is determined by a variety of factors beyond dietary carbohydrate (55–57). Indeed, basal insulin concentrations are similarly affected by overall energy imbalance regardless of whether the imbalance is achieved by manipulating dietary carbohydrates or fat (58). Thus, there are potentially many paths to fat accumulation despite Taubes believing it to be an inescapable conclusion that “by stimulating insulin secretion, carbohydrates make us fat and cause obesity” (9).

儘管脂肪中心的 CIM 在基礎邏輯上存在問題，但它被更廣泛地採用（ 6–8 ），強調這個“模型將脂肪細胞視為肥胖病因的核心”，因此“高碳水化合物飲食……會產生餐後高胰島素血症，促進卡路里在脂肪細胞中的沉積，而不是在瘦組織中的氧化，從而通過增加飢餓感、減慢新陳代謝率或兩者兼而有之來使體重增加”（ 7 ）。因此，基於脂肪中心 CIM 的一本流行飲食書聲稱，胰島素作為“終極脂肪細胞肥料”，它“將卡路里引入脂肪細胞，但限制它們回流”，因此“我們的脂肪細胞使我們過度進食。”（ 6 ）。根據觀察，胰島素對飲食碳水化合物的變化迅速作出反應，並對脂肪組織產生迅速的影響，讀者被建議“減少碳水化合物是降低胰島素和啟動減重的最快和最簡單的方法”，而低碳水化合物飲食會導致“飢餓感大幅下降，有時在第一天就會出現”（ 6 ）。

Despite problems with the foundational logic of the adipocentric CIM, it was adopted more widely (6–8) with an emphasis that this “model considers fat cells as central to the etiology of obesity” such that “a high-carbohydrate diet…produces postprandial hyperinsulinemia, promotes deposition of calories in fat cells instead of oxidation in lean tissues, and thereby predisposes to weight gain through increased hunger, slowing metabolic rate, or both” (7). Accordingly, a popular diet book based on the adipocentric CIM claimed that insulin acts as “the ultimate fat cell fertilizer” that “ushers calories into fat cells, but restricts their passage back out”, and consequently “our fat cells make us overeat.” (6). Based on observations that insulin rapidly responds to changes in dietary carbohydrate and has expeditious effects on adipose tissue, readers were advised that “decreasing carbohydrate is the quickest and easiest way to lower insulin and jump-start weight loss” and low-carbohydrate diets result in “big declines in hunger, sometimes as early as day 1” (6).

精確地說，碳水化合物驅動的胰島素作用於脂肪組織如何驅動飢餓或減慢新陳代謝率並未在 CIM 中具體說明，但在高血糖負荷餐後的晚期，循環燃料的低濃度被提出可能是直接被大腦感知，或是通過周邊器官如肝臟的能量狀態下降來感知的。當然，血糖的下降可以通過與 CIM 所提出的機制無關的機制來增加飢餓，這在 Mayer（ 59 ， 60 ）、LeMagnen（ 61 ）和 Campfield（ 62 ， 63 ）的葡萄糖靜態理論中早已被描述。事實上，餐後 2-3 小時內血糖的更大下降最近與人類的食慾增加相關聯（ 64 ）。

Precisely how carbohydrate-driven insulin action on adipose tissue drives hunger or slows metabolic rate is not specified by the CIM, but low concentrations of circulating fuels in the late postprandial period after high- compared with low-glycemic-load meals have been proposed to be either sensed directly by the brain or via decreased energy status of peripheral organs like the liver. Of course, dips in blood glucose can increase hunger by mechanisms independent of those proposed by the CIM as described long ago in the glucostatic theories of Mayer (59, 60), LeMagnen (61), and Campfield (62, 63). Indeed, greater dips in blood glucose occurring 2–3 h after meals were recently associated with increased appetite in humans (64).

脂肪中心的 CIM 擴展到飲食碳水化合物之外，並提出了一個“綜合範式”，其中所有促肥因素（例如，飲食蛋白質的量、微量營養素、睡眠不足、壓力、身體不活動和環境內分泌干擾化學物質）“直接影響胰島素分泌或脂肪細胞生物學”，隨之而來的是能量攝入增加和能量消耗減少的必要後果（ 7 ）。因此，脂肪中心的 CIM 實現了廣受推崇的因果關係方向的逆轉，即“正能量平衡並不導致肥胖增加；相反，偏向脂肪儲存的基質分配轉變驅動了正能量平衡”（ 5 ）。

The adipocentric CIM was expanded beyond dietary carbohydrates and a “comprehensive paradigm” was proposed whereby all obesogenic factors (e.g., amount of dietary protein, micronutrients, poor sleep, stress, physical inactivity, and environmental endocrine-disrupting chemicals) “affect insulin secretion or adipocyte biology directly” with increased energy intake and decreased energy expenditure as necessary downstream consequences (7). Hence, the adipocentric CIM achieves the much-touted reversal of the direction of causation whereby “positive energy balance does not cause increasing adiposity; rather, a shift in substrate partitioning favoring fat storage drives a positive energy balance” (5).

