Effects of Cigarette Smoking and Its Cessation on Lipid Metabolism and Energy Expenditure in Heavy Smokers
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1 Effects of Cigrette Smoking nd ts Cesstion on Lipid Metbolism nd Energy Expenditure in Hevy Smokers Mrc K. Hellerstein,* Neil L. Benowitz,t Richrd A. Neese,* Jen-Mrc Schwrtz,' Rebecch Hoh, * Peyton Jcob, * Jmes Hsieh, nd Dennis Fix Divisions of *Endocrinology nd Metbolism, nd $Clinicl Phrmcology, Deprtment ofmedicine, Sn Frncisco Generl Hospitl, University ofcliforni, Sn Frncisco, Cliforni 941 1; nd Deprtment ofnutritionl Sciences, University ofcliforni t Berkeley, Berkeley, Cliforni 9472 Abstrct The reltionship between thermogenic nd potentilly therogenic effects of cigrette smoking (CS) nd its cesstion ws investigted. Hevy smokers (n = 7, serum cotinine > 2 ng/ ml, > 2 cigrettes/d) were mintined on isoenergetic, constnt diets for 2 wk, 1 wk with nd wk without CS. Stble isotope infusions with indirect clorimetry were performed on dy 7 of ech phse, fter n overnight fst. CS fter overnight bstention incresed resting energy expenditure by 5% (not significnt vs. non-cs phse; P =.18). CS incresed the flux of FFA by 77%, flux of glycerol by 82%, nd serum FFA concentrtions by 73% (P <.2 for ech), but did not significntly ffect ft oxidtion. Heptic reesterifiction of FFA incresed more thn threefold (P <.3) nd dipocyte recycling incresed nonsignificntly (P =.1). CS-induced lipid substrte cycles represented only 15% (estimted 11 kcl/d) of observed chnges in energy expenditure. De novo heptic lipogenesis ws low (< 1-2 g/d) nd unffected by either cute CS or its chronic cesstion. Heptic glucose production ws not ffected by CS, despite incresed serum glycerol nd FFA fluxes. Cesstion of CS cused no rebound effects on bsl metbolic fluxes. n conclusion, metbolic mechnism for the therogenic effects of CS on serum lipids (incresed heptic reesterifiction of FFA) hs been documented. ncresed entry of FFA ccounts for CS-induced increses in serum FFA concentrtions. The thermogenic effect of CS is smll or bsent in hevy smokers while the potentilly therogenic effect is mintined, nd cesstion of CS does not induce rebound lipogenic milieu tht specificlly fvors ccrul of body ft in the bsence of incresed food intke. (J. Clin. nvest : ). Key words: lipolysis * substrte cycles * clorigenesis * therogenesis * stble isotopes ntroduction Cigrette smoking (CS)' is ssocited with reduced body weight nd cesstion of CS results in weight gin (1-11) The. public is wre of this effect of CS, nd concern bout weight Address correspondence to Dr. Mrc K. Hellerstein, Division ofendocrinology nd Metbolism, Deprtment of Medicine, Sn Frncisco Generl Hospitl, 11 Potrero Avenue, Sn Frncisco, CA Receivedfor publiction 12 April 1993 nd in revisedform 3 September J. Clin. nvest. C) The Americn Society for Clinicl nvestigtion, nc /94/1/265/8 $2. Volume 93, Jnury 1994, gin is one of the most common resons given for continuing or returning to CS (1-4). Concern bout weight gin fter quitting smoking nd the use ofcs to control body weight is prticulrly prevlent in women smokers (3), who represent the fstest growing popultion of new smokers. Although the dverse helth effects of CS gretly outweigh the benefits of lower body weight (1, 12), cosmetic or other fctors clerly come into ply Ṫhe mechnism by which CS reduces body weight remins uncertin. Contrry to the generl belief tht CS reduces food intke, most published studies hve reported incresed food intke in smokers, in the rnge of 35 kcl/d (13, 14), lthough others hve reported reduced food intke in smokers (15-17). n experimentl nimls, chronic dministrtion of nicotine or exposure to CS increses oxygen consumption nd results in weight loss (1) nd rts given nicotine lose weight without significnt reduction in food intke (18). Recent metbolic wrd studies confirm tht CS hs n cute clorigenic effect in humns. Smoking increses 24-h energy expenditure (EE) by 2 kcl/d (19) nd intrnsl or intrvenous nicotine increses resting EE (REE) by 5-1% (2, 21), lthough we (22) hve recently observed lower CS-induced increse in REE in hevy smokers compred with light smokers. The metbolic bsis of CS-induced clorigenesis is not understood. Nicotine cuses ctivtion of the sympthetic nervous system nd the relese of ctechols (23, 24), which increse EE in humns (25, 26). CS or ctechol dministrtion increses serum FFA concentrtions (27-29). One hypothesis hs been tht lipolysis or elevtions in serum FFA concentrtions contribute to the thermogenesis of CS (26). Consistent with this suggestion, norepinephrine-induced thermogenesis hs been reported to be prtilly prevented by nicin (25), lipolysis inhibitor, in humns. A precedent exists for lipolysis/ reesterifiction substrte cycling contributing to thermogenesis in hyper-drenergic clinicl condition, body burns (3). FFA themselves re lso known to increse crdic oxygen consumption (31). Potentilly linked but undesirble consequences of nicotine-induced lipolysis re the incresed triglyceride nd LDL cholesterol concentrtions nd reduced HDL cholesterol concentrtions ssocited with CS (32, 33). There is dose-response reltionship between the number of cigrettes smoked per dy nd serum cholesterol concentrtions (34), nd cesstion of CS increses HDL cholesterol (33). n severl dyslipi- 1. Abbrevitions used in this pper: CS, cigrette smoking; DNL, de novo heptic lipogenesis; EE, energy expenditure; FAME, ftty cidmethyl esters; GC, gs chromtogrphy; LPL, lipoprotein lipse; M.E., molr excess; NPRQ, non-protein respirtory quotient; R, rte ofppernce; REE, resting energy expenditure; TG, triglyceride. Metbolic nd Thermogenic Effects ofcigrette Smoking nd ts Cesstion 265
