Dietologi (217) 6:176 183 DOI 1.17/s125-17-424-4 ARTICLE Effects of heptic glycogen on food intke nd glucose homeostsis re medited y the vgus nerve in mice Ilin López-Solddo 1,2 & Reec Fuentes-Romero 1 & Jordi Durn 1,2 & Jon J. Guinovrt 1,2,3 Received: 12 Decemer 216 /Accepted: 14 Ferury 217 /Pulished online: 15 Mrch 217 # Springer-Verlg Berlin Heidelerg 217 Astrct Aims/hypothesis Liver glycogen plys key role in regulting food intke nd lood glucose. Mice tht ccumulte lrge mounts of this polyscchride in the liver re protected from high-ft diet (HFD)-induced oesity y reduced food intke. Furthermore, these nimls show reversl of the glucose intolernce nd hyperinsulinemi cused y the HFD. The im of this study ws to exmine the involvement of the heptic rnch of the vgus nerve in regulting food intke nd glucose homeostsis in this model. Methods We performed heptic rnch vgotomy () or shm opertion on mice overexpressing protein trgeting to glycogen (Ptg OE ). Strting 1 week fter surgery, mice were fed n HFD for 1 weeks. Results did not lter liver glycogen or ATP levels, therey indicting tht this procedure does not interfere with heptic energy lnce. However, reversed the effect of glycogen ccumultion on food intke. In wild-type mice, led to significnt reduction in ody weight without chnge in food intke. Consistent with their ody weight reduction, these nimls hd decresed ft deposition, Ilin López-Solddo nd Reec Fuentes-Romero contriuted eqully to this study. Jon J. Guinovrt guinovrt@irrcelon.org dipocyte size, nd insulin nd leptin levels, together with incresed energy expenditure. Ptg OE mice showed n increse in energy expenditure nd glucose oxidtion, nd these differences were olished y. Moreover, Ptg OE mice showed n improvement in HFDinduced glucose intolernce, which ws suppressed y. Conclusions/interprettion Our results demonstrte tht the regultion of food intke nd glucose homeostsis y liver glycogen is dependent on the heptic rnch of the vgus nerve. Keywords Dietes. Food intke. Glucose homeostsis. Glycogen. Heptic vgus nerve. High-ft diet. Liver. Metolism. Mice Arevitions CNS Centrl nervous system Heptic rnch vgotomy HFD High-ft diet PTG Protein trgeting to glycogen Introduction 1 2 3 Institute for Reserch in Biomedicine (IRB Brcelon), Brcelon Institute of Science nd Technology (BIST), Bldiri i Reixc 1, 828 Brcelon, Spin Centro de Investigción Biomédic en Red de Dietes y Enfermeddes Metólics Asocids (CIBERDEM), Mdrid, Spin Deprtment of Biochemistry nd Moleculr Biomedicine, University of Brcelon, Brcelon, Spin The min cuse of oesity nd overweight is n imlnce etween energy consumption nd energy expenditure. Severl mechnisms re involved in mintining energy homeostsis. Secreted humorl fctors convey informtion out energy storge from dipose tissue to the centrl nervous system (CNS). In ddition to these fctors, neuronl signls ply key roles in energy homeostsis [1 4]. Heptic
Dietologi (217) 6:176 183 177 signls re postulted to e trnsmitted to the CNS y the vgus nerve ecuse vgl ctivity is incresed y portl or jejunl infusion of lipids [5]. Severl reports hve highlighted the contriution of the vgus nerve to regulting food intke. The stimultion of feeding y 2,5-nhydro-D-mnnitol ws shown to e dependent on this nerve [6]. Heptic rnch vgotomy () locks the stimultion of stiety y vriety of fuels [7]. In ddition, the heptic vgus nerve medites ft-induced inhiition of dietic hyperphgi y enling the restortion of hypothlmic neuropeptide expression [8, 9]. Furthermore, inhiition of ftty cid oxidtion y mercptocette increses food intke, nd this effect is olished y [1]. Furthermore, hs een shown to ttenute the feeding response to peripherl 2-deoxyglucose [11 13]. The serch for metolic