放棄以脂肪為中心的 CIM
Abandonment of the Adipocentric CIM

我們中的一些人（JRS 和 KDH）最近對以脂肪為中心的 CIM 提出了反對意見，並建議胰島素和其他因素對多種器官施加多重作用，影響能量平衡（ 10 ）。有趣的是，最新的 CIM 公式（ 5 ）也降低了脂肪組織的中心角色，從而放棄了以脂肪為中心的 CIM 的“綜合範式”（ 7 ）。新的 CIM“認為基質分配和脂肪沉積是由胰島素的綜合作用以及其他激素和自主神經輸入在多個器官中的作用決定的，而不僅僅是脂肪組織”（ 5 ）。不幸的是，涉及這一綜合的多器官、多激素 CIM 的提議機制仍不清楚，包括非脂肪組織的“內部飢餓”機制以及在肥胖發展過程中如何感知這一點。

Some of us (JRS and KDH) recently argued against the adipocentric CIM and suggested that insulin and other factors exert pleotropic actions on a variety of organs that influence energy balance (10). Interestingly, the latest formulation of the CIM (5) also de-emphasizes the formerly central role of adipose tissue and thereby abandons the “comprehensive paradigm” of the adipocentric CIM (7). The new CIM “considers that substrate partitioning and fat deposition are determined by the integrated actions of insulin, together with other hormones and autonomic inputs, in multiple organs, not just adipose tissue” (5). Unfortunately, the proposed mechanisms involved in this integrated, multiorgan, multihormone CIM remain unclear, including the mechanisms of “internal starvation” of nonadipose tissue and how this is sensed during the development of obesity.

重要的是，儘管仍然聲稱新的「CIM 提出了因果方向的逆轉」（ 5 ），但這不再是一個必要的特徵，因為所有通往正能量平衡的途徑並不需要在脂肪組織脂肪積累的下游發揮作用。事實上，新的 CIM 提出了影響能量平衡的平行途徑的存在，但這些途徑究竟是什麼或它們如何運作尚不清楚。其中一條途徑涉及飲食的血糖負荷對能量攝入的直接影響，這可能是通過大腦介導的（ 5 ）。如果這條新的直接途徑將高血糖負荷飲食與增加的能量攝入聯繫起來，並且主導了在脂肪組織下游提出的間接影響，那麼新的 CIM 將導致通常的因果方向，即增加的能量攝入導致脂肪組織脂肪積累。在這種情況下，新的 CIM 可以被視為 EBM 的一個過於簡化的版本，重點放在血糖負荷作為過量能量攝入的主要驅動因素。

Importantly, despite continued claims that the new “CIM proposes a reversal of causal direction” (5), this is no longer a necessary feature because all pathways to positive energy balance are not required to act downstream of adipose tissue fat accumulation. Indeed, the new CIM proposes the existence of parallel pathways influencing energy balance, but it is unclear exactly what these pathways are or how they might work. One such pathway involves a direct effect of dietary glycemic load on energy intake, presumably mediated by the brain (5). If this new direct pathway linking high-glycemic-load diets to increased energy intake dominates the proposed indirect effect downstream of adipose tissue, then the new CIM results in the usual causal direction of increased energy intake leading to adipose tissue fat accumulation. In that case, the new CIM can be considered an oversimplified version of the EBM with a focus on glycemic load as the main driver of excess energy intake.

EBM 和 CIM 的評估
Evaluation of the EBM and CIM

雖然數據可能支持 EBM 和 CIM 的各個方面，但一個有效的模型應該能夠經受住其各種預測的考驗，或者適當地進行修改或放棄。最重要的是，肥胖的理論模型必須解釋個體之間的脂肪變異性，以及最近全球分佈的變化。以下，我們將描述大量證據，這些證據對 CIM 和 EBM 作為解釋脂肪異質性和肥胖大流行的合理模型的有效性具有重要意義。

Although data might support various aspects of both the EBM and CIM, a valid model should withstand tests of its various predictions or be suitably modified or abandoned. Most importantly, theoretical models of obesity must explain between-person variability in adiposity as well as the recent global shift in its distribution. Below, we describe a wide body of evidence with implications for the validity of the CIM and EBM as plausible models that explain the heterogeneity of adiposity and the obesity pandemic.

囓齒動物模型在測試飲食和體重調節的假設方面非常有價值，因為它們可以在長時間內嚴格控制飲食，並且不受潛在混淆因素的影響，例如有意識地想要減肥。此外，不同囓齒動物品系對飲食中可變大營養素的反應可以提供有關參與調節系統的見解。然而，高度的控制帶來的代價是對人類肥胖的可轉譯相關性存疑（ 10 ）。例如，囓齒動物研究在證明胰島素對新陳代謝、食物攝入和脂肪沉積方面的因果作用方面至關重要（ 65–71 ）；然而，這些證據並未區分能量平衡模型（EBM）和卡路里攝入模型（CIM），因為這兩種模型都認識到這些過程的重要性（ 10 ）。

Rodent models are valuable for testing hypotheses of diet and body weight regulation because they are amenable to rigorous control of diet for extended periods and independent of potentially confounding factors such as the conscious desire to lose weight. Moreover, responses of different rodent strains to variable macronutrients in the diet can provide insights into the regulatory systems involved. However, the high level of control comes at the cost of questionable translational relevance to human obesity (10). For example, rodent studies have been critical in demonstrating the causal role of insulin affecting aspects of metabolism, food intake, and fat deposition (65–71); however, this evidence does not discriminate between EBM and CIM because both models recognize the importance of these processes (10).

