Adipose tissue plays a major role in the regulation of systemic metabolic homeostasis, and defects in insulin action and lipolysis have the capacity to impact systemic glycaemic control. In this respect, the AP2 adaptor complex plays an important role in clathrin-mediated endocytosis of various cell surface receptors in adipose tissue, including the glucose transporter GLUT4, the insulin receptor and beta-adrenergic receptors. The AP2 complex is a hetero-tetramer (α, ß, µ and σ subunits), with the alpha-subunit being important for attachment of the AP2 complex to the membrane and for cargo internalization. The alpha-subunit exists in two isoforms, Ap2a1 and Ap2a2. Of interest, Ap2a2 (but not Ap2a1) has recently been identified as a peroxisome proliferator-activated receptor alpha (PPARα) target gene. The effects of PPARα on the AP2 adaptor complex and clathrin-mediated endocytosis in adipose tissue are not well described.
We have generated adipose tissue-specific Ap2a2 knockout mice and investigated metabolic alterations on a standard chow diet, in the presence of lipid overload (8 weeks high-fat feeding) as well as with dietary supplementation with the PPARα-agonist pirinixic acid (WY-14643). Supplementation with WY was required to drive expression of Ap2a2 in adipose tissue of wild-type mice and produce genotype-specific effects. Deletion of Ap2a2 led to minor improvements on systemic level, and did not affect basal or insulin-stimulated glucose uptake, or fatty acid metabolism. However, deletion of Ap2a2 had a substantial impact on beta-adrenergic activation of lipolysis. Adipose tissue of Ap2a2-KO mice lost its ability to respond to beta-adrenergic stimuli, as evidenced by a lack in increases in cAMP, PKA activation and glycerol release. These differences were not due to differential expression of beta-adrenergic receptors, but more likely to defects in AP2-mediated receptor endocytosis and recycling.
This study indicates a novel role for PPARα in beta-adrenergic regulation of lipolysis in adipose tissue.