sensor tht regultes food intke hs een ctively pursued for mny yers. Myer [14] developed the glucosttic theory of feeding ehviour, proposing tht chnges in glucose utilistion rtes regulte hunger nd stiety. Russek [15, 16] lter put forwrd heptosttic theory, which ws further refined y Fltt into the glycogenosttic model [17], in which heptic glycogen stores ct s glucoreceptor involved in the regultion of food intke. Lnghns nd collegues descried reltionship etween heptic glycogen levels nd spontneous eting [18]. In the following yers, lrge ody of experimentl evidence estlished n ssocition etween the size of glycogen stores in the liver nd the regultion of food intke [19 23]. We recently showed tht mice tht ccumulte high levels of heptic glycogen re protected from high-ft diet (HFD)-induced oesity s result of reduced food intke [23]. We propose tht incresed liver glycogen stores contriute to decresed ppetite nd diposity, nd tht this effect is proly triggered y signls from the liver tht re trnsmitted to the rin vi the heptic vgus nerve. To test this hypothesis, we studied the effects of in mice overexpressing protein trgeting to glycogen (Ptg OE )nd control mice fed HFD. Methods Animls nd diets All procedures were pproved y the Brcelon Science Prk Animl Experimenttion Committee nd crried out in ccordnce with the Europen Community Council Directive nd the Ntionl Institute of Helth guidelines for the cre nd use of lortory nimls. Mice tht overexpress Ptg (lso known s Ppp1r3c) in the liver (Ptg OE ) were generted s previously descried [23]. Mle Ptg OE nd control mice were housed with free ccess to wter nd stndrd chow diet (Envigo, Indinpolis, IN, USA) efore surgery. Strting 1 week fter surgery, mice were fed HFD (45% ft content; D12451 Formul, Reserch Diets, New Brunswick, NJ, USA) for 1 weeks. Vgus nerve denervtion nd shm opertion The common heptic rnch of the vgus nerve of 6-week-old mice ws cut. Briefly, mice were nesthetised with isoflurne (2 3% with O 2 ) nd plced on surgicl heting pd. After the dominl region hd een shved nd disinfected, lprotomy ws performed. The heptic loules were gently displced in dorsl nterior direction. The ligments surrounding the liver were removed to expose the oesophgus nd stomch. The heptic rnch of the vgus nerve ws then seprted from the left side of the liver. Cre ws tken not to dmge the dorsl nd ventrl prts of the vgus tht innervte the stomch nd dominl tissue. The dominl wll nd skin were then closed. Buprenorphine ws dministered, together with.9% NCl, to compenste for intropertive fluid loss. Control mice underwent shm opertion, i.e. we repeted the surgery without cutting the nerves or connective tissue. After surgery, mice were housed individully for the reminder of the experiment. After 1 weeks on the HFD, mice were either fed or fsted for 16 h efore eing killed. Tissues were collected nd stored t 8 C until nlysis or preserved in 1% phosphte-uffered formlin for histologicl nlysis. Blood nd liver iochemicl nlysis Heptic glycogen ws quntified s previously descried [24]. The intrcellulr concentrtion of ATP ws mesured in perchloric cid extrcts of livers y HPLC. Approximtely 5 mg frozen tissue ws homogenised in 5 μl1%hclo 4. Smples were clrified t 3 g t 4 C for 15 min nd superntnts were neutrlised with.5 M K 2 CO 3. Smples were plced on ice for 5 min nd then centrifuged t 3 g t 4 C for 1 min. ATP nlysis ws performed using Bris LC2 C18 column (4.6 15 mm, 3 μm prticle size) interfced with photodiode rry detector (26 nm) nd constnt flow rte of.6 ml/min. ATP ws seprted using moile phse grdient (7:3 rtio of eluent A [5 mmol/l KH 2 PO 4, 4 mmol/l (C 4 H 9 ) 4 N(HSO 4 ), ph 6]/methnol) for 37 min nd quntified ginst known stndrds in