Substrate Utilization by Brown Adipose Tissue: What's Hot and What's Not?

Abstract

Our understanding of brown adipose tissue (BAT) function in humans has increased rapidly over the past 10 years. This is predominantly due to the development of powerful non-invasive imaging techniques such as positron emission tomography that can quantify BAT mass and function using metabolic tracers. Activation of BAT during cold-induced thermogenesis is an effective way to dissipate energy to generate heat and requires utilization of multiple energy substrates for optimal function. This has led to interest in the activation of BAT as a potential therapeutic target for type 2 diabetes, dyslipidaemia, and obesity. Here, we provide an overview of the current understanding of BAT substrate utilization in humans and highlight additional mechanisms found in rodents, where BAT more prominently contributes to energy expenditure. During thermogenesis, BAT demonstrates substantially increased glucose uptake which appears to be critical for BAT function. However, glucose is not fully oxidized, with a large proportion converted to lactate. The primary energy substrate for thermogenesis is fatty acids, released from brown adipocyte triglyceride stores. Active BAT also sequesters circulating lipids to sustain optimal thermogenesis. Recent evidence reveals that metabolic intermediates from the tricarboxylic acid cycle and glycolytic pathways also play a critical role in BAT function. Understanding the role of these metabolites in regulating thermogenesis and whole body substrate utilization may elucidate novel strategies for therapeutic BAT activation.

Keywords: brown adipose tissue; glucose; lipids; metabolism; obesity; positron emission tomography (PET); substrate; thermogenesis.

Figure 1

Diagram of substrate utilization and suspected pathways in BAT. Glucose enters the brown adipocyte via GLUT4 and GLUT1 where it undergoes glycolysis to form pyruvate. Pyruvate is converted to lactate and exported from the cell by the monocarboxylate (MCT) transporters, this pathway accounts for the majority of glucose uptake by human BAT during both warm and cold exposure. Following export, lactate may activate GPR81 which inhibits lipolysis. Alternatively, pyruvate can enter the mitochondria and be incorporated into the TCA cycle following conversion to acetyl-CoA. Citrate, one of the TCA cycle intermediates, may also be converted to acetyl-CoA in the cytosol as the first step of de novo lipogenesis (DNL). A proportion of glucose may be converted to glycerol-3-phosphate (Glycerol-3-P), generated from glyceraldehyde-3-phosphate during glycolysis, to form the backbone for replenishment of intracellular triglycerides (TRGs). Free fatty acids (FFAs) hydrolysed from local TRGs are the primary energy substrate used for uncoupled respiration during thermogenesis, which is mediated by mitochondrial UCP1. Glycerol released by this process can either be exported or recycled through conversion to Glycerol-3-P by glycerol kinase (GK) for subsequent TRG synthesis. In addition to DNL, uptake of circulating FFAs either directly or following lipoprotein lipase (LPL)-mediated hydrolysis of triglyceride rich lipoproteins (TRLs) occurs via the fatty acid transporters or potentially by passive diffusion. BAT utilizes other circulating substrates during thermogenesis such as BCAAs, succinate and glutamate which are all likely incorporated into the TCA cycle. Arrows in black indicate substrate transport/movement. Arrows in red represent enzymatic conversion. Wording in black indicate pathway confirmed both in human and rodent BAT. Wording in blue indicate pathways confirmed in rodent BAT. Some reactions have been simplified/omitted for brevity. ACC, acetyl-CoA carboxylase; ACL, ATP citrate lyase; AGPAT2, 1-acyl-sn-glycerol-3-phosphate acyltransferase beta; AQP7, aquaporin-7; ATGL, adipose triglyceride lipase; CD36, fatty acid translocase; CoQ, coenzyme Q; DGAT2, diacylglycerol acyltransferase 2; FABP, fatty acid binding protein; FASN, fatty acid synthase; FATP, fatty acid transport protein; GPAT3, glycerol-3-phosphate acyltransferase 3; GPR81, G-protein coupled receptor 81; HSL, hormone sensitive lipase; LDH, lactate dehydrogenase; MPC1/2, mitochondrial pyruvate carrier 1 and 2; PDH, pyruvate dehydrogenase; SLC13A3, solute carrier family 13 member 3; SLC25A10, solute carrier family 25 member 10; SLC25A44, solute carrier family 25 member 44.