2 demic conditions, including dibetes (35-37), incresed delivery of FFA to the liver nd heptic reesterifiction hs been proposed to be the cuse of incresed VLDL triglyceride secretion nd secondry ltertions in serum lipids. Conversely, the mechnism by which nicin improves lipids in humns is believed to be through inhibition of lipolysis (38-4). Heptic reesterifiction of FFA my therefore link the thermogenic nd therogenic effects of CS. The effects of CS on lipolysis, serum FFA flux, nd heptic reesterifiction of FFA hve not been determined in humns, however, nor hve their reltionships to CS-induced clorigenesis been evluted. With regrd to cesstion of CS, the suggestion hs been mde (41, 42) tht rebound metbolic effects occur fter smoking cesstion tht specificlly fvor the deposition of body ft nd could therefore provide metbolic driving force for incresed diposity (obesity) fter smoking cesstion. This proposl hs not been tested from quntittive perspective, however, by mesuring ft synthesis nd ft oxidtion under conditions of constnt dietry ft nd energy intke. Our objectives in this study were to evlute reltionships between lipolytic, clorigenic, nd dyslipidemic effects of CS nd determine the metbolic effects of cesstion of CS. Four questions were ddressed. () Wht re the effects of CS on lipid metbolism, crbohydrte metbolism, nd REE in hevy smokers? (b) Do substrte cycles ccount for the clorigenic effect of CS? (c) f potentilly therogenic effects of CS re documented, re these mechnisticlly linked to clorigenesis? (d) Does cesstion of CS induce rebound metbolic milieu tht specificlly fvors ccumultion of body ft (i.e., reduced ft mobiliztion or oxidtion, incresed ft synthesis) in the bsence of ltered food intke? Methods Humn subjects. Volunteers were recruited by dvertisement. Subjects gve written informed consent before enrollment nd ll protocols received prior pprovl from the University of Cliforni, Sn Frncisco, Committee on Humn Reserch. Seven hevy smokers (serum cotinine > 2 ng/ml, > 2 cigrettes/d) were enrolled. Exclusion criteri were history of medicl illnesses (liver, kidney, metbolic, hemtologic, pulmonry, gstrointestinl, neurologic), bnormlities on screening physicl exm or by lbortory testing (chemistry profile, complete blood count), > 12% idel body weight, or chnge in body weight > 1 lb over the preceding 6 mo. Subjects were documented to be humn immunodeficiency virus seronegtive (since bnormlities of lipid metbolism my be present in symptomtic seropositivity; reference 43). Subjects using medictions with potentil metbolic effects (e.g., fl-blockers, f,-gonists, theophylline, diuretics, glucocorticoids, phenytoin) were lso excluded. The seven subjects' ge ws 4±4 yr, weight ws 71.3±4.7 kg, height ws 172.3±3.1 cm, nd body mss index ws 24.±1.3 kg/im2 (men±se). Durtion of CS ws 14±3 yr. Study design. Subjects took prt in 2-wk inptient metbolic wrd study, 1 wk with CS nd 1 wk without CS, in the Generl Clinicl Reserch Center (GCRC) of Sn Frncisco Generl Hospitl. The sequence of CS nd non-cs ws rndomized. Four subjects ended up in the CS phse first while three subjects were in the non-cs phse first. No effect of rndomiztion sequence ws observed here or previously (44). Subjects were plced on constnt, weight-mintining metbolic diet throughout the GCRC dmission, to void potentil confounding effects of cesstion of CS on food intke. Diets were prepred by the metbolic kitchen, fter subjects nd dieticins estblished dily diet providing estimted energy needs (bsed on Hrris-Benedict equtions with comprison to 3-d dietry reclls for usul intke). Food intke ws djusted over the first 3 d on the metbolic wrd on the bsis of subjects' report of hunger, up to mximum of 75 kcl/d bove predicted energy needs. On dys 8 nd 15 (dy 7 of ech phse), metbolic infusion studies were performed. These metbolic studies were designed to mesure number of metbolic processes: dipose lipolysis, reesterifiction of FFA in dipose nd liver, de novo heptic lipogenesis, cycling through ft oxidtion/resynthesis, heptic glucose production, ft oxidtion, crbohydrte oxidtion, nd EE. The protocol consisted ofintrvenous infusions of sodium [1-'3C]cette ( mmol/kg per h) from 2:.m. until 6: p.m.; [d5]-glycerol (9.7 Ag/kg per min) from 6:.m. until noon; [1,2,3,4-13C]plmitte (7 Ag/kg per min) complexed with humn serum lbumin (25 g) from 6:.m. until noon; nd [6,6-d2]-glucose (.4 mg/kg per min) from 6:.m. until noon. ndirect clorimetry ws performed between 7:.m. nd 6: p.m. using Delttrc Metbolic Crt (Sensor Medix, Yorb Lind, CA) in the hooded mode. Urinry