Peroxisomal regulation of energy homeostasis: Effect on obesity and related metabolic disorders

Abstract

Background: Peroxisomes are single membrane-bound organelles named for their role in hydrogen peroxide production and catabolism. However, their cellular functions extend well beyond reactive oxygen species (ROS) metabolism and include fatty acid oxidation of unique substrates that cannot be catabolized in mitochondria, and synthesis of ether lipids and bile acids. Metabolic functions of peroxisomes involve crosstalk with other organelles, including mitochondria, endoplasmic reticulum, lipid droplets and lysosomes. Emerging studies suggest that peroxisomes are important regulators of energy homeostasis and that disruption of peroxisomal functions influences the risk for obesity and the associated metabolic disorders, including type 2 diabetes and hepatic steatosis.

Scope of review: Here, we focus on the role of peroxisomes in ether lipid synthesis, β-oxidation and ROS metabolism, given that these functions have been most widely studied and have physiologically relevant implications in systemic metabolism and obesity. Efforts are made to mechanistically link these cellular and systemic processes.

Major conclusions: Circulating plasmalogens, a form of ether lipids, have been identified as inversely correlated biomarkers of obesity. Ether lipids influence metabolic homeostasis through multiple mechanisms, including regulation of mitochondrial morphology and respiration affecting brown fat-mediated thermogenesis, and through regulation of adipose tissue development. Peroxisomal β-oxidation also affects metabolic homeostasis through generation of signaling molecules, such as acetyl-CoA and ROS that inhibit hydrolysis of stored lipids, contributing to development of hepatic steatosis. Oxidative stress resulting from increased peroxisomal β-oxidation-generated ROS in the context of obesity mediates β-cell lipotoxicity. A better understanding of the roles peroxisomes play in regulating and responding to obesity and its complications will provide new opportunities for their treatment.

Keywords: Diabetes; Fatty liver; Lipid metabolism; Obesity; Peroxisomes; Plasmalogen.

Figure 1

Role of peroxisomes in various organs across lean and obese states. In brown adipose tissue, peroxisome-derived ether lipids promote mitochondrial fission, which increases thermogenesis and energy expenditure. Certain species of plasmalogen, a form of ether lipid, are decreased in serum of obese individuals. Peroxisomal β-oxidation promotes fatty liver through multiple distinct mechanisms and contributes to non-esterified fatty acid (NEFA)-induced lipotoxicity in pancreatic β-cells, likely contributing to impaired glucose-stimulated insulin secretion (GSIS). Reactive oxygen species (ROS) from both peroxisomal and mitochondrial β-oxidation induce oxidative stress in adipose tissue of obese individuals, causing systemic insulin resistance.

Figure 2

Peroxisomal lipid synthetic pathway. Glyceraldehyde 3-phosphate, a glycolysis intermediate, can be converted to dihydroxyacetone phosphate (DHAP) by triose phosphate isomerase (TPI). Glycerol-3-phosphate dehydrogenase (GPDH) catalyzes the conversion of DHAP to glycerol 3-phosphate (G3P), though both DHAP and G3P are believed to be transported to the peroxisomal matrix by peroxisomal membrane protein 2 (PXMP2). In peroxisomes GPDH may convert G3P back to DHAP, which subsequently has an acyl chain added to its sn-1 carbon by glyceronephosphate O-acyltransferase (GNPAT), yielding acyl-DHAP. Acyl-DHAP may have its sn-2 carbonyl reduced by PexRAP (Peroxisomal Reductase activating PPARγ; encoded by Dhrs7b) to yield lysophosphatidic acid (LPA) or it may have its sn-1 acyl chain replaced by a new sn-1 alkyl chain to yield alkyl-DHAP, a reaction catalyzed by alkylglycerone phosphate synthase (AGPS). Alkyl-DHAP is then reduced by PexRAP to form 1-O-Alkyl-G3P (AGP). LPA and AGP are shuttled to the endoplasmic reticulum for formation of diacyl phospholipids and ether-linked phospholipids, respectively. Ether lipids may be processed further to generate plasmalogens, a subclass of ether lipids with a cis-double bond.

Figure 3

Adipose-specific peroxisome deficiency impairs mitochondrial fission and increases diet-induced obesity. Mice with adipose-specific knockout of Pex16 (Pex16-AKO) display impaired mitochondrial fission in brown adipose tissue, decreased thermogenesis, and increased diet-induced obesity. This phenotype is rescued by supplementation of ether-lipid synthetic intermediates, implicating ether lipids as the mediator linking peroxisomes with mitochondrial fission and thermogenesis.

Figure 4

Peroxisomal β-oxidation promotes nonalcoholic fatty liver disease through multiple unique mechanisms. The first step of peroxisomal β-oxidation reduces FAD to FADH₂, which in turn reduces O₂ to H₂O₂. The oxidant stabilizes disulfide bonds in peroxisomal biogenesis factor 2 (Pex2), thus increasing the protein levels of Pex2, which mediates poly-ubiquitination of adipose triglyceride lipase (ATGL). This promotes targeted degradation of ATGL by proteasomes, resulting in impaired lipolysis and increased hepatic steatosis. An alternative mechanism involves the use of acetyl-CoA, a product of peroxisomal β-oxidation, in acetylation of regulatory-associated protein of mTOR (Raptor), part of the mammalian target of rapamycin complex 1 (mTORC1). Acetylation of Raptor activates mTORC1, resulting in impaired lipophagy and aberrant hepatic lipid accumulation.