相反，其他的啮齿動物研究顯示，根據 CIM 假設，飲食中碳水化合物在決定體重方面的作用在很大程度上是站不住腳的。大多數標準實驗室啮齒動物飲食中碳水化合物含量較高。典型的老鼠未精製飲食（“飼料”）由約 70%的碳水化合物、約 10%的脂肪和約 20%的蛋白質（按能量計算）組成，這並不會導致肥胖。將大營養素的分佈轉向較低比例的碳水化合物和較高比例的脂肪，蛋白質保持不變，會在許多品系中引起肥胖，並且在 20%碳水化合物、60%脂肪和 20%蛋白質的組合下觀察到對體脂肪的峰值影響（ 72 ， 73 ）。儘管有人認為這是因為這類飲食中的碳水化合物不是高升糖指數的碳水化合物（ 74 ），但這是錯誤的。商業老鼠未精製飲食的主要碳水化合物成分是玉米澱粉、麥芽糊精和蔗糖（ 75 ），這些在啮齒動物中具有大致相等的升糖指數（ 76 ）。 即使專注於蔗糖，給老鼠餵食 73%卡路里來自蔗糖的飲食（82%卡路里來自碳水化合物，8%來自脂肪，10%來自蛋白質）對抗肥胖是有保護作用的（ 77 ），這與在 51.3%葡萄糖飲食（按重量計）下的老鼠體重增長較低一致（ 74 ）。這些發現的其他解釋包括，餵食低升糖指數飲食的齧齒動物可能因攝入較高的飽和脂肪酸而產生的潛在混淆，從而導致飽和脂肪引起胰島素抵抗、高胰島素血症和隨後的肥胖（ 5 ， 74 ）。因此，這一論點強調了除了碳水化合物本身之外的飲食因素在肥胖發病機制中的重要性，強調某些品系抵抗飲食引起的脂肪儲存變化的能力，並直接駁斥了 CIM 所提出的飲食碳水化合物是體脂累積主要驅動因素的觀點。

Conversely, other rodent studies show that the role of dietary carbohydrates in determining body weight, as postulated by the CIM, is largely untenable. Most standard laboratory rodent diets are high in carbohydrates. Typical mouse unpurified diet (“chow”) consists of ∼70% carbohydrate, ∼10% fat, and ∼20% protein (by energy), which does not induce obesity. Shifts in the macronutrient distribution towards lower percentage carbohydrate and higher percentage fat, with protein constant, induces obesity in many strains, with a peak effect on body fatness observed at 20% carbohydrate, 60% fat, and 20% protein (72, 73). Although it has been argued that this is because the carbohydrates in such diets are not high-glycemic-index carbohydrates (74), this is incorrect. The main carbohydrate components of commercial mouse unpurified diet are corn starch, maltodextrin, and sucrose (75), which all have roughly equivalent glycemic indices in rodents (76). Even if one focuses on sucrose alone, feeding mice a diet with 73% calories as sucrose (82% of calories as carbohydrates, 8% as fat, and 10% as protein) was protective against obesity (77), consistent with the lower body weight gain of rats on a 51.3% glucose diet (by weight) (74). Alternative explanations for these findings include potential confounding by higher intakes of SFAs by rodents fed low-glycemic-index diets, such that saturated fats induce insulin resistance, hyperinsulinemia, and subsequent obesity (5, 74). As such, this argument underscores the importance of dietary factors other than carbohydrate per se in the pathogenesis of obesity, emphasizes the ability of some strains to resist diet-induced changes in fat storage, and directly refutes the notion that dietary carbohydrate is the main driver of body fat accumulation as proposed by the CIM.

EBM 暗示大腦是導致肥胖的主要器官，而 CIM 則暗示脂肪組織。考慮到肥胖的高遺傳性，不同器官中常見肥胖基因的相對表達提供了有關這些模型相對有效性的證據。除了導致大腦無法感知足夠體脂儲存的瘦素基因中的罕見突變外，沒有主要影響脂肪細胞或增強胰島素作用的遺傳疾病被重複報導為導致肥胖。擁有脂肪三酸甘油酯脂肪酶（ATGL）或比較基因識別-58（CGI58）基因的純合突變的人類在脂肪細胞脂解方面有嚴重缺陷，但不會發展成肥胖（ 78 ， 79 ）。儘管如此，富含脂肪組織的基因包括影響體脂分佈和代謝綜合徵特徵（如胰島素抵抗）的變異體（ 80 ）。

The EBM implicates the brain as the primary organ responsible for obesity whereas the CIM implicates adipose tissue. Given the high heritability of obesity, the relative expression of common obesity genes in different organs provides evidence regarding the relative validity of these models. Other than rare mutations in the leptin gene that result in obesity due to the inability of the brain to sense adequate body fat stores, no genetic disorder primarily affecting the adipocyte or enhanced insulin action has been reproducibly reported to cause obesity. Humans who have homozygous mutations in genes encoding adipose triglyceride lipase (ATGL) or comparative gene identification-58 (CGI58) have a severe defect in adipocyte lipolysis yet do not develop obesity (78, 79). Nevertheless, adipose-enriched genes include variants influencing body fat distribution and features of the metabolic syndrome, such as insulin resistance (80).