ure nitrogen ws mesured in order to clculte nonprotein respirtory quotient. Subjects were fsted (noncloric fluids llowed) from 1: p.m. of the preceding night until noon of the study dy. Cffeine ingestion ws not permitted during the metbolic study, nd CS ws not permitted between 1: p.m. nd 9:.m. Bsl blood drws were performed every 1 min between 8:3 nd 9:.m. From 9:.m. until noon, subjects smoked cigrette every 3 min on the hlfhour nd hour (CS phse) or did not smoke (non-cs phse). Repet blood drws were every 1 min from 11:3.m. to noon. At noon, mel of defined content ws served, identicl in both phses (consisting of 1,57±12 kcl, 42±6 g protein, 121±12 g crbohydrte, nd 45±9 g ft), nd smoking ofone cigrette every 3 min continued until 2: p.m. (in the CS phse). Complince during the nonsmoking phse ws estblished by mesurement of breth crbon monoxide t rndom times throughout the dy nd urinry cotinine from 24-h urine collections, s described previously (45). All subjects complined of nervousness, reduced concentrtion, nd/or some irritbility during the non-cs phse. No specific tretment for these or other withdrwl symptoms ws instituted. Withdrwl scores were not mesured, but we hve found in previous studies tht withdrwl scores re not high in closed metbolic wrd setting, due to the lck of externl cues for smoking (Benowitz, N., unpublished observtions). Clinicl lbortory mesurements. Serum nicotine nd cotinine concentrtions were mesured by gs chromtogrphy (GC)/mss spectrometry (MS) (45). Serum lipids nd thyroid function tests (triiodothyronine [T3], tetriodothyronine [T4]) were mesured by stndrd methods (Roche Lbortories, Sn Frncisco, CA). Serum insulin ws determined by rdioimmunossy. Serum FFA concentrtions were mesured by GC/flme ioniztion detection. Quntifiction ws by comprison to known stndrds, with n internl stndrd ofpentdecnoic cid dded to the extrction mixture to determine recovery. nfuste glycerol concentrtions were mesured by glycerokinse enzyme ssy, infuste glucose concentrtions by glucose oxidse ssy, nd infuste plmitte concentrtions by GC fter extrction of the infuste with heptne/isopropyl lcohol (3:7). Urinry nitrogen ws mesured from 24-h collections by the Kjeldhl method. Mss spectrometry. GC/MS (5971; Hewlett-Pckrd, Plo Alto, CA) ws used for nlysis of isotopic enrichments of serum glucose, glycerol, nd ftty cid-methyl esters (FAME) from VLDL. A GC/MS (597; HP) ws used for nlysis of FAME from serum. For glucosepentcette, we used DB m,.25-mm i.d. fused silic column. The moleculr ion - cette nd its isotopomers (mss/chrge [m/z] 331 nd 333) were quntified using selected ion monitoring (SM) by comprison to stndrd curves of [6,6-d2]-glucose t known enrichments. Chemicl ioniztion ws used. For FAME nlyses, 2-m fused DB-l silic column, isotherml t 2C, ws used with electron impct ioniztion. ons t m/z were monitored by SM, representing the prent Mo through the M4 isotopomers with electron impct ioniztion. Glycerol tricette ws nlyzed using DB-225 column nd chemicl ioniztion, monitoring m/z 159 nd 164 (the moleculr ion minus cette, nd its isotopomers). 266 Hellerstein et l.
3 Sttisticl nlyses. We performed two-fctor repeted mesures nlysis of vrince, with the two tril fctors being smoking phse (chronic smoking vs. chronic nonsmoking) nd time (bseline vs. 3-h vlues, the ltter fter cute smoking or nonsmoking). The existence of significnt chronic phse by time interction represents sttisticl significnce of cute smoking. f significnt interction ws found, follow-up comprisons of the four individul cell mens were by Tukey's studentized rnge test t procedurewise error rte of 5%. Clcultions. The rte of ppernce of glycerol (R glycerol), RFFA, nd R glucose were clculted by the dilution technique (46): R (Amol/kg per min) = [isotope infusion rte (,gmol/kg per min)/ metbolite enrichment (M.E.)]-, (1) where M.E. is molr excess, nd is isotype infusion rte. Reesterifiction of FFA, or lipolytic substrte cycling, ws clculted using the method ofwolfe et l. nd Klein et l. (3,47). Reesterifiction offfa cn be intrcellulr in the dipocyte, or extrcellulr in the liver (Fig. 1). Reesterifiction in the dipocyte is clculted s the difference between 3X R glycerol nd RFFA, bsed on the ssumption tht glycerol relesed from triglycerides must escpe the dipocyte, due to the bsence of glycerokinse (47), while FFA relesed from triglycerides cn either be relesed or reesterified: ntrcellulr recycling (,umol/kg per min) = [ 3x R glycerol (,umol/kg per min)] - RFFA ( umol/kg per min). (2) Heptic or extrcellulr reesterifiction is clculted s the difference between RFFA nd totl body ft oxidtion, representing nonoxidtive FFA disposl. This clcultion is bsed on the ssumption tht ll FFA entering the circultion undergoes disposl by oxidtion in tissues or reesterifiction in the liver nd tht ft oxidized in tissues t stedy-stte is derived from circulting FFA (3, 47): Heptic reesterifiction (Amol/kg per min) = RFFA (,umol/kg per min) - ft oxidtion (Amol/kg per min). (3) RFFA (,umol/kg per min) = R plmitte (Amol/kg per min)/ frction of plmitte in FFA. Frctionl DNL ws clculted using mss isotopomer distribution nlysis, s described previously (48-5). The rtio of excess M2/excess Ml in FAME isotopomers from VLDL revels the true precursor (cetyl-coa) isotopic enrichment for de novo heptic lipogenesis (DNL) during infusion of [1-'3Clcette, using probbility nlysis bsed on the binomil expnsion (48, 51). The contribution from DNL to VLDL-plmitte is then clculted using the precursor-product reltionship (48, 51 ): Frctionl DNL (%) = 1 x [EM (M.E.)