The role of Ap2a2 in PPARα‐mediated regulation of lipolysis in adipose tissue

Abstract

Adipose tissue plays a major role in the regulation of systemic metabolic homeostasis, with the AP2 adaptor complex being important in clathrin-mediated endocytosis (CME) of various cell surface receptors, including glucose transporter 4, the insulin receptor, and b-adrenergic receptors (ARs). One of the AP2 subunits, adaptor-related protein complex 2, a2 subunit (Ap2a2), has recently been identified as a peroxisome proliferatoractivated receptor (PPAR)a target gene. The effects of PPARa on the AP2 adaptor complex and CME are unknown. We generated adipocyte-specific Ap2a2 knockout mice and investigated their metabolism when fed a standard chow or high-fat diet, without and with supplementation with the PPARa-agonist WY-14643 (WY). Although Ap2a2 deletion had only minor effects on glycaemic control, it led to substantial impairment in b-adrenergic activation of lipolysis, as evidenced by a loss of cAMP response, PKA activation, and glycerol/fatty acid release. These differences were related to increased cell surface localization of the b2and b3-ARs. Lipolytic defects were accompanied by impaired WY-mediated loss of fat mass and whole-body fat oxidation. This study demonstrates a novel role for PPARa in b-adrenergic regulation of adipose tissue lipolysis and for adipose tissue in supplying adequate substrate to other peripheral tissues to accommodate the increase in systemic fatty acid oxidation that occurs upon treatment with PPARa agonists.-

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

“…Interestingly, PPARα-dependent regulation of fatty acid oxidation in extrahepatic tissues plays an important role during fasting and can compensate, at least in part, for the absence of PPARα in hepatocyte-specific Ppara-null mice [261]. A role for adipose PPARα in the β-adrenergic regulation of lipolysis has been suggested [262]. Overexpression of PPARα in adipose tissue is associated with improvement in HFD-induced alterations in glucose metabolism, mostly through modulation of BCAA metabolism [263].…”

Cardiotrophin‐1 contributes to metabolic adaptations through the regulation of lipid metabolism and to the fasting‐induced fatty acid mobilization

“…PPARγ is highly expressed in healthy adipose tissue with important metabolic activities and functions in the regulation of adipocytokines secretion 19 . Although PPARα has been suggested to have a less pronounced role in adipose tissue, recent studies have shown that the activation of this transcription factor stimulates FAO, 30 mitochondrial biogenesis, oxidative capacity, 31 and activates lipolysis in adipose 32 . We observed that epididymal WAT (eWAT) from PPARα –/– mice had significantly lower levels of Ct‐1 mRNA expression than the WT animals (Figure 2A).…”

“…Interestingly, it has been reported that defective PPARγ in adipocytes causes impairment in the catecholamine‐induced lipolysis due to a dysfunction of the PKA, as well as defects in the expression of major lipases and specific dysregulation of lipid droplet proteins 45 . Recently, it has been shown a novel role for PPARα in β‐adrenergic regulation of adipose tissue lipolysis 32 . In this sense, our data support the idea that physiological levels of CT‐1 are necessary in prolonged food restriction states to permit lipid mobilization and are in line with the concept that PPAR coordinates both catabolic and anabolic processes in the adipocyte and that these effects are fundamental to maintaining the metabolic flexibility required for the efficient management of nutritional fluxes in and out of adipose tissue.…”

Proteome analysis of human visceral and subcutaneous adipocytes identifies depot-specific heterogeneity at metabolic control points

“…Our results show that many enzymes involved with fatty acid catabolism, TCA cycle flux and oxidative phosphorylation are expressed at significantly higher levels in GFAT adipocytes compared with VAT and ASAT adipocytes. PPARa is critical for the transcription of genes that translate proteins involved in adipocyte lipolysis, fatty acid oxidation and mitochondrial biogenesis, and PPARa agonists exert weight loss (Lazennec et al, 2000;Li et al, 2005;Montgomery et al, 2019;Shalev et al, 1996). PPARα-RXRα activation was over-represented in the GFAT adipocyte proteome and the enrichment of PPARα target pathways suggest that enhanced oxidative disposal of fatty acids may be a component underpinning the so-called 'safe' disposal of fatty acids in GFAT.…”