考慮到神經系統已進化以控制能量攝入（ 81 ），因此每一種已知的單基因疾病導致人類肥胖都涉及一個與下丘腦控制能量攝入密切相關的基因（ 82 ）並不令人驚訝。此外，無偏的全基因組關聯和基因表達研究已確定，人們之間的總脂肪量變異主要是由於在大腦中表達最為強烈的基因的差異（ 82–84 ）。對於常見變異，其對脂肪量的影響非常小，因此很難明確確定每個單獨變異對食物攝入、能量消耗或能量分配的影響。一個例外是影響力最大的常見變異，即脂肪量和肥胖相關（FTO）基因，攜帶風險等位基因的人被一致報導有增加的食慾和/或客觀測量的食物攝入量（ 85 ， 86 ）。

Given that nervous systems have evolved to control energy intake (81), it is not surprising that every known monogenic disorder that causes human obesity involves a gene intimately involved in the control of energy intake by the hypothalamus (82). Furthermore, unbiased genome-wide association and gene expression studies have determined that variations in total adiposity between people are primarily due to differences in genes that are most highly expressed in the brain (82–84). For common variants, their effects on fat mass are so small that it is hard to definitively establish the impact of each individual variant on food intake, energy expenditure, or energy partitioning. An exception is the common variant with highest effect size, the fat mass and obesity-associated (FTO) gene, where carriers of the risk allele have consistently been reported to have increased appetite and/or objectively measured food intake (85, 86).

全球各地的平均 BMI 在性別和國家收入方面存在異質性，並且在 1980 年至 2008 年期間觀察到的 BMI 趨勢也存在差異（ 87 ）。全球肥胖流行病在很大程度上被歸因於向工業化西方飲食的轉變（ 88 ， 89 ），這種飲食以精製穀物、加工油、含糖飲料、動物產品以及低攝入量的非澱粉類蔬菜和全穀物為特徵。全球貿易和技術的進步促進了食品商品的快速傳播，既是為了解決營養不良危機，也通過食品行業的隱性擴張（ 88–91 ）。這導致全穀物、蔬菜和豆類的減少，取而代之的是卡路里甜味劑和精製油在加工食品中的增加。

 is heterogeneity both in the mean BMI among regions globally, by sex, and national income, and in BMI trends observed from 1980 to 2008 (87). The worldwide obesity epidemic has been attributed in large part to shifting toward industrialized Western diets (88, 89), characterized by refined grains, processed oils, sugar-sweetened beverages, animal products, and low intakes of nonstarchy vegetables and whole grains. Global trade and improved technologies have facilitated the rapid dissemination of food commodities both intentionally, to address crises of undernutrition, and via stealth expansion of the food industry (88–91). These have led to declines in whole grains, vegetables, and legumes, replaced by increases in caloric sweeteners and refined oils in the form of processed foods.

儘管飲食質量有如此顯著的變化，但美國成人平均食物攝入的趨勢顯示，來自碳水化合物、脂肪和蛋白質的卡路里宏觀營養素組成保持了顯著的穩定性（ 92 ）。此外，雖然來自食物的添加糖也保持穩定，但來自飲料的攝入在肥胖流行的前半期經歷了顯著增加（ 93 ）。自 2000 年左右以來，飲食質量有了適度的改善，例如從精製穀物轉向全穀物以及減少含糖飲料的攝入（ 94 ）

Despite such notable shifts in diet quality, US trends of average adult food intake indicate a remarkable stability in the macronutrient composition of calories from carbohydrate, fat, and protein (92). Further, whereas added sugar from foods has also been stable, its intake from beverages underwent a significant increase in the first half of the obesity epidemic (93). Since around 2000, modest improvements in diet quality have been observed, such as substituting from refined back to whole grains and a reduction in sugary beverages (94).

全球經過驗證的身體活動數據相對於營養來說是稀少的。1985 年至 2014 年間，生活在城市地區的全球人口比例從 41%增加到 55%（ 95 ），這表明久坐的生活方式在肥胖中扮演了角色；然而，來自非傳染性疾病風險因素合作組織的分析顯示，許多國家在農村地區的 BMI 增長幅度大於城市地區，這表明單靠城市化的趨勢不足以解釋全球肥胖的趨勢（ 96 ）。

Global validated physical activity data are sparse relative to nutrition. There was an increase in the portion of the global population living in urban compared with rural areas, from 41% to 55% over 1985 to 2014 (95), suggesting a role for a sedentary lifestyle in obesity; however, an analysis from the NCD Risk Factor Collaboration indicated many countries experienced greater increases in BMI in rural rather than urban areas, suggesting trends in urbanization alone are insufficient to explain global obesity trends (96).

總體而言，累積的趨勢數據暗示了伴隨著複雜的全球營養、經濟和技術轉型的多種潛在體重增加驅動因素（ 97 ）。然而，它們的相對因果貢獻無法在整體人口層面上推斷。儘管如此，沒有證據表明碳水化合物攝入解釋了國與國之間體重的差異，最近的趨勢也不支持飲食中的碳水化合物是美國肥胖流行的主要驅動因素。

Overall, the accumulated trend data implicate a myriad of potential drivers of weight gain accompanying complex global nutrition, economic, and technological transitions (97). Their relative causal contributions, however, cannot be inferred on the population level. Nonetheless, evidence to suggest that carbohydrate intake explains between-country differences in body weight is nonexistent and recent trends do not support that dietary carbohydrate is the main driver of the US obesity epidemic.