/A, (M.E.)], (5) where EM, is the enrichment of the Ml isotopomer of VLDL-plmitte, nd A, * is the clculted symptotic enrichment of the M, isotopomer if 1% of VLDL-plmitte were derived from heptic DNL. Absolute heptic DNL ws clculted by combining the clcultions of frctionl DNL with bsolute heptic reesterifiction of FFA (52). The frction of VLDL-plmitte derived from DNL is known (eq. 5), so tht the proportion from non-dnl (reesterifiction) is lso known (unity minus frctionl DNL). By combining this with the mesured pprent heptic reesterifiction rte, unidirectionl or bsolute heptic DNL cn be clculted whether NPRQ is < 1. or > 1. (53). When NPRQ is < 1., the eqution is: (4) Absolute heptic DNL (mg/kg per min) = (% DNL) x [RFFA - ft oxidtion (mg/kg per min)]. (6) This technique is bsed on severl ssumptions (53), including the ssumption tht ft oxidized in tissues derives from circulting FFA under stedy-stte fsting conditions. To the extent tht tissues oxidize endogenous ft stores, which did not trverse the circultion, this technique my underestimte bsolute DNL. The quntittive effect of devitions from this or other ssumptions ofthe method cn be clculted (53), nd under the metbolic conditions present in these subjects, reltively minor influence would be exerted even if very lrge error due to oxidtion of endogenous ft stores were introduced (see below). The energy cost of lipolysis/reesterifiction substrte cycling ws clculted s described elsewhere (3), ssuming the ATP cost of triglyceride reesterifiction to be 8 mol ATP/mol triglyceride, nd the energy vlue of ATP to be 2 kcl/mol ATP (54). The energy cost of DNL/ft oxidtion cycling ws clculted on the ssumption tht 28% of the energy content of crbohydrte is lost if it is converted to lipid before oxidtion (54), or 3.2 kcl lost/g plmitte synthesized from glucose before oxidtion. Results Serum nicotine, cotinine, nd insulin concentrtions. Bsl serum nicotine concentrtions fter overnight bstention from CS during the smoking phse were 4.4±1.6 ng/ml (men±se). Blood vlues during the CS period were drwn immeditely before strting cigrette (representing ndir concentrtions) nd rose to 33.2±4.8 ng/ml fter 3 h of CS (P <.1), remining incresed (26.7±.8 ng/ml; P <.1 vs. bsl vlues) 2 h fter lunch. During the non-cs week, bsl levels were undetectble (< 1. ng/ml). Bsl serum cotinine concentrtions in the smoking phse were 39±4 ng/ml nd were not chnged significntly by cute CS (354±34 ng/ml fter 3 h of CS nd 347±53 ng/ml 2 h fter lunch). Serum cotinine ws < 1 ng/ml during the non-cs phse. Fsting serum insulin concentrtions were not different between phses (6.2±.5,uU/ml in CS phse nd 6.9±.7 AU/ml in non-cs phse). Figure 1. Sites of reesterifiction of FFA. 1, dipocyte; 2, liver. TG, triglyceride; GP, -glycerol-phosphte; DNL, de novo lipogenesis; AcCoA, cetyl-coa; CG2, crbon dioxide; KB, ketone bodies; E, stimultion of process indicted. Metbolic nd Thermogenic Effects of Cigrette Smoking nd ts Cesstion 267
4 b d T D] Bsl i 3h i post-lunch 5 - E -c 4- C:D ) E 3 - '- 2- U, b C: Bsl E 3h Non-CS phse Figure 2. Effects of CS on resting EE. Detils re described in the text. Ctegories shring common letter re not significntly different. Energy expenditure. EE ws mesured hourly, during the 4-6th min of ech hour. REE ws not significntly different fter n overnight fst in the CS nd non-cs phses (64.4±3.5 nd 64.1±4.3 kcl/h, respectively; Fig. 2). REE incresed by 4.6% fter cute CS (64.4±3.5 to 67.3±3.9 kcl/h) with increses observed in seven of seven subjects, but the chnge did not rech sttisticl significnce when compred by repeted mesures two-fctor ANOVA to the nlogous 3-h period of the non-cs phse (P =.18 for phse by time interction). ngestion of mixed mel incresed EE by 2.3% (to 77.6±6.4 kcl/h ) in non-cs phse nd by 18.9% (to 8.6±5.4 kcl/h ) in the CS phse (P =.82 for phse by time interction, P <.1 for smoking phse vs. non-smoking phse ll time points, nd P <.2 for postprndil vs. preprndil in ech phse). Serum FFA nd lipid concentrtions nd lipolysis. FFA concentrtions did not differ in the bsl stte between phses, but serum FFA concentrtions incresed from 381±94 to 658±117,M fter cute CS ( 73% increse, P <.2; Fig. 3). Serum FFA concentrtions were unchnged (228±36 to 281±5,uM; NS) in the non-cs phse. RFFA ws not different fter n overnight fst (bsl stte) in the CS nd non-cs phses (Fig. 4). Acute CS significntly incresed RFFA by 77% (from 2.95±.53 to 5.21±.72,imol/kg per min compred with 2.43±.24 to 2.71±.19 ttmol/kg per min in non- CS phse [P <.1] ). Bsl R glycerol ws lso not different 1 - N o-spechs Figure 4. Effects of CS on R FFA. Detils re described in the text. Ctegories shring common letter re not significntly different. between CS nd