eluent A. Liver lctte ws mesured in perchloric cid extrcts using commercil spectrophotometric kit (Hori, ABX, Montpellier, Frnce). Blood glucose levels were mesured using glucometer (Ascensi Breeze 2, Byer Helthcre, Leverkusen, Germny). Plsm insulin nd leptin were nlysed y ELISA (Crystl Chem, Downers Grove, IL, USA). In vivo metolic nlysis Glucose tolernce tests were performed s previously descried [23]. Indirect clorimetry ws performed using n eight-chmer Oxymx system (Columus Instruments Interntionl, Columus, OH, USA) to mesure energy expenditure, clculted from oxygen consumption nd cron dioxide production, s previously
178 Dietologi (217) 6:176 183 descried [23]. In order to monitor food intke, mice were housed individully nd food ws mesured dily. RNA preprtions nd quntittive PCR Totl RNA ws isolted from frozen liver smples using Trizol regent (Life Technologies, Crlsd, CA, USA) nd purified with n RNesy Mini Kit (Qigen, Hilden, Germny) nd treted with DNse I (Qigen) to degrde genomic DNA. Reverse trnscription ws then performed using qscript cdna Synthesis Kit (Qunt Biosciences, Beverly, MA, USA). Quntittive (q)pcr ws performed using Quntstudio 6 Flex (Applied Biosystems, Foster City, CA, USA). The following TqMn primer nd proe sets (Applied Biosystems) were used for qpcr: Pklr (Mm 4439_m1), Ppi (Mm2342429_g1). The ltter ws used s reference gene. Histology A portion of sucutneous ft ws H&E stined nd dipocyte size ws mesured s previously descried [23]. Sttisticl nlysis Dt re expressed s mens ± SEM. Groups were compred using two-wy or three-wy ANOVA with post hoc Tukey tests. A p vlue of <.5 ws considered significnt. Results Liver glycogen, ATP nd heptic lctte levels re unffected y Ptg OE nd wild-type mice underwent or shm opertion, followed y HFD for 1 weeks. First, we mesured the glycogen content of livers of the different experimentl groups. In the fed stte, Ptg OE mice showed twofold increse in liver glycogen compred with control nimls (Fig. 1). After overnight fsting, control mice hd lower heptic glycogen levels, while Ptg OE mice mintined similr levels s in the fed stte (Fig. 1). Furthermore, there were no differences in liver glycogen levels etween shm-operted nd groups, indicting tht heptic denervtion did not lter the liver glycogen content (Fig. 1). To exmine whether ffects heptic energy sttus, we mesured ATP levels in the liver. The heptic ATP content ws higher in Ptg OE mice compred with control mice in the fed stte. ATP levels decresed significntly in control mice in the fsted stte compred with the fed stte; in contrst, ATP levels in the livers of fsted Ptg OE mice were similr to those in the fed stte. Remrkly, we did not oserve chnges in the level of ATP etween nd shm-operted groups for either genotype (Fig. 1). Levels of liver lctte incresed in Ptg OE mice compred with control mice in the fsted stte (Fig. 1c). The mrna levels of pyruvte kinse in the livers of Ptg OE mice were lso higher under fsting conditions compred with those of control mice (Fig. 1d). There were no differences in heptic lctte levels or mrna levels of Pklr etween shm-operted nd groups (Fig. 1c, d). reverses the effect of PTG overexpression on HFD food intke To study whether hs n effect on food ingestion, we mesured food intke. Consistent with our previous report [23], shm-ptg OE mice te less compred with Fig. 1 Liver glycogen, ATP nd lctte levels re unffected y. Control (white rs) nd Ptg OE (lck rs) mice underwent or shm surgery (). After surgery, mice were fednhfdfor1weeksndthen killed fter norml feeding (Fed) or 16 h fsting (Fsted). Liver glycogen content (), liver ATP content (), liver lctte levels (c) nd liver Pklr mrna (d) under fed conditions nd fsting conditions. p <.5 vs control mice sujected to the sme surgicl procedures; p<.5, fed vs fsted mice Liver glycogen (mg/g liver) c Liver lctte (µmol/g liver) 1 8 6 4 2 2 15 1 5 Fed Fsted Liver ATP (µmol/g liver) d Pklr mrna (reltive units) 1.5 1..5 2.5 2. 1.5 1..5 Fed Fsted Fed Fsted Fed Fsted
