Diabetes Metab J.  2021 Nov;45(6):840-852. 10.4093/dmj.2020.0291.

Brown Fat as a Regulator of Systemic Metabolism beyond Thermogenesis

• Yuko OO
• Saito M

• KMID: 2522723
• DOI: http://doi.org/10.4093/dmj.2020.0291

Abstract

Brown adipose tissue (BAT) is a specialized tissue for nonshivering thermogenesis to dissipate energy as heat. Although BAT research has long been limited mostly in small rodents, the rediscovery of metabolically active BAT in adult humans has dramatically promoted the translational studies on BAT in health and diseases. Moreover, several remarkable advancements have been made in brown fat biology over the past decade: The molecular and functional analyses of inducible thermogenic adipocytes (socalled beige adipocytes) arising from a developmentally different lineage from classical brown adipocytes have been accelerated. In addition to a well-established thermogenic activity of uncoupling protein 1 (UCP1), several alternative thermogenic mechanisms have been discovered, particularly in beige adipocytes. It has become clear that BAT influences other peripheral tissues and controls their functions and systemic homeostasis of energy and metabolic substrates, suggesting BAT as a metabolic regulator, other than for thermogenesis. This notion is supported by discovering that various paracrine and endocrine factors are secreted from BAT. We review the current understanding of BAT pathophysiology, particularly focusing on its role as a metabolic regulator in small rodents and also in humans.

Keyword

Adipocytes, beige; Adipose tissue; Adipose tissue, brown; Energy metabolism; Thermogenesis; Uncoupling protein 1

Figure

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  Fig. 1. Uncoupling protein 1 (UCP1)-dependent and independent thermogenesis in brown and beige adipocytes. UCP1, a protein located in the mitochondrial inner membrane, has the ability to leak proton gradient across the mitochondrial membrane, and thereby uncouples oxidative phosphorylation to generate heat. Thus, UCP1 thermogenesis is not dependent on adenosine triphosphate (ATP). On the other hand, thermogenesis by the futile cycles of creatine and creatine phosphate, release and re-uptake of calcium, and triglyceride (TG) hydrolysis and fatty acid (FA) re-esterification is dependent on the breakdown of ATP to adenosine diphosphate (ADP). These thermogenic mechanisms are activated by cold exposure primarily through the sympathetic nerve activation. RyR, ryanodine receptor; SERCA, sarco-endoplasmic reticulum ATPase.

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  Fig. 2. Cod-induced uncoupling protein 1 (UCP1)-dependent and -independent metabolic changes in brown adipose tissue (BAT). Cold exposure triggers triglyceride (TG) hydrolysis, fatty acid (FA) uptake, oxidation of FA via β-oxidation and tricarboxylic acid (TCA) cycle, and UCP1 activation. These are intimately associated with anaerobic glycolysis, and uptake of succinate and glutamine. In UCP1-KO brown adipocytes, cold exposure triggers TG hydrolysis, FA uptake, and β-oxidation of FA, similarly in wild-type brown adipocytes. Resulting acetyl-coenzyme A (CoA) is not oxidized by TCA cycle but used to re-synthesis of FA and TG. αKG, α-ketoglutaric acid.

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  Fig. 3. Endocrine actions of brown adipose tissue (BAT)-derived factors. Brown/beige adipocytes secrete various molecules, some of which such as nerve growth factor (NGF) and vascular endothelial growth factor (VEGF) function as paracrine factors, while others as endocrine factors, acting on the liver and skeletal muscle, thereby regulating systemic metabolism. 12,13-diHOME, 12,13-dihydroxyoctadecaenoic acid; FA, fatty acid; FGF21, fibroblast growth factor 21; IL-6, interleukin-6; miR, microRNA; NRG4, neuregulin 4.

• 

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