non-cs phses in the bsl stte (Fig. 5). Acute CS incresed R glycerol by 82% from 1.15±.2 to 2.9±.34 Atmol/kg per min compred with 1.15±.15 to 1.8±.1,umol/kg per min in non-cs phse (P <.1). Bsl serum lipid concentrtions were not significntly different in the two phses (HDL cholesterol, 38±3 nd 41±3 mg/dl in CS nd non-cs phses, respectively; triglycerides, 83±13 nd 96±17 mg/dl in CS nd non-cs phses; totl cholesterol, 165±28 nd 177±2 mg/dl in CS nd non-cs phses; NS for ll comprisons of CS nd non-cs phses). Substrte cycling of FFA nd energy costs ttributble to cycling. ntrcellulr (dipose) cycling of FFA incresed by.57umol/kg per min fter cute CS (Fig. 6), from.49±.32 to 1.6±.58,gmol/kg per min, but the effect of cute CS did not chieve sttisticl significnce (P =.1 for phse by time interction). Extrcellulr (heptic) cycling of FFA incresed more thn threefold, from.59±.48 to 2.3±.54,umol/kg per min fter cute CS (+1.44,umol/kg per min; P <.3; Fig. 7). No chnge in heptic reesterifiction of FFA ws observed during the non-cs phse (.74±.16 to.53±.23,mol/kg per min, chnge of -.21,umol/kg per min; NS). The energy cost of lipolysis/reesterifiction of FFA, clculted s described bove, is lso shown (Tble ). Energy costs of dipose cycling r b Z Bsl M 3h 2.5- E 2.- CD -e E 'D 1.- T b L Bsl M 3h CD Cu r.5- phse Figure 3. Effects of CS on serum FFA concentrtions. Detils re described in the text. Ctegories shring common letter re not significntly different..- Figure 5. Effects of CS on R glycerol. Detils re described in the text. Ctegories shring common letter re not significntly different. 268 Hellerstein et l.
5 LL LL - C.) ) )CU.5% C-)E U phse Figure 6. Effects of CS on dipoyte reesterifiction of FFA. Detils re described in the text. No significnt differences re present. U- U- c E Bsl L c 2.5-3h c 2.- T o r n w5.- x T CS Phse b D Bsl 3 h Figure 7. Effects of CS on heptic reesterifiction of FFA. Detils re described in the text. Ctegories shring common letter re not significntly different. of FFA incresed by 3.1 kcl/24 h (from 2.7 to 5.8 kcl/24 h) fter cute CS nd decresed by 2.7 kcl/24 h in the non-cs phse. For heptic cycling, the energy cost incresed from 3.2 to 11.1 kcl/d (+7.9 kcl/d) during the CS phse but did not increse from bsl to 3-h mesurements in the non-cs phse (from 4.1 to 2.9 kcl/d). DNL nd DNL/ft oxidtion substrte cycling. Frctionl DNL ws low nd ws unchnged by cute or chronic CS (Fig. 8). Absolute DNL ws estimted to be.5±.2 nd.4±.2 g/d t bsl nd 3-h time points in the non-cs phse nd.4±.2 g/d in the bsl stte for CS phse, using the recently described method (53) tht combines frctionl DNL with heptic reesterifiction of FFA. This technique underestimtes bsolute DNL to the extent tht heptic reesterifiction offfa is underestimted. Since the ltter depends on the ssumption tht intrcellulr ft oxidized hd trversed the circultion in the form of FFA, oxidtion ofintrcellulr ft stores will result in n underestimtion of bsolute heptic DNL (53). f we llow tht intrcellulr ft provided 25% of totl ft oxidtion (.4-.8,umol/kg per min), bsolute heptic DNL increses by.4 g/d. Even if we llow tht intrcellulr ft provided s much substrte for oxidtion s plsm FFA, bsolute DNL only increses to g/d. Thus, the low estimte of bsolute heptic DNL is not quntittively sensitive to this devition from the model under the metbolic conditions present here. R glucose. Under fsting conditions, R glucose is equl to heptic glucose production. R glucose vlues were higher fter 3 h thn 6 h of trcer infusion in both CS nd non-cs phses (Fig. 9). This my represent the bsence of n isotopic plteu fter 3 h of trcer infusion. Alterntively, heptic glucose production my hve fllen during the dditionl 3 h of fsting. There ws no effect ofcute smoking on 6-h R glucose vlues (2.8±.21 mg/kg per min in CS phse vs. 1.67±.13 mg/kg per min in non-cs phse; P =.28). Fuel selection. Nonprotein respirtory quotient (NPRQ) decresed from.88±.2 to.85±.2 during the 3-h dditionl fsting period in the non-cs phse, nd decresed from.83±.2 to.79±.2 in the CS phse (significnt time effect in both phses; P <.1). There ws no significnt effect of cute smoking (P =.73 for phse by time interction), lthough the NPRQ for ll smoking phse time points ws significntly lower thn in the nonsmoking phse (P <.2). After lunch, NPRQ rose to.85±.3 nd.85±.1 for CS nd non-cs phses, respectively. Whole body ft oxidtion ws significntly higher in the smoking phse thn the nonsmoking phse (2.36±.33 vs. 1.69±.31,umol/kg per min, respectively, t bsl time point nd 3.18±.35 vs. 2.19±.24,mol/kg per min t second time point; P <.2 for CS vs. non-cs phse). Acute CS did not further increse whole body ft oxidtion compred to non-cs phse (P =.42). Tble. Lipid Substrte Cycling nd Energy Costs Adipose cycling of FFA Heptic cycling of FFA DNL/ft oxidtion cycling Study phse Time Rte Energy cost Rte Energy cost Rte Energy cost 1smol/kg per min kcl/d Amol/kg per min kcl/d g/d kcl/d CS Bsl.49± ± ± h 1.6±.58* ±.54* 11.1 ND ND Chnge ND ND Non-CS Bsl 1.3± ± ± h.53± ± ± Chnge -.49± See text for detils of clcultions. Energy costs of cycling re expressed s the costs if the mesured rtes were extrpolted over 24-h period. ND, not done (stedy-stte not present for DNL mesurement). * P <.5 vs. bsl vlues. Metbolic nd Thermogenic Effects ofcigrette Smoking nd ts Cesstion 269
