Redox Regulation of Lipid Mobilization in Adipose Tissues

Abstract

Lipid mobilization in adipose tissues, which includes lipogenesis and lipolysis, is a paramount process in regulating systemic energy metabolism. Reactive oxygen and nitrogen species (ROS and RNS) are byproducts of cellular metabolism that exert signaling functions in several cellular processes, including lipolysis and lipogenesis. During lipolysis, the adipose tissue generates ROS and RNS and thus requires a robust antioxidant response to maintain tight regulation of redox signaling. This review will discuss the production of ROS and RNS within the adipose tissue, their role in regulating lipolysis and lipogenesis, and the implications of antioxidants on lipid mobilization.

Keywords: antioxidants; lipogenesis; lipolysis; oxidative stress; redox signaling.

Figure 3

Antioxidant effect on lipolysis. Catalase (CAT), an enzyme produced by peroxisomes, catalyzes the breakdown of H₂O₂ into O₂ and H₂O. CAT knockout models (CKO) fed a high-fat diet (HFD) have a higher lipolysis rate and are more susceptible to obesity and insulin resistance compared to wild-type littermates. Peroxiredoxins (Prx) catalyze the reduction of H₂O₂. Prx3/6 knockout mice (PRDX3/6 KO) have increased lipolysis and insulin resistance. Glutathione peroxidase (GPx) catalyzes the breakdown of H₂O₂ to water. GPx overexpression results in an increase in body weight (BW) possibly by decreasing lipolysis. Selenium promotes lipolysis during obesity. Vitamin E decreases plasma triacylglycerol (TAG). Resveratrol increases β-adrenergic receptor (βAR)-stimulated lipolysis and impairs insulin’s antilipolytic effect. Apelin decreases lipolysis by promoting the expression of antioxidant enzymes (superoxide dismutase (SOD), CAT, and GPx) and suppressing the expression of nicotinamide adenine dinucleotide phosphate oxidase (NOX). Nuclear factor E2-related factor 2 (Nrf2) increases lipid accumulation and decreases lipolysis.

Figure 1

ROS and RNS sources in AT cells. (1) Cytosol: The oxidation of hypoxanthine to xanthine by xanthine oxidoreductase (XO) produces superoxide (O₂^•−) and hydrogen peroxide (H₂O₂). Nitric oxide synthase (NOS) produces nitric oxide (NO^•). (2) Endoplasmic reticulum: Oxidative protein folding, carbohydrate addition, disulfide bond formation, and desaturation of FA generate O₂^•− and H₂O₂. (3) Mitochondria: O₂^•− is produced by complexes I and III of the electron transport chain (ETC). O₂^•− is then converted to H₂O₂ by superoxide dismutase (SOD), or to peroxynitrite (ONOO⁻) in the presence of NO^•. (4) Peroxisomes: O₂^•− and H₂O₂ are produced during FA oxidation by peroxisomal enzymes such as amino acids (AA), aspartate (Asp), and xanthine oxidases. (5) Macrophages and neutrophils: Generate O₂^•− and H₂O₂ by nicotinamide adenine dinucleotide phosphate oxidase (NOX) during the respiratory burst. NOX in the cytosol, cellular membrane, and mitochondria also produces O₂^•− and H₂O₂. (6) Cellular membrane: Phospholipases (PLA) hydrolyze phospholipids to produce free fatty acids, which are later oxidized by cyclooxygenases and lipoxygenases, releasing hydroxyl radicals (^•OH).

Figure 2

Redox signaling and lipolysis. ROS and RNS alter lipolytic pathways at different points. (1) Growth hormone receptor: ROS, especially H₂O₂, production increases upon growth hormone (GH) binding to the growth hormone receptor, consequently activating β-adrenergic receptor (βAR), adenylyl cyclase (AC), and protein kinases downstream, increasing lipolysis. (2) β-adrenergic receptor: Adrenalin (Adr) binds to βAR and increases the production of ROS. O₂^•− and H₂O₂ also oxidize βAR, increasing adipocyte sensitivity to lipolysis. On the other hand, NO^• suppresses βAR activation. (3) Natriuretic peptide receptor: O₂^•− and H₂O₂ produced upon activation of NPRA enhance the activation of βAR, AC, and cAMP synthesis, increasing lipolysis. (4) Nicotinamide adenine dinucleotide phosphate oxidase: NOX converts O₂ to O₂^•− and H₂O₂. Moreover, insulin, through the production H₂O₂ by NOX4, inhibits PKA activation, reducing adrenergic stimulated lipolysis. (5) Protein kinase C (PKC): at high concentration, O₂^•− and H₂O₂ activate PKC through the release of diacylglycerol (DAG) or may inactivate it by impairing its substrate-binding affinity. At low concentrations, ROS activate PKC by oxidizing its structural cysteine residues. H₂O₂ activates PKC by increasing Ca²⁺ concentrations. (6) Protein kinase A (PKA): at high concentration, ROS inhibit cAMP-dependent PKA, but at low concentration, ROS prolong the activation of PKA by inhibiting the phosphatase that suppresses it. (7) Protein kinase G (PKG): it is currently unknown how ROS affect PKG activity in adipocytes. Black arrows represent the classic lipolytic pathway, blue arrows represent the production of ROS/RNS, and red arrows represent the effect (activation or inhibition) of ROS/RNS.

Figure 4

Redox signaling and lipogenesis. (a) H₂O₂ acts as a secondary messenger of insulin in adipocytes by suppressing the oxidation of protein tyrosine phosphatases (PIP), thus facilitating insulin signaling. H₂O₂ also increases lipogenesis by increasing NADPH and glucose incorporation into glyceride-FA, and stimulating pyruvate dehydrogenase (PD); (b) enhanced Fat ROS, through the depletion of glutathione in adipocytes, decreases insulin sensitivity, reduces lipogenic gene expression, and display smaller adipocytes.