Abstract
Recent studies suggest that the AMP-activated protein kinase (AMPK) acts as a major energy sensor and regulator in adipose tissues. The objective of this study was to investigate the role of AMPK in nicotine-induced lipogenesis and lipolysis in 3T3L1 adipocytes. Exposure of 3T3L1 adipocytes to smoking-related concentrations of nicotine increased lipolysis and inhibited fatty acid synthase (FAS) activity in a time- and dose-dependent manner. The effects of nicotine on FAS activity were accompanied by phosphorylation of both AMPK (Thr(172)) and acetyl-CoA carboxylase (ACC; Ser(79)). Nicotine-induced AMPK phosphorylation appeared to be mediated by reactive oxygen species based on the finding that nicotine significantly increased superoxide anions and 3-nitrotyrosine-positive proteins, exogenous peroxynitrite (ONOO(-)) mimicked the effects of nicotine on AMPK, and N-acetylcysteine (NAC) abolished nicotine-enhanced AMPK phosphorylation. Inhibition of AMPK using either pharmacologic (insulin, compound C) or genetic means (overexpression of dominant negative AMPK; AMPK-DN) abolished FAS inhibition induced by nicotine or ONOO(-). Conversely, activation of AMPK by pharmacologic (nicotine, ONOO(-), metformin, and AICAR) or genetic (overexpression of constitutively active AMPK) means inhibited FAS activity. Notably, AMPK activation increased threonine phosphorylation of FAS, and this effect was blocked by adenovirus encoding dominant negative AMPK. Finally, AMPK-dependent FAS phosphorylation was confirmed by (32)P incorporation into FAS in adipocytes. Taken together, our results strongly suggest that nicotine, via ONOO(-) activates AMPK, resulting in enhanced threonine phosphorylation and consequent inhibition of FAS.
Highlights
(AMPK) acts as a major energy sensor and regulator in adipose units, each of which has at least two isoforms [1,2,3,4]
Nicotine Increases the Phosphorylation of AMPK, ACC, and LKB1—Because phosphorylation of AMPK at Thr172 is correlated with increased kinase activity and ACC is a downstream target of AMPK [6], we examined the effects of nicotine on the levels of Thr172-phosphorylated AMPK (AMPK-P) and Ser79phosphorylated ACC (ACC-P) in adipocytes
Differentiated 3T3L1 adipocytes were exposed to nicotine ranging from 6 nM to 60 M for 1 h
Summary
(AMPK) acts as a major energy sensor and regulator in adipose units, each of which has at least two isoforms [1,2,3,4]. TnoicboetimneedsiiagitnmeidfimbcaynurtenlaycoitnibvcerloeoaxtsyegidnensuFsppigeerc.oie6xsiBdbeawsaendeioornnestharneedfuin3sd-eninidtgrtoahtyas-t AM((71–0P9–K)1,-3cα)a,lacinniudmFtirgcaan.lsmfoordmuilning-dgreopwenthdefancttkoirn-as-eacktiinvaasteed(CkainMasKeK-1) rosine-posi6tivCe.pTrohteeinws, eixtohgdenroauws pienrgoxyanuittrhiteo(rOsNwOOe؊re) maimb-le t(oTAloK-c1a)t(e14d, 1a5t).aAfMoPrKahraes pbeeeantimedplicated in the regulation icked the efefexctps oefrniimcoteinnetoncoAMndPKu,catneddN-aactettyhlceystteiimnee(NoAfC)theofosreivgeirnalaalspwecotsrkoffionrtetrmheediary metabolism, including gluabolished of AMPK nicotine-enhanced AMPK phosphorylation. Nspiceoctitnfeuhlalys addiisreacgt reeffeec.t Fonurthtehreerlemasoe orfec,ytokines and Notably, AMPK activation increased threonine phosphorylation of FAS, and thtisheeffewctiwtahsdblroackwedinbgy aadeuntohviorurssensctoadtinegtdhomatintahnte rfaerceseeutyfllatctshtyoolaifnceitdhrseifcsreoppmtaoarpsdei(p1ro9hc).yatHevsuem(2ba0ne), eswtnuhdiciehs e(x2p1r, e2s4s)niincdoitcinatiec negative AMcoPKn.fFirinmalley,dAbMyPKt-hdeeprenedseunlttFsAoS fphcoospmhoprylelamtioennttahrayt seysxtpemeircimniceontitnse pinrfeussioennstteimduilnatetshleipolysis in human wtoagsecthoenrf,iromuaerrdrtebiscyul3le2tsPasintnrcodonrgptlohyrasauttigogtnehsintettohpaFrtAinnSicicnoitpaidnaiepl,ovociyabtOesseN. AMPK Inhibits FAS in Adipocytes its carnitine palmitoyltransferase I, which transports fatty acids into mitochondria for oxidation. The simple inhibition of ACC prevents a futile cycle by promoting synthesis and blocking oxidation [29]
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