Adapalene induces adipose browning through the RAR beta-p38 MAPK-ATF2 pathway

Abstract

Adipose browning has recently been reported to be a novel therapeutic strategy for obesity. Because the retinoic acid receptor (RAR) is a potential target involved in browning, adapalene (AD), an anti-acne agent with RAR agonism, was examined in detail for its effects on adipose browning and the underlying mechanisms in vitro and in vivo. AD upregulated the expression of adipose browning-related markers in a concentration-dependent manner, promoted mitochondrial biogenesis, increased oxygen consumption rates, and lowered lipid droplet sizes in differentiated 3T3/L1 white adipocytes. Among the three retinoic acid receptors (RAR alpha, RAR beta, and RAR gamma), knockdown of the gene encoding RAR beta mitigated AD-induced adipose browning. Similarly, LE135 (a selective RAR beta antagonist) attenuated AD action, suggesting that AD promotes adipose browning through RAR beta. Sequential phosphorylation of p38 mitogen-activated protein kinase (MAPK) and activating transcription factor 2 (ATF2) was critical for AD-induced adipose browning, based on the observations that either SB203580 (a p38 MAPK inhibitor) or ATF2 siRNA reduced the effects of AD. In vivo browning effects of AD were confirmed in C57BL/6J mice and high-fat diet-induced obese (DIO) mice after oral administration of AD either acutely or chronically. This study identifies new actions of AD as an adipose browning agent and demonstrates that RAR beta activation followed by increased phosphorylation of p38 MAPK and ATF2 appears to be a key mechanism of AD action.