6 j z 2-1- Non-CS phse! Figure 8. Effects of CS on DNL. Detils re described in the text. No significnt differences re present. C: Bsl D 3h * post-lunch Whole body crbohydrte oxidtion ws nonsignificntly higher in the non-cs phse (1.75±.25 vs. 1.28±.21 mg/kg per min t bsl time point nd 1.48±.17 vs. 1.17±.19 mg/ kg per min t second time point, for non-cs nd CS phses, respectively; P =.6 for comprison between phses). Acute CS did not significntly lter crbohydrte oxidtion (P =.54 vs. non-cs phse). After lunch, whole body crbohydrte oxidtion incresed in both phses (2.9±.41 mg/kg per min in CS phse nd 1.92±.31 mg/kg per min in non-cs'phse; P <.1 for effect of lunch, NS for interction between cute CS nd lunch). Dietry energy intke nd body weight. Subjects te 2, kcl/d in the CS phse nd 3,92±32 kcl/d in the non-cs phse (NS). Predicted energy needs, bsed on the Hrris-Benedict eqution with n ctivity fctor of 1.6, were 2, kcl/d. Body weight incresed by.5±.1 kg in the CS phse (P <.5) nd.6±.3 kg in the non-cs phse (NS between phses), consistent with the slightly positive energy blnce estimted to be present. Discussion ) ) E cm -e CD E CD (n C-Z (' Nor Figure 9. Effects of CS on R glucose. Detils re described in the text. Ctegories shring common letter re not significntly different. A 4 The mjor questions sked in this study were: () Wht re the cute effects of CS on lipid metbolism, crbohydrte metbolism, nd EE in hevy smokers? (b) Are substrte cycles in-..l...n 127'. duced by CS tht could explin incresed EE? (c) Are potentilly therogenic metbolic ltertions induced by CS nd, if so, re they integrlly relted to the thermogenic effects? And, (d) re there rebound metbolic effects fter cesstion of CS tht would specificlly predispose to body ft ccumultion in the bsence of incresed dietry energy intke? We observed effects of cute CS on lipolysis, FFA substrte cycling, nd REE but no effect on DNL, ft synthesis/ft oxidtion substrte cycling, or heptic glucose production. The lck of n effect on heptic glucose production is interesting in view ofthe incresed glycerol flux ( precursor for heptic gluconeogenesis), incresed FFA flux ( potentil inhibitor of pyruvte oxidtion nd stimultor of gluconeogenesis, in ccordnce with the Rndle cycle [ 55, 56] ), nd incresed ctechol relese (23,29,57) induced by CS. Compenstory heptic utoregultory djustments, such s reduced glycogenolysis (58) or slight increses in serum insulin, might hve restrined heptic glucose production in these norml subjects. Although CS-induced increses in circulting FFA concentrtions hd been demonstrted previously (28, 29), direct kinetic evidence tht this is explicble by incresed FFA entry rther thn reduced FFA clernce in humns hd not to our knowledge previously been reported. FFA concentrtions incresed proportiontely to RFFA (73 nd 77%, respectively), suggesting tht the primry mechnism for elevted FFA concentrtions is incresed production. Since ctechols increse FFA concentrtions in humns (25-27) nd nicotine releses ctechols from the sympthetic nervous system (23, 58), mobiliztion of FFA is presumbly medited by ctechols. The effect is not persistent, though, in tht bsl RFFA, R glycerol, nd FFA concentrtions were not different during the CS nd non-cs phses. The lck of lipolytic stimultory effect fter overnight bstention from CS is lso consistent with the phrmcology of nicotine (54). n contrst, the hlf-lives ofserum lipoproteins re much longer (severl dys for LDL nd HDL), so tht effects induced by hbitul CS during the course of the dy might ultimtely ffect fsting lipoprotein concentrtions (32, 33). Our 1-wk CS nd non-cs periods were not long enough to llow differences in fsting serum lipoproteins to become pprent, however. Altertion in lipolysis/reesterifiction substrte cycling were observed s consequence of cute CS. Two types of substrte cycling cn be distinguished, intrcellulr (dipocyte) reesterifiction nd extrcellulr (heptic) reesterifiction (3, 47). Mesurement of R glycerol represents bsolute lipolysis, since the dipocyte lcks glycerokinse needed to reuse glycerol relesed from triglyceride (47), wheres RFFA reflects FFA tht escped reuse within the dipocyte (Fig. 1). The difference between 3x R glycerol nd RFFA therefore is n index of intrcellulr reesterifiction of FFA. We observed nonsignificnt (P =.1) increse in intrcellulr reesterifiction during cute CS (Fig. 6). ntrcellulr cycling represents thermogenic process tht is reltively benign in terms of systemic metbolism, the only systemic consequence being relese of glycerol. n contrst, extrcellulr recycling lso involves entry offfa into the systemic circultion nd reesterifiction in the liver, which will tend to increse heptic VLDL-triglyceride (TG) production nd secondrily lter plsm lipoproteins (35-41). Ofthe two possible sites for reesterifiction offfa, the liver is clerly the lest desirble metboliclly. Unfortuntely, this process is significntly stimulted by cute CS (Fig. 7). The 27 Hellerstein et l.