縱向隊列數據同樣識別出幾個潛在的營養風險因素，這些因素遠超過簡單的宏觀營養素組成，對中年體重增加有影響。例如，對 121,335 名健康美國成年人進行的分析將個體層面的飲食脂肪與碳水化合物的變化與 20 年隨訪期間的體重變化相關聯（ 98 ）。參與者在增加來自總脂肪的卡路里以取代碳水化合物的情況下，體重隨時間的增加相對較少，這支持了減少碳水化合物在減輕中年體重增加中的潛在作用。然而，當考慮取代碳水化合物卡路里的脂肪類型時，很明顯，貢獻飲食脂肪的食物質量的變化解釋了體重增加的顯著差異，這超出了單純減少碳水化合物卡路里的貢獻。減少碳水化合物並增加動物來源脂肪與顯著更大的體重增加相關，而在減少碳水化合物的同時增加多不飽和脂肪則與顯著較少的體重增加相關。

Longitudinal cohort data have similarly identified several potential nutritional risk factors well beyond simple macronutrient composition for midlife weight gain. For example, an analysis of 121,335 healthy US adults related individual-level changes in dietary fats compared with carbohydrates with concomitant changes in body weight over 20 y of follow-up (98). Participants increasing calories from total fat at the expense of carbohydrate had modestly less weight gain over time, supporting a potential role for carbohydrate reduction in mitigating increases in weight gain in middle age. However, when the type of fat replacing the carbohydrate calories was considered, it was clear that changes in the quality of foods contributing dietary fat explained significant differences in weight gain above and beyond any contribution from a reduction in carbohydrate calories per se. A reduction in carbohydrates with increases in animal source fats was associated with significantly greater weight gain, whereas the same reduction in carbohydrates with increases in polyunsaturated fats was correlated with significantly less weight gain.

大量流行病學證據一致發現，根據長期遵循各種健康飲食模式（ 99 ）和食物（ 100 ， 101 ）的情況，超重和肥胖的風險存在顯著差異，這些飲食的碳水化合物含量變化很大。例如，增加薯片、未加工紅肉和含糖飲料的攝入量與中年體重增加顯著相關，而全穀物、酸奶和堅果的攝入量增加則與體重減輕相關（ 102 ）。因此，除了遺傳因素外，體重增加的異質性還可以通過幾種營養因素和飲食質量的變化來解釋，這與碳水化合物和血糖指數無關（ 103 ， 104 ）。這些數據與能量平衡模型一致，表明存在多種潛在的飲食驅動因素導致過量熱量攝入，但不支持飲食碳水化合物是肥胖主要驅動因素的 CIM 主張。

A large body of epidemiological evidence consistently finds meaningful differences in risk of overweight and obesity according to long-term adherence to a variety of healthful dietary patterns (99) and foods (100, 101), all with highly variable carbohydrate contents. For example, increasing intakes of potato chips, unprocessed red meat, and sugary beverages were significantly related to midlife weight gain, whereas increases in servings of whole grains, yogurt, and nuts related to weight loss (102). Thus, in addition to genetic factors, heterogeneity in weight gain is explained by variation in several nutritional factors and diet quality, independent of carbohydrate and glycemic index (103, 104). These data, consistent with the EBM, suggest a variety of potential dietary drivers of excess calorie intake but do not support the CIM proposition that dietary carbohydrates are the primary driver of obesity.

CIM 預測，通過減少飲食中的碳水化合物和血糖負荷，可以輕鬆實現有意義的長期減重，因為這些干預措施直接針對肥胖的根本原因，從而應該促進其逆轉。事實上，CIM 聲稱“患者可能會感到較少的饑餓和改善的能量水平，促進自發性減重”，並且“通過限制碳水化合物產生的體重減輕將…導致較低的自發性食物攝入”（ 5 ）。然而，飲食干預試驗發現，與高血糖負荷飲食相比，低血糖負荷飲食通常不會導致顯著更大的長期減重（ 105–112 ）。

The CIM predicts that meaningful long-term weight loss is readily achieved through a reduction in dietary carbohydrate and glycemic load because such interventions directly address the fundamental cause of obesity and should thereby facilitate its reversal. Indeed, the CIM claims that “patients may experience less hunger and improved energy level, promoting spontaneous weight loss” and “weight reduction produced by carbohydrate restriction would…result in lower spontaneous food intake” (5). However, diet intervention trials have found that low-glycemic-load diets do not generally result in significantly greater long-term weight loss as compared with higher-glycemic-load diets (105–112).

飲食中的蛋白質在飲食干預研究中可能是一個重要的混淆因素，應在評估血糖負荷本身的影響時進行匹配。例如，一項研究檢查了在 6 個月期間維持減重的情況，發現只有高蛋白、低血糖指數的飲食能夠防止體重回升，而較低蛋白、低血糖指數的飲食和高或低蛋白的高血糖指數飲食則觀察到顯著的體重回升（ 113 ）。有趣的是，較長的研究調查減重維持情況時，未能顯示低血糖指數飲食與高血糖指數飲食相比的好處（ 114 ， 115 ）。一項對 53 項持續時間≥1 年的隨機對照試驗的綜合分析評估了低脂與高脂飲食干預的效果，發現當飲食干預以相似強度進行時，低脂與高脂飲食的平均體重減輕沒有顯著差異（ 116 ）。一項更新的 121 項隨機對照試驗的網絡綜合分析發現，在 6 個月時，低脂、低碳水化合物或中等碳水化合物飲食與常規飲食對照組的平均體重減輕沒有顯著差異（ 117 ）。 對於個別飲食類型，Jenny Craig（55-60% 碳水化合物）和 Atkins（約 10% 碳水化合物）在 6 個月時最有效；然而，在 12 個月時，Jenny Craig 的平均體重減輕顯著大於 Atkins。

