Fatty acid metabolism and the basis of brown adipose tissue function

Abstract

Obesity has reached epidemic proportions, leading to severe associated pathologies such as insulin resistance, cardiovascular disease, cancer and type 2 diabetes. Adipose tissue has become crucial due to its involvement in the pathogenesis of obesity-induced insulin resistance, and traditionally white adipose tissue has captured the most attention. However in the last decade the presence and activity of heat-generating brown adipose tissue (BAT) in adult humans has been rediscovered. BAT decreases with age and in obese and diabetic patients. It has thus attracted strong scientific interest, and any strategy to increase its mass or activity might lead to new therapeutic approaches to obesity and associated metabolic diseases. In this review we highlight the mechanisms of fatty acid uptake, trafficking and oxidation in brown fat thermogenesis. We focus on BAT's morphological and functional characteristics and fatty acid synthesis, storage, oxidation and use as a source of energy.

Keywords: brown adipose tissue; fatty acid oxidation; lipid metabolism; obesity.

Figure 1.

FA uptake and lipogenesis in brown adipocytes. Schematic representation of FA uptake, transport, synthesis and storage in brown adipocytes, which provide substrate to mitochondria for thermogenesis. While brown adipocytes synthesize FAs, the enzyme lipoprotein lipase (LPL) is the major source of FAs in BAT. Once triglyceride (TG) rich-lipoproteins reach the bloodstream, LPL hydrolyzes them into FFAs for BAT uptake. FAs are sensed and taken up by FFAs 3 (FFA3) proteins, cluster of differentiation 36 (CD36) and/or FA transport proteins (FATPs). Inside the cytoplasm, FAs are transported by FA binding proteins (FABP). On the other hand, FAs can be synthesized by lipogenesis. This process takes place in the cytosol, and the first phase begins with the formation of malonyl-CoA from acetyl-CoA by the action acetyl-CoA caboxylase (ACC). Then, FA synthetase (FAS) catalyzes various reactions to finally generate palmitate, a 16-carbon saturated FA. In BAT, the last phases of lipogenesis are carried out by very long chain FA 3 (ELOVL3) and stearoyl-CoA desaturase 1 (SCD1). Once FAs are synthesized they can be esterified, becoming available for FAO or stored as TG in lipid droplets (LD). Blue arrows indicate enhanced processes or expression of proteins after cold stimulation and β3-adrenergic receptor activation.

Figure 2.

Neutral lipolysis players and regulation in BAT. Neutral lipolysis allows cells to obtain 3 free fatty acids (FFAs) and glycerol from the hydrolysis of triglycerides (TG). Three enzymes control this process: adipose triglyceride lipase (ATGL), which hydrolyzes TG into diacylglycerol (DG), hormone sensitive lipase (HSL), which has high affinity for DG and converts them into monoacylglycerols (MG) and monoacylglycerol lipase (MGL), which finalizes the hydrolysis of MG into glycerol and FFA that are used as a fuel for thermogenesis. In basal state ATGL is inhibited by G0/G1 switch gene 2 (G0S2) and ATGL co-activator comparative gene identification-58 (CGI-58) is kidnapped by perilipin. In addition, HSL is located in the cytosol and thus unable to reach its substrates. Upon β3-adrenergic stimulation, adenyl cyclase (AC) increases cAMP levels that activate protein kinase A (PKA), which phosphorylates HSL promoting its translocation to the membrane of lipid droplets (LD). PKA also phosphorylates perilipin, which releases CGI-58 that can then fully activate ATGL. Phosphorylated perilipin also enhances HSL activity. On the other hand, insulin stimulation, through protein kinase B (PKB) activates phosphodiesterase 3B (PDE3B) which converts cAMP into AMP decreasing PKA activation and its lipolytic action. Figure insert: mouse models of the enzymes involved in neutral lipolysis. ATGL KO mice accumulate TGs and have enlarged BAT, which displays defective thermogenesis. aP2-ATGL overexpressing mice show a reduction in TGs and increased thermogenesis. HSL KO mice accumulate TGs and specially large amounts of DG leading to an enlarged BAT.

Figure 3.

Mitochondrial and peroxisomal fatty acid oxidation. Transport of long-chain fatty acids (LCFAs) from the cytosol to the mitochondrial matrix for FAO involves the activation to acyl-CoA by acyl-CoA synthetase-1 (ACSL), conversion of LCFA-CoA to LCFA-carnitines by carnitine palmitoyltransferase (CPT) 1, translocation across the inner mitochondrial membrane by the carnitine/acylcarnitine translocase (CACT) and reconversion to LCFA-CoA by CPT2. These acyl-CoAs are β-oxidized and render acetyl-CoA. The entry of acetyl-CoA to the tricarboxylic acid cycle generates NADH and FADH. These cofactors transfer the electrons to the electron transport chain, where the protons are transported to the mitochondrial intermembrane space to generate energy as ATP. UCP1 dissipates the proton gradient, releasing energy as heat. Very long chain fatty acids (VLFA) enter the peroxisome to be shortened by peroxisomal FAO. Shortened acyl-CoAs and acetyl-CoA are transported to the mitochondria to be completely oxidized.