White adipose tissue
White adipose tissue (WAT) maintains energy homeostasis by storing and releasing lipids, and by functioning as an endocrine organ. Adipose tissue contains adipocytes, comprising 35-70% of WAT mass but only ∼25% of the cells. The other cell types include stromal preadipocytes and immune cells. Adipocytes typically contain a large lipid droplet, occupying >90% of the cell volume. Fat and water contents in adipose tissue are variable, ∼60-94% and ∼6-36%, respectively (Thomas, 1962). As an average, fat and water contents of 80% and 15%, respectively, and specific gravity of 0.916 g/mL can be used (ICRP Publication 23, 1975). Protein content is 4±1 mg/g tissue (Stroh et al., 2021).
Brown adipose tissue (BAT) contains thermogenic brown adipocytes, but also WAT can contain thermogenic "brite" or "beige" adipocytes (BeAT) with UCP1 expression. Cold exposure and β3AR agonists induce beiging in WAT (Finlin et al., 2018). Insulin promotes lipid storage, while catecholamines signal adipocytes via β-adrenergic receptors and other mechanisms to release free fatty acids for liver and muscle. Lipolysis in adipocytes is activated by sympathetic nervous system, releasing noradrenaline in the parenchyma of adipose tissues. Sympathetic neurons can release ATP as a co-transmitter of noradrenaline, affecting metabolism via P2 purinoceptors, or ATP can be converted into adenosine. Eosinophils can activate M2 macrophages in adipose tissue to secrete catecholamines.
Lipids are primarily stored in subcutaneous adipose tissue (sWAT, SAT), but also in fat deposits in visceral tissue inside the peritoneum (visceral fat, vWAT, VAT), surrounding liver, kidneys, heart, stomach, intestine, and other internal organs. Subcutaneous WAT represents >80% of total WAT, and is located, not only under the skin, but also inside the abdominal cavity, and interspersed inside skeletal muscle. Within-tissue (ectopic) fat in the pancreas (pancreatic steatosis) and liver is being studied in relation to obesity and type 2 diabetes. Excessive lipid load leads to adipocytokine release and inflammatory response, and if prolonged, to insulin insensitivity. Scarcity of WAT is also associated with severe metabolic disorders. CT and MRI can be used to detect WAT and assess its volume (Wang et al., 2014), but PET is more reliable in measuring the metabolism in WAT. [18F]FDG-PET can improve CT-based segmentation of abdominal visceral and subcutaneous adipose tissue (Hussein et al., 2016; de Boer et al., 2018).
WAT adipocytes take up fatty acids as chylomicrons and lipoprotein particles from circulation. Fatty-acid transport proteins and Fatty-acid binding protein are necessary for the uptake of the lipids into adipocytes. Overexpression of fatty acid translocase/CD36 contributes to inflammation and cell death. Adipocytes can also synthesize fatty acids from glucose; insulin stimulates GLUT4-mediated glucose uptake in WAT in normal subjects. WAT becomes insulin resistant in obesity and type 2 diabetes (Virtanen et al., 2001), but increasing amount of adipose tissue can compensate for reduced glucose uptake per WAT mass (Virtanen et al., 2005). Dopamine stimulates glucose uptake in WAT via D2Rs and by regulating insulin receptors (Tavares et al., 2021). Fatty acids are intracellularly esterified to glycerol, and triacylglycerols are then stored as lipid droplets. Glycerol is transported into and out of adipocytes via AQP7. WAT in trained subjects have higher content of enzymes for lipolysis, oxidative phosphorylation, and glyceroneogenesis (Bertholdt et al., 2018).
While most amino acids are metabolized in the liver, branched-chain amino acids (BCAAs, including leucine, isoleucine, and valine) are metabolized mainly in WAT and skeletal muscle. The first step in the catabolism of BCAAs is catalysed by mitochondrial branched-chain aminotransferase (BCAT2), which is not expressed in the liver. Plasma concentrations of BCAAs are increased in obesity and insulin resistance, because BCAA catabolism is reduced.
WAT is normally well vascularized. Capillary density is markedly lower in obese than non-obese subjects, as well as perfusion, in both fasted and postbrandial states, because only the non-lipid droplet part of the adipocyte requires blood flow. Perfusion in WAT can be measured using radiowater PET. Meal increases perfusion in WAT; in obese individuals with T2DM this response is blunted in sWAT but not in vWAT, and bariatric surgery improves the effects of meal on sWAT perfusion (Saari et al., 2022). In normal-weight subjects, WAT accounts for ∼5% of the O2 consumption of the whole body. The reduced capillary density in WAT may lead to hypoxia, which via hypoxia-inducible factor HIF1α could stimulate inflammation and the synthesis and cross-linking of ECM components. However, Hodson et al., 2013 did not find evidence of hypoxia in WAT in obesity. Exercise training increases WAT vasculature in insulin resistant subjects (Honkala et al., 2020). All RAAS components are also found in the adipose tissue.
Glucose uptake can be assessed using [18F]FDG-PET. Ex vivo FDG uptake in abdominal visceral WAT relates positively with GLUT4, negatively with GLUT3, and is not related to GLUT1 mRNA expression (Reijrink et al., 2021). Inflammation in WAT does not affect FDG uptake, as ex vivo FDG uptake in abdominal visceral adipose tissue was not related to CD68+ infiltration, or IL-1β and IL-6 mRNA expression (Reijrink et al., 2021). Exercise training increases glucose uptake in WAT (Honkala et al., 2020).
WAT releases adipokines that includes >50 cytokines, such as adiponectin, leptin, apelin, IL-1, IL-6, and IL-10, TNF-α, TGF-β2, angiotensinogen, and CRP. Not all adipokines are excreted by adipocytes. WAT can influence systemic metabolism also by excreting miRNAs (Thomou et al., 2017).
Adenosine has anti-inflammatory effects in adipose tissue: Adenosine and other A1R agonists inhibit lipolysis, which promotes inflammation. Adenosine also inhibits the release of pro-inflammatory mediators from macrophages via their A2A and A2B receptors. Adenosine is one of the regulators of adipogenesis (Eisenstein & Ravid, 2014).
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Updated at: 2023-01-28
Created at: 2016-05-14
Written by: Vesa Oikonen