Dietary protein can be a significant confounder in diet intervention studies and should be matched when evaluating the effects of glycemic load per se. For example, a study examining maintenance of lost weight over a 6 mo period found that only a high-protein, low-glycemic-index diet prevented weight regain whereas significant weight regain was observed for a lower-protein, low-glycemic-index diet and higher-glycemic-index diets with high or low protein (113). Interestingly, longer studies investigating maintenance of lost weight failed to show a benefit of low- compared with high-glycemic-index diets (114, 115). A meta-analysis of 53 randomized controlled trials of ≥1-y duration evaluated the effects of low-fat compared with higher-fat dietary interventions and found no significant difference in mean weight loss comparing the low-fat with higher-fat diets when dietary interventions were delivered with similar intensity (116). An updated network meta-analyses of 121 randomized controlled trials found no significant difference in mean weight loss at 6 mo comparing low-fat, low-carbohydrate, or moderate-carbohydrate with usual diet controls (117). For the individual diet types, Jenny Craig (55–60% carbohydrate) and Atkins (∼10% carbohydrate) were the most effective at 6 mo; however, at 12 mo, mean weight loss was significantly greater for Jenny Craig compared with Atkins.

CIM 觀點承認“這些研究中的大多數參與者在維持飲食改變方面存在困難”（ 5 ），但這一解釋與 CIM 的預測相悖，因為低升糖負荷飲食應該通過自發性地減少飢餓來促進飲食遵從性，相較於高升糖負荷的替代品。相反，EBM 預測各種宏量營養素組成和飲食模式可以導致長期減重，只要它們最終能持續減少能量攝入。EBM 不受維持不同飲食類型遵從所需努力程度的限制，並且能夠輕鬆適應內部信號的直接影響以及複雜和動態的食品環境對能量攝入的長期控制，這使得維持飲食遵從變得困難（ 118–120 ）。

The CIM Perspective admitted that “most participants in these studies have difficulty sustaining dietary change” (5), but this explanation is contrary to predictions of the CIM because low-glycemic-load diets should promote diet adherence by spontaneously decreasing hunger in comparison with higher-glycemic-load alternatives. In contrast, the EBM predicts that a variety of macronutrient compositions and eating patterns can result in long-term weight loss, so long as they ultimately confer a sustained reduction in energy intake. The EBM is not constrained by the degree of effort necessary to sustain adherence across diet types, and readily accommodates a direct influence of internal signals and the complex and dynamic food environment on the long-term control of energy intake that make it difficult to sustain dietary adherence (118–120).

為了避免飲食遵從性的混淆因素，住院餵養研究禁止接觸研究外的食物。在這種情況下，根據 CIM 的預測，高升糖負荷飲食會導致過量的胰島素分泌、體脂肪的積累，以及隨之而來的食慾增加，與低升糖負荷飲食相比，導致更高的隨意能量攝入。然而，最近一項為期一個月的住院研究發現，對高升糖負荷飲食的兩週接觸導致的隨意能量攝入比同一參與者在非常低升糖負荷飲食上花費的兩週低約 700 kcal/d，並且體脂肪減少。此外，儘管低升糖負荷飲食導致胰島素分泌顯著降低，但這些結果仍然發生。 儘管這項研究提供了直接反駁 CIM 預測的重要證據，但在 CIM 觀點中卻完全被駁斥，作為“從幾週的研究中推斷慢性宏量營養素影響的陷阱”的例子，因為高升糖負荷飲食和過量餐後胰島素對食慾的影響顯然被“與慢性能量平衡的關係可疑的因素——例如餐具大小或盤子顏色”所主導（ 5 ）。有趣的是，最近的一項門診控制餵養研究發現，10 到 15 週的高碳水化合物飲食顯著增加了飽腹感，與低碳水化合物飲食相比，儘管導致餐後胰島素顯著升高和循環燃料降低（ 122 ），這再次反駁了 CIM 的預測，並與較短的住院研究一致（ 121 ）。

To avoid the confounder of diet adherence, inpatient feeding studies prevent access to off-study food. Under such conditions, exposure to a high-glycemic-load diet is predicted by the CIM to lead to excess insulin secretion, accumulation of body fat, and downstream increases in appetite leading to greater ad libitum energy intake as compared with a lower-glycemic-load diet. However, a recent month-long inpatient study found that a 2 wk exposure to a high-glycemic-load diet resulted in ∼700 kcal/d lower ad libitum energy intake and body fat loss compared with the 2 wk spent by the same participants on a very-low-glycemic-load diet (121). Additionally, these results occurred despite the low-glycemic-load diet resulting in substantially lower insulin secretion. Although this study provides important evidence directly contradicting the CIM’s predictions, it was wholly dismissed in the CIM Perspective as an example of “the pitfalls of extrapolating chronic macronutrient effects from studies of a few weeks’ duration” when the effects of the high-glycemic-load diet and excess postprandial insulin on appetite were apparently dominated by “factors of dubious relation to chronic energy balance—such as utensil size or plate color” (5). Interestingly, a recent outpatient controlled feeding study found that 10 to 15 wk of a high-carbohydrate diet significantly increased satiety compared with a low-carbohydrate diet despite resulting in significantly higher postprandial insulin and lower circulating fuels (122), which again refutes the CIM predictions and is consistent with the shorter inpatient study (121).