7 increse in extrcellulr reesterifiction of FFA represents mechnism by which CS might increse VLDL-TG production nd lter serum lipids in n therogenic direction (35-37). The ssocition of incresed FFA flux nd delivery to the liver with high crdiovsculr risk (e.g., dibetes [35]; CS), or reduced FFA flux with reduced crdiovsculr risk (e.g., nicotinic cid therpy [38-4]), rises the possibility tht this is generl cusl reltionship. t will be ofinterest to evlute how these lipid metbolic effects of CS re influenced by the presence of other crdiovsculr risk fctors, such s hypertension, dibetes, insulin resistnce, nd obesity. Systemic FFA relese my represent mechnistic link between CS or nicotine nd other risk fctors. f so, the benefit of nicotine replcement therpy to prevent weight gin fter cesstion of CS (59, 6) my hve to be considered in this light. The effect of nicotine replcement therpy (i.e., nicotine ptches nd chewing gum) on energy expenditure, lipid kinetics, nd serum lipoproteins is therefore n importnt re for future reserch. To the extent tht CS-induced thermogenesis is medited by substrte cycling of FFA, the sought-fter thermogenic effect nd the undesirble, possibly therogenic effect on lipids might be two sides of the sme coin, i.e., inseprble becuse they re bsed on shred lipolytic mechnism. Our quntittive clcultions do not support this notion, however. The totl thermogenic contribution from reesterifiction offfa ws clculted to be only 1 1. kcl/d, or 15% of observed chnges in REE fter cute CS in these hevy smokers. The impliction is tht inhibition of lipolysis nd subsequent reesterifiction might substntilly reduce dyslipidemic effects but not prevent ny thermogenic effects ofcs, ifthese results in hevy smokers lso pply in light smokers, in whom CS-induced thermogenesis is greter ( 19-22). This mechnistic question is not just of theoreticl interest. Although it certinly would not be desirble from generl helth point of view to dminister lipolysis inhibitor in order to llow people to continue smoking with less therogenic risk, the question my hve prcticl relevnce for use of nicotine ptches. Nicin is believed to increse dipocyte reesterifiction of FFA nd thereby reduce FFA relese (38). fthis mechnism ofction of nicin cn be confirmed, it might in principle mintin the net reesterifiction rte induced by nicotine but redirect it to the dipocyte nd wy from the liver. We re in the process of determining the effect of nicotine ptch therpy on EE nd lipid metbolism. The thermogenic effect of cute CS in these hevy smokers ( 5% nd not sttisticlly significnt) ws less thn tht reported by some previous investigtors. Hofstetter et l. ( 19) reported n 8% increse in 24-h expenditure. Gluser et l. (33) found tht cesstion of CS cused n 8% decrese in EE. On the other hnd, Perkins et l. (2) reported tht intrnsl nicotine (15,.tg/kg), which chieves serum nicotine concentrtions similr to those observed in our subjects during CS, incresed EE by 6%. We hve elsewhere observed (22) tht - intrvenous nicotine dministrtion hs lower thermogenic effect in hevy smokers thn light smokers, which my explin some of the differences between studies. Nevertheless, hevy smokers continue to be exposed to the lipolytic nd heptic FFA reesterifying effects of CS even while experiencing less thermogenesis thn light smokers. Finlly, we sked whether rebound effects on REE or intermediry metbolism tht would specificlly promote ft deposition would be pprent fter 1 wk of non-cs. Bsl ft mobiliztion ws not reduced nor ws new ft synthesis (de novo lipogenesis) incresed by cesstion of CS. REE ws lso unchnged. Thus, in the bsence of surplus energy intke, the only metbolic driving force tht could promote gin of body ft fter cesstion ofcs ws reduced whole body ft oxidtion. Crney nd Goldberg (41 ) reported n increse in serum lipoprotein lipse (LPL) ctivity fter cesstion of CS, nd suggested tht predisposition to ccrul ofbody ft would result. t should be pointed out tht, on metbolic principles, incresed flux of triglyceride through LPL would not result if there were incresed LPL ctivity, since there is no lterntive fte for serum triglyceride. Rther, lower serum triglyceride concentrtion with the sme flux would result, t stedy-stte. ncresed flux through LPL hs not been documented fter cesstion of CS. Accordingly, we do not believe tht there currently exists convincing evidence for rebound metbolic milieu tht specificlly fvors body ft gin fter cesstion of CS. Through its cute clorigenic effects, CS my induce lower body weight thn would otherwise be present in n individul, but the proposl tht cesstion ofcs should result in n overshoot (higher thn usul) body weight or body ft content due to