Does activating brown fat contribute to important metabolic benefits in humans? Yes!
Does activating brown fat contribute to important metabolic benefits in humans? Yes!
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DOI：
10.1172/jci175282
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发表时间：
2023-12-01
影响因子：
15.9
通讯作者：
Cypess, Aaron M.
中科院分区：
文献类型：
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作者：
Cypess, Aaron M.
脂肪组织是在人体健康和疾病中具有重要生理作用的器官。功能上，白色脂肪组织（WAT）是甘油三酯能量的主要储存库，而棕色脂肪组织（BAT）消耗脂肪和葡萄糖，通过化学解偶联和无效循环产生热量(1)。储存在WAT中的多余卡路里会导致超重和肥胖，并导致许多器官系统功能障碍，包括WAT和BAT本身。扭转肥胖的危害需要净负能量平衡，这可以通过减少食物消耗、减少热量吸收和增加能量消耗的组合来实现。几十年来，人们已经认识到啮齿动物BAT的慢性肾上腺素能刺激，无论是生理上的冷暴露还是药理学上的肾上腺素能受体（AR）激动剂，都能带来一系列代谢益处，包括抵抗饮食性肥胖（DIO）、改善血糖、改善脂蛋白和心血管风险(2)。在这种情况下，问题出现了：如果成年人具有功能性BAT，那么它的激活和生长是否可以用于治疗肥胖和相关的代谢疾病？2009年，在成年人中证实了功能性BAT的存在，为回答这个问题迈出了第一步(3)。最近，研究人员致力于下一步研究，在细胞水平上确定小鼠和人类脂肪细胞具有相似的遗传和功能特征，特别是在产热和可溶性内分泌介质（如肽激素、生物活性脂质和细胞外囊泡）的释放方面(4)。与第二步同时，临床研究人员首次表明，轻度低温暴露或mirabegron激活β3-AR对人BAT的急性刺激可增加BAT的产热和葡萄糖摄取（5,6）。接下来，他们确定慢性刺激增加了BAT的质量和代谢活性(6)。到2023年，人们普遍认为成年人具有功能性BAT，其在细胞水平上的行为类似于啮齿动物的BAT，并且可以急性和慢性地刺激它。此外，人们普遍认为BAT在人类儿童中具有生理相关性，由于儿童体型小且肌肉量有限，BAT有助于儿童保暖(7)。然而，令人担忧的是，尽管脂肪细胞之间存在相似性，但在组织水平上，啮齿动物和成人的BAT存在根本不同。成年人类比老鼠大三个数量级，因此表面积体积比要小得多，这从根本上改变了它们的热动力学：啮齿动物必须产生热量来维持体温，BAT占体重的2%-5%，起着核心作用。相比之下，人类通常使用代谢过程中所谓的“废热”来维持体温，成人BAT通常只占体重的0.1%至0.5%(1)。目前，该领域处于一种平衡的对立状态，这导致ENDO 2023的组织者提议在安德罗·卡彭迪埃博士和我之间进行一场辩论，以解决这个问题：“激活BAT是否有助于人类重要的代谢益处？”有三个具体的好处：(a)葡萄糖代谢；(b)心脏代谢疾病；(c)肥胖。我的回答是“是的”，具体如下。
Adipose tissues are organs that have vital physiological roles in human health and disease. Functionally, white adipose tissue (WAT) is the principal repository for triglyceride energy, while brown adipose tissue (BAT) consumes fat and glucose to generate heat via chemical uncoupling and futile cycling (1). Excess calories stored in WAT lead to overweight and obesity and cause dysfunction in many organ systems, including WAT and BAT themselves. Reversing the ravages of obesity requires a net negative energy balance, which can be achieved through a combination of reduced food consumption, reduced caloric absorption, and increased energy expenditure. For decades, it has been recognized that chronic adrenergic stimulation of rodent BAT, either physiologically by cold exposure or pharmacologically via adrenergic receptor (AR) agonists, leads to a range of metabolic benefits, including resistance to diet-induced obesity (DIO), improved glycemia, and improved lipoprotein and cardiovascular risk profile (2). In this context, the question emerged: if adult humans had functional BAT, could its activation and growth be utilized to treat obesity and related metabolic diseases? The first step toward answering this question was conclusively established by 2009 with the demonstration of the presence of functional BAT in adult humans (3). More recently, investigators have devoted efforts to the next step, establishing at the cellular level that mouse and human adipocytes have similar genetic and functional features, particularly related to thermogenesis and the release of soluble endocrine mediators such as peptide hormones, bioactive lipids, and extracellular vesicles (4). In parallel with this second step, clinical researchers first showed that acute stimulation of human BAT by either mild cold exposure or activation of the β3-AR with mirabegron increased BAT thermogenesis and glucose uptake (5, 6). Next, they determined that chronic stimulation increased BAT mass and metabolic activity (6). By 2023, it is well accepted that adult humans have functional BAT, that it behaves like rodent BAT at the cellular level, and that it can be stimulated acutely and chronically. In addition, it is accepted that BAT has physiological relevance in human children, where it contributes to keeping them warm given their small size and limited muscle mass (7). However, a gnawing concern was that, despite similarities among the adipocytes, at the organismal level, rodent and adult human BAT were fundamentally different. Adult humans are three orders of magnitude larger than mice and therefore have a much smaller surface area–to–volume ratio that fundamentally alters their thermal dynamics: rodents must generate heat to maintain body temperature, and BAT plays a central role at 2%–5% of body weight. In contrast, humans generally maintain body temperature using what has been termed the “waste” heat from metabolic processes, with adult BAT typically only composing 0.1% to 0.5% of body weight (1). At this time, the field is in a state of balanced opposition, which led the organizers of ENDO 2023 to propose a debate between Dr. André Carpentier and me to address the question:“does activating BAT contribute to important metabolic benefits in humans?” Three specific benefits were addressed:(a) glucose metabolism;(b) cardiometabolic disease; and (c) obesity. The answer I defended was “Yes”, as detailed below.