CIM 預測低碳水化合物飲食會降低胰島素，從而動員脂肪從脂肪組織中釋放出來，與匹配蛋白質的等熱量高碳水化合物飲食相比，導致更大的脂肪損失。然而，控制飲食的研究結果與這一預測不一致。例如，選擇性碳水化合物限制導致肥胖患者每日胰島素分泌顯著減少，但與同一患者的等熱量選擇性脂肪限制相比，體脂肪損失略少（ 58 ）。一項比較匹配蛋白質的等熱量飲食的控制飲食研究的元分析發現，高碳水化合物飲食的體脂肪損失雖然小，但顯著更大（ 123 ）。此外，最近的一項為期 6 週的控制飲食研究發現，與匹配蛋白質的低脂飲食相比，等熱量的極低碳水化合物飲食在體脂肪損失上沒有顯著差異（ 124 ）。最後，一項為期 17 週的控制飲食研究使用了在血糖負荷上變化但匹配蛋白質的等熱量飲食，也未觀察到體脂肪損失的顯著差異（ 109 ）。

The CIM predicts that lower-carbohydrate diets decrease insulin and thereby mobilize fat from adipose tissue to result in greater fat loss compared with isocaloric higher-carbohydrate diets with matched protein. However, controlled feeding studies have produced results inconsistent with this prediction. For example, selective carbohydrate restriction led to substantial decreases in daily insulin secretion in patients with obesity but resulted in slightly less body fat loss compared with isocaloric selective fat restriction in the same patients (58). A meta-analysis of controlled feeding studies comparing isocaloric diets matched for protein found a small but significantly greater body fat loss with higher-carbohydrate diets (123). Furthermore, a recent 6-wk controlled feeding study found no significant differences in body fat loss between isocaloric very-low-carbohydrate compared with low-fat diets matched for protein (124). Finally, a 17-wk controlled feeding study employing isocaloric diets varying in glycemic load but matched for protein also failed to observe significant differences in body fat loss (109).

EBM 提出高飲食能量密度可能是過量能量攝入的重要驅動因素，幾項試驗已顯示出能量密度不同的飲食對長期效果的顯著影響（ 125–128 ）。然而，這些數據在 CIM 觀點中被忽視，並且基於一項探索性發現，即建議乳腺癌患者多吃水果和蔬菜並未顯示出顯著的長期減重效果（ 5 ），因此拒絕了能量密度在長期控制能量攝入中可能重要的可能性（ 129 ）。此外，CIM 觀點將食物的可口性與超加工食品混為一談，並聲稱在該主題上缺乏相關的人類干預研究（ 5 ）。但這忽略了一項為期一個月的住院人類試驗的結果，該試驗顯示當人們暴露於受控的食品環境中，無論是超加工還是未加工的飲食，均被評為同樣可口，並在可用能量、宏量營養素、糖、鈉、纖維和血糖負荷方面密切匹配時，會出現過量的隨意能量攝入和體重增加（ 130 ）。 這些結果表明，除了飲食的宏量營養素組成和血糖負荷之外，其他因素也可以在影響人類能量攝入方面發揮重要作用。

The EBM proposes that high dietary energy density is a potentially important driver of excess energy intake, and several trials have demonstrated significant long-term effects of diets differing in energy density (125–128). However, these data were ignored in the CIM Perspective, and the possibility of energy density being potentially important in long-term control of energy intake was rejected (5) on the basis of a single exploratory finding of no significant long-term weight loss in patients with breast cancer who were advised to eat more fruits and vegetables (129). Furthermore, the CIM Perspective conflated the concept of food palatability with ultraprocessed food, and it was claimed that there is a lack of relevant human intervention studies on the topic (5). But this ignored the results of a month-long inpatient human trial demonstrating excess ad libitum energy intake and weight gain when people were exposed to controlled food environments characterized by either ultraprocessed or unprocessed diets rated as similarly palatable and closely matched for available energy, macronutrients, sugar, sodium, fiber, and glycemic load (130). Such results demonstrate that factors other than dietary macronutrient composition and glycemic load can play important roles influencing human energy intake.

藥物操控也可以用來檢驗肥胖模型的有效性。一個常被引用的支持 CIM 的例子是，對糖尿病患者進行外源性胰島素治療通常會導致體重增加。但對於未接受過治療的 1 型糖尿病患者，胰島素療法會使他們的病理生理性分解代謝狀態正常化，並導致瘦體重增加、ATP 需求的代謝無效循環減少、脂肪組織脂解正常化、糖尿病消失，並且與 CIM 相反，食慾亢進得到緩解。此外，儘管胰島素療法會降低循環燃料，但這一切仍然發生。在 2 型糖尿病中，胰島素療法導致的體重增加部分可能是由於重新獲得最近失去的體重（ 131–133 ）。急性外周胰島素輸注對人類的食慾和食物攝入有混合影響（ 134 ， 135 ），但經鼻胰島素輸送到大腦會抑制食物攝入（ 136 ），這與啮齒動物的研究一致（ 137 ），並且與 CIM 相反。