incresed ft synthesis or storge remins to be proven quntittively, in the bsence of overeting. Our results lso provide no purely metbolic rtionle for provision of nicotine to prevent ft gin fter cesstion of CS, independent of effects on food intke or thermogenesis. n conclusion, cute CS in hevy smokers results in incresed FFA entry into the circultion, elevted serum FFA concentrtions, nd incresed heptic reesterifiction of FFA, which my explin the dyslipidemic effect of CS. Although heptic reesterifiction represents substrte cycle, it contributes only smll proportion of ny clorigenesis induced by cute CS, implying tht the thermogenic nd potentilly therogenic effects of nicotine my not be integrlly connected. Thus, hevy smokers re exposed to deleterious ltertions in lipid metbolism despite reduced thermogenic effect nd cn stop smoking without fer of inducing rebound metbolic propensity fvoring ft gin in the bsence of incresed food intke. Acknowledgments We grtefully cknowledge the technicl help of rving Fong, the nurses in the Sn Frncisco Generl Hospitl GCRC for their help, nd Cici Hyde for typing of the mnuscript. This work ws supported by grnt RT475 from the Tobcco-Relted Disese Reserch Progrm of the University of Cliforni (to M. K. Hellerstein); grnt DA-2277 from the Ntionl nstitutes of Helth (to N. L. Benowitz), nd the Division of Reserch Resources (NH grnt RR-83) for the Generl Clinicl Reserch Center. J. M. Schwrz ws supported by the Fonds Ntionl Suisse de l Recherche Scientifique nd by Fondtion Rymond Berger. References 1. Gritz, E. R., R. C. Klesges, nd A. W. Meyers Smoking nd body weight: implictions for interventions nd post-cesstion weight control. Ann. Behv. Med. 11: Rigotti, N. 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Benowitz, R. Hoh, D. Fix,. Fong, A. Bsinger, K. Pun, nd M. K. Hellerstein Effects of surplus dietry energy intke on lipogenesis, lipolysis, ft oxidtion nd substrte cycling in humns during cigrette smoking nd fter its cesstion. Clin. Res. 41:298A. (Abstr.) 45. Jcob, P., L. Yu, M. Wilson, nd N. L. Benowitz Selected ion monitoring for determintion of nicotine, cotinine, nd deuterium-lbeled nlogs: bsence of n isotope effect in the clernce of (S)-nicotine-3', 3'-D2 in humns. Biol. Mss Spectrom. 2: Wolfe, R. R Trcers in Metbolic Reserch. Rdio-sotope nd Stble sotope/mss Spectrometric Methods. Aln R. Liss, nc., New York. 471 pp. 47. Klein, S., V. R. Young, G. L. A. Blckburn, B. R. Bistrin, nd R. R. Wolfe Plmitte nd glycerol kinetics during brief strvtion in norml weight young dult nd elderly subjects. J. Clin. nvest. 78: Hellerstein, M. K., M. Christinsen, S. Kempfer, C. Kletke, K. Wu, J. S. Reid, N. S. Hellerstein, nd C. H. L. Shckleton Mesurement ofde novo heptic lipogenesis in humns using stble isotopes. J. Clin. nvest. 87: Hellerstein, M. K., K. Wu, S. Kempfer, C. Kletke, nd C. H. L. Shckleton Smpling the lipogenic heptic cetyl-coa pool in vivo in the rt. Comprison of xenobiotic probe to vlues predicted from isotopomeric distribution in circulting lipids nd mesurement of lipogenesis nd cetyl-coa dilution. J. Biol. Chem. 266: Prk, O.-J., D. Cesr, D. Fix, K. Wu, C. H. L. Shckleton, nd M. K. Hellerstein Mechnisms of fructose-induced hypertriglyceridemi in the rt: ctivtion of heptic pyruvte dehydrogense (PDH) through inhibition of PDH kinse. Biochem. J. 282: Hellerstein, M. K., nd R. Neese Mss isotopomer distribution nlysis: technique for mesuring biosynthesis nd turnover of polymers. Am. J. Physiol. 263:E988-E Hellerstein, M. K., R. A. Neese, nd J.-M. Schwrz Mesurement of bsolute rtes of heptic de novo lipogenesis nd re-esterifiction of free ftty cids in humns. FASEB (Fed. Am. Soc. Exp. Biol.) J. 7:A28. (Abstr.) 53. Hellerstein, M. K., R. A. Neese, nd J.-M. Schwrz Mesurement of bsolute rtes of heptic de novo lipogenesis nd re-esterifiction of free ftty cids in humns. Am. J. Physiol. n press. 54. Fltt, J. P The biochemistry of energy expenditure. Recent Adv. Obes. Res. 2: Rndle, P. J., C. N. Hles, P. B. Grlnd, nd E. A. Newsholme The glucose ftty-cid cycle. ts role in insulin sensitivity nd the metbolic disturbnces of dibetes mellitus. Lncet. i: Rndle, P. J Fuel selection in nimls. Biochem. Soc. Trns. 14: Benowitz, N. L Phrmcologic spects of cigrette smoking nd nicotine ddiction. N. Engl. J. Med. 319: Giccri, A., nd L. Rossetti Predominnt role of gluconeogenesis in the heptic glycogen repletion of dibetic rts. J. Clin. nvest. 89: Hjek, P., P. Jckson, nd M. Belcher Long-term use of nicotine chewing gum: occurence, determinnts nd effect on weight gin. J. Am. Med. Assoc. 26: Sutherlnd, G., J. A. Stpleton, M. A. Russell, M. J. Jrvis, P. Hrek, M. Belcher, nd C. 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