Brown adipocyte glucose metabolism: a heated subject

Abstract

The energy expending and glucose sink properties of brown adipose tissue (BAT) make it an attractive target for new obesity and diabetes treatments. Despite decades of research, only recently have mechanistic studies started to provide a more complete and consistent picture of how activated brown adipocytes handle glucose. Here, we discuss the importance of intracellular glycolysis, lactate production, lipogenesis, lipolysis, and beta-oxidation for BAT thermogenesis in response to natural (temperature) and artificial (pharmacological and optogenetic) forms of sympathetic nervous system stimulation. It is now clear that together, these metabolic processes in series and in parallel flexibly power ATP-dependent and independent futile cycles in brown adipocytes to impact on whole-body thermal, energy, and glucose balance.

Keywords: brown adipose tissue thermogenesis; fatty acid metabolism; glucose metabolism; positron emission tomography; uncoupling protein 1.

Figure 1. The distribution of thermogenic adipose tissue depots in mice and humans

Molecular imaging techniques such as positron emission tomography (PET) and single‐photon emission computed tomography (SPECT) have allowed for the identification of various thermogenic adipose tissue depots in animals and humans. This is principally because these depots consume large amounts of glucose and fatty acids. Cervical, supraclavicular, axillary, and spinal depots are shared between species, whereas scapular and gonadal depots are unique to adult rodents. Gene expression profiling has revealed that the molecular signature of interscapular brown adipose tissue (BAT) of mice is unique, whereas that of the browned anterior subcutaneous and epigonadal adipose tissue depots of mice are more similar to the supraclavicular BAT depot of humans.

Figure 2. The metabolic fate of glucose in brown adipocytes during thermogenesis

Upon beta‐3 adrenergic receptor activation following noradrenaline release by sympathetic nerve endings in response to cold, glucose is taken up by brown adipocytes via glucose transporters 1 and 4 (GLUT1/4). Glucose then undergoes glycolysis to generate dihydroxyacetone phosphate (DHAP), pyruvate, and lactate in the cytosol. Simultaneously, glucose‐6‐phosphate (glucose‐6‐P) feeds into the pentose phosphate pathway to generate ribulose‐5‐P and NADPH which is used for lipogenesis and also into glycogen synthesis and breakdown pathways. Pyruvate and/or lactate are next transported into the mitochondria via monocarboxylate transporter 1 (MCT1) and for pyruvate, the pyruvate carrier 1 (PC1), while DHAP is converted into glycerol‐3‐P by glycerol‐3‐phosphate dehydrogenase 1 (GPD1). Once inside the mitochondria, pyruvate is converted into acetyl‐CoA by pyruvate dehydrogenase (PDH). If lactate is indeed transported into mitochondria, it would be converted by LDH back into pyruvate. Acetyl‐CoA then undergoes partial breakdown in the TCA cycle into citrate by citrate synthase (CS) which is then exported by the citrate carrier (CC) into the cytosol. Citrate then feeds into a lipogenic pathway after being converted back into acetyl‐CoA by ATP citrate lyase (ACL). Acetyl‐CoA carboxylase (ACC), fatty acid synthase (FASN), glycerol‐3‐phosphat‐O‐acyltransferase 3 (GPAT3), AGPAT2, lipin 1, and diacylglycerol O‐acyltransferase 2 (DGAT2) then contribute to the generation of triglycerides (TG) from fatty acids and glycerol‐3‐P. These then rapidly undergo lipolysis in cytosolic lipid droplets through the action of adipose triglyceride lipase (ATGL), hormone‐sensitive lipase (HSL), and monoacylglycerol lipase (MGL). The liberated fatty acids either activate UCP1 to generate heat or are next converted into acyl‐CoA by long chain acyl‐CoA synthase 1 (ACSL1) and then transported into the mitochondria via the sequential action of carnitine palmitoyltransferase 1 (CPT1), translocase, and CPT2. Once inside the mitochondria, acyl‐CoA undergoes β‐oxidation by acyl‐CoA deyhyrogeneses (ACD) to generate the necessary proton gradient across the inner mitochondrial membrane. The liberated glycerol from lipolysis is phosphorylated by glycerol kinase (GK) into glycerol‐3‐P to facilitate fatty acid re‐esterification. Similarly, pyruvate carboxylase (PC) generates oxaloacetate (OA) from pyruvate, which is then converted into malate (MA) by malate dehydrogenase 2 (MD2). MA is exported outside of the mitochondria into the cytosol by the alpha‐ketoglutarate malate uniporter (AKMU) where it is reconverted back into OA by MD1. Finally, phosphoenolpyruvate carboxykinase 1 (PCK1) generates phosphoenolpyruvate which feeds G3P synthesis required for fatty acid re‐esterification. Fatty acids and glycerol released from lipolysis may enter an extracellular loop via fatty acid transport protein1 (FATP) and aquaporin 3/7/9 (AQP 3/7/9) as part of the fatty acid recycling pathway. Abbreviations: HK2, hexokinase 2; PGM, phosphoglucomutase; G1P, glucose‐1‐phosphate; G6PDx, glucose‐6‐phosphate dehydrogenase X‐type; GL, gluconolactolase GYP, glycogen phosphorylase; PGD, 6‐phosphogluconate dehydrogenase; UDP, uracil‐diphosphate; UDPGP, UDP glucose pyrophosphorylase; PK, pyruvate kinase; and TPI, triosephosphate isomerase. Some reactions have been omitted for clarity.

Figure 3. BAT crosstalk with other organs in health and disease

Here we provide examples of crosstalk between BAT and other organs in health and disease states. During a high‐fat meal, cholesterol in the form of chylomicrons is delivered first to the liver and then in the form of triglyceride‐rich lipoproteins to BAT. Cholesterol‐rich lipoprotein remnants are then released from the action of lipoprotein lipase and are in turn delivered via the bloodstream back to the liver where hepatocytes convert cholesterol into bile acids. These dietary cholesterol‐derived circulating bile acids then return to BAT to promote thermogenesis. There may also be a line of communication from BAT to the brain during feeding due to the heat‐sensing properties of hypothalamic pro‐opiomelanocortin neurons. During chronic consumption of a high‐carbohydrate diet, increased glucose kinase activity in the liver results in the activation of vagal afferents which inhibit sympathetic efferents to BAT resulting in decreased thermogenesis in those susceptible to weight gain. Similarly, during aging decreased acylcarnitine released from the liver produced by free fatty acids released from WAT lipolysis results in diminished BAT thermogenesis and cold intolerance. BAT itself releases neuregulin 4 to protect against fatty liver and diabetes from chronic consumption of a high‐fat diet. Fatty acids released by WAT lipolysis also promote insulin release from the pancreas which then causes glucose, fatty acid and triglyceride‐rich lipoprotein uptake by BAT to sustain thermogenesis.