Pharmacological manipulations can also be used to interrogate the validity of obesity models. An oft cited example in support of the CIM is that exogenous insulin treatment in people with diabetes often induces weight gain. But insulin therapy in treatment-naïve patients with type 1 diabetes normalizes their pathophysiological catabolic state and results in increased lean mass, reductions in ATP-requiring metabolic futile cycles, normalization of adipose tissue lipolysis, elimination of glycosuria, and, contrary to the CIM, resolution of polyphagia. Further, this all occurs despite insulin therapy decreasing circulating fuels. In type 2 diabetes, weight gain with insulin therapy can be due, in part, to regain of recently lost weight (131–133). Acute peripheral infusions of insulin have mixed effects on appetite and food intake in humans (134, 135), but intranasal insulin delivery to the brain inhibits food intake (136), consistent with rodent studies (137) and contrary to the CIM.

CIM 假設胰島素引起體重增加的主要原因是其對抑制脂肪組織脂解的影響，從而使脂肪被困在脂肪細胞中（ 5 ）。然而，儘管在肥胖成年人中實現了血漿游離脂肪酸濃度顯著降低 38%的效果，但使用阿西匹莫克治療 6 個月抑制脂肪脂解對能量攝入、靜息能量消耗或身體組成沒有顯著影響（ 138 ）。最後，儘管急性增加胰島素分泌，GLP-1 受體激動劑目前是治療肥胖的最有效批准藥物（ 139 ）。

The CIM posits that a major reason why insulin induces weight gain is due to its effect on inhibiting adipose tissue lipolysis thereby trapping fat in fat cells (5). However, inhibiting adipose lipolysis with acipimox treatment for 6 mo had no significant effects on energy intake, resting energy expenditure, or body composition despite achieving a marked 38% reduction of plasma free fatty acid concentrations in adults with obesity (138). Finally, despite acutely increasing insulin secretion, GLP-1 receptor agonists are currently the most effective approved medications to treat obesity (139).

結論 Conclusions

能量平衡原則是所有潛在可行的肥胖模型的必要約束，包括 CIM 和 EBM。這兩個模型都同意飲食質量和組成在預防和治療肥胖方面的重要性。這兩個模型都考慮了內分泌調節、外周能量感知和能量分配。CIM 的最新版本從之前對餐後胰島素對脂肪組織直接影響的重點退回，但新的 CIM 與 EBM 的不同之處在於，高升糖負荷飲食被認定為導致肥胖流行的主要驅動因素。然而，壓倒性的證據表明，食物環境中的許多變量超越了高升糖食物，可能導致能量攝入增加，而 EBM 則假設如果這些因素中的任何一個或多個在起作用，肥胖就可能產生。

The principle of energy balance is a necessary constraint on all potentially viable models of obesity, including the CIM and EBM. Both models agree that diet quality and composition are important in prevention and treatment of obesity. Both models account for endocrine regulation, peripheral energy sensing, and energy partitioning. The latest iteration of the CIM retreats from its previous focus on postprandial insulin’s direct effect on adipose tissue, but the new CIM differs from the EBM in that high-glycemic-load diets are identified as the main driver of increasing obesity prevalence. However, an overwhelming amount of evidence indicates that numerous variables in the food environment beyond high-glycemic foods can result in increased energy intake and the EBM posits that obesity can arise if any one or more of these factors are in play.

EBM 承認低碳水化合物或低升糖負荷飲食在某些個體中管理體重或心臟代謝結果的潛在好處。精準營養倡議源於一種假設，即在優化個體飲食時存在固有的生物異質性（ 108 ， 140–142 ）。雖然這些努力與多因素 EBM 一致，但 CIM 提出單一暴露作為常見肥胖的主要決定因素，並建議通過開處方低升糖負荷飲食（ 5 ）來治療肥胖，儘管有證據表明這種干預措施並不比開處方高升糖負荷替代品更有效（ 105–112 ， 114 ， 115 ）。

The EBM acknowledges the potential benefits of low-carbohydrate or low-glycemic-load diets in managing body weight or cardiometabolic outcomes in some individuals. Precision nutrition initiatives have stemmed from a hypothesis of inherent biological heterogeneity when an optimizing individuals’ diet (108, 140–142). Whereas such efforts are consistent with the multifactorial EBM, the CIM sets forth a single exposure as the primary determinant of common obesity and proposes a single “practical strategy” to treat obesity by prescribing low-glycemic-load diets (5) despite evidence that such interventions are no more effective than prescribing higher-glycemic-load alternatives (105–112, 114, 115).

總體而言，我們已經記錄了大量與能量平衡模型（EBM）一致但與卡路里攝入模型（CIM）不一致的證據。進一步發展 EBM 需要闡明在動態食品環境中最能引發肥胖的因素、這些因素如何改變控制食物攝入的腦回路的機制，以及為什麼某些個體比其他人更容易發展成肥胖。回答這些問題將有助於改善公共健康和醫療干預，以預防和治療肥胖。

Overall, we have documented a large body of evidence aligning with the EBM but inconsistent with the CIM. Further development of the EBM requires elucidation of the factors in the dynamic food environment that are most responsible for instigating obesity, the mechanisms by which these factors alter the brain circuits controlling food intake, and why some individuals are more susceptible to development of obesity than others. Answering these questions will result in improved public health and medical interventions for prevention and treatment of obesity.

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