Hypothalamic Research Center, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Mol Aspects Med. 2019 Aug;68:60-73. doi: 10.1016/j.mam.2019.07.005. Epub 2019 Aug 5.
Endothermy requires a source of endogenous heat production. In birds, this is derived primarily from shivering, but in mammals it is mostly non-shivering thermogenesis (NST). Brown adipose tissue (BAT) is a specialized tissue found in Eutherian mammals that is the source of most NST. Heat production in BAT depends primarily on the activity of uncoupling protein 1 (UCP1), which decouples transport of protons across the inner mitochondrial membrane from synthesis of ATP. UCP1 and hence heat production of BAT is regulated by many factors. In this paper we discuss the main factors activating UCP1 and increasing heat production. Probably the most well-known activator is the catecholamine norepinephrine (NE) which is released from sympathetic nerve endings and binds to adrenergic receptors that are abundantly expressed on BAT. NE stimulates release of free-fatty acids. It was previously thought that such FFAs were essential for activation of UCP1. However recent work has suggested intracellular lipolysis is not essential and FFAs can be derived from extracellular sources. Thyroid hormones also exert impacts on metabolic rate via effects on brown adipocytes which express type 2 deiodinase. Knocking out DIO2 makes mice cold intolerant. Parathyroid hormone appears to also be a potent regulator of BAT activity and may be an important mediator of elevated expenditure during cancer cachexia, although this is disputed by observations that cachexia wasting is not blunted in UCP1 KO mice. Cardiac natriuretic peptides have also been implicated in regulating BAT thermogenesis and the interconversion of beige adipocytes from their white to brown form. Activation of BAT thermogenesis may be an important component of the post-ingestion rise in heat production. Recent work suggests the gut derived hormone secretin may play a key role in this effect, directly linking BAT activation to the alimentary tract. Not only gut hormones but also metabolites derived from gut microbiota such as butyrate may be an important activator of BAT during cold exposure. Additional regulatory factors include bone morphogenic proteins, fibroblast growth factor 21, Vascular endothelial growth factors and transient receptor potential vanilloid receptors which are important components of thermal sensing and hence how brown adipose tissue responds to the cold. In the future the main challenge is to understand how these regulatory factors combine with each other and with inhibitory factors to control heat production from BAT, and what their relative importance is in differing circumstances. Knocking out UCP1 has revealed other sources of heat production in BAT including creatine-dependent cycles and a futile cycle of Ca shuttling into and out of the endoplasmic reticulum via the SERCA and ryanodine receptors.
产热需要内源性热源。在鸟类中，热源主要来自颤抖，但在哺乳动物中，热源主要是非颤抖产热（NST）。棕色脂肪组织（BAT）是真兽类哺乳动物中特有的一种组织，是大多数 NST 的来源。BAT 的产热主要依赖于解偶联蛋白 1（UCP1）的活性，它将质子穿过线粒体内膜的运输与 ATP 的合成解偶联。UCP1 及其产热受许多因素调节。本文讨论了激活 UCP1 并增加产热的主要因素。最著名的激活剂可能是儿茶酚胺去甲肾上腺素（NE），它从交感神经末梢释放，与 BAT 上丰富表达的肾上腺素能受体结合。NE 刺激游离脂肪酸的释放。以前认为，这种 FFA 对于 UCP1 的激活是必需的。然而，最近的研究表明，细胞内脂解不是必需的，FFA 可以来自细胞外来源。甲状腺激素也通过对表达 2 型脱碘酶的棕色脂肪细胞的作用对代谢率产生影响。DIO2 基因敲除使小鼠不耐寒。甲状旁腺激素似乎也是 BAT 活性的有效调节剂，并且可能是癌症恶病质期间代谢增加的重要介质，尽管这与 UCP1 KO 小鼠中恶病质消耗不受抑制的观察结果存在争议。心钠素肽也被牵连到调节 BAT 产热和从白色到棕色的米色脂肪细胞的相互转化。BAT 产热的激活可能是摄入后产热增加的一个重要组成部分。最近的研究表明，肠道来源的激素促胰液素可能在这一效应中发挥关键作用，直接将 BAT 激活与消化道联系起来。不仅是肠道激素，肠道微生物群衍生的代谢物，如丁酸盐，也可能是寒冷暴露期间 BAT 的重要激活剂。其他调节因素包括骨形态发生蛋白、成纤维细胞生长因子 21、血管内皮生长因子和瞬时受体电位香草素受体，它们是热感的重要组成部分，因此棕色脂肪组织对寒冷的反应。未来的主要挑战是了解这些调节因子如何相互结合以及与抑制因子结合来控制 BAT 的产热，以及它们在不同情况下的相对重要性。UCP1 基因敲除揭示了 BAT 中其他产热来源，包括肌酸依赖性循环和 Ca 通过肌浆网 Ca-ATP 酶（SERCA）和兰尼碱受体进出内质网的无效循环。