Dietologi (217) 6:176 183 179 shm-control nimls (Fig. 2) when fed HFD. However, -Ptg OE micehdsimilrfoodintketothtof -control nimls, indicting tht reversed the effect of PTG overexpression on food intke. In control mice, did not hve ny effect on food intke. Next, we studied the contriution of the heptic vgus nerve to ody weight nd ft weight in control nd Ptg OE mice. Ptg OE mice hd lower ody weight thn control mice when the heptic vgus nerve ws intct. However, this difference ws not oserved etween -Ptg OE nd -control mice, which hd similr ody weights (Fig. 2). Body weights of shm-ptg OE nd -Ptg OE mice were lso similr (Fig. 2). Furthermore, cused reduction in ody weight in control mice (Fig. 2). Consistent with their reduced ody weight, -control mice hd decrese in sucutneous ft weight, epididyml ft weight nd dipocyte size compred with shm-control mice (Fig. 2c e). As previously descried [23], shm-ptg OE mice hd lower sucutneous ft weight nd lower dipocyte size compred with shm-controls (Fig. 2c, e). In contrst, locked the decrese in dipose tissue weight nd dipocyte size seen in Ptg OE mice. These oservtions thus indicte tht the vgus nerve medites the remote effects of heptic glycogen content. decreses glucose oxidtion in Ptg OE mice We next investigted whether hs n impct on energy expenditure. In control mice, led to significnt increse in energy expenditure throughout the light nd drk phses. Ptg OE mice showed greter energy expenditure during the light nd drk phses when the vgus nerve ws not lted (Fig. 3). This difference in energy expenditure ws olished y (Fig. 3). As previously descried [23], Ptg OE nimls showed n increse in the respirtory exchnge rtio, indicting tht they used more crohydrtes s n energy source compred with the control group. This increse ws reversed y (Fig. 3). Consistent with this finding, glucose oxidtion ws incresed in Ptg OE mice compred with control mice, nd olished this effect (Fig. 3c). No Fig. 2 The heptic vgus nerve is required to medite the suppressive effect of food intke in Ptg OE mice. Control nd Ptg OE mice underwent or shm surgery (). After surgery, mice were fed n HFD for 1 weeks. () Food intke in control (white rs) nd Ptg OE (lck rs) mice. () Men ody weight ± SEM of control-shm (white circles), Ptg OE -shm (lck circles), control- (lue circles) nd Ptg OE - (red tringles) mice. (c, d) Sucutneous (c) nd epididyml (d) ft weight in control (white rs) nd Ptg OE (lck rs) mice. (e) H&E stined sucutneous dipose tissue (scle rs, 1 μm); the histogrm shows dipocyte size in sucutneous dipose tissue in control (white rs) nd Ptg OE (lck rs) mice. p <.5 vs control mice sujected to the sme surgicl procedure; p<.5, shm-operted vs mice of the sme genotype Food intke (kj/dy) c Sucutneous ft weight (g) e 8 6 4 2 1.5 1..5 Control Ptg OE Body weight (g) d Epididyml ft weight (g) 5 4 3 2 1 2 4 6 8 1 2.5 2. 1.5 1..5 Control Time (weeks) Ptg OE Adipocyte dimeter (µm) 15 1 5
18 Dietologi (217) 6:176 183 RER Energy expenditure (kj kg -1 h -1 ) c Glucose oxidtion (g min -1 kg -.75 ) 8 6 4 2 1..8.6.4.2 1..8.6.4.2 -.2 Light phse Drk phse differences in physicl ctivity were found etween groups (dt not shown). lters lood metolite levels Consistent with our previous report [23], shm-ptg OE mice hd lower lood glucose levels nd lower plsm insulin concentrtions thn shm-control nimls when fed HFD (Fig. 4, ). Remrkly, in the fed stte, Ptg OE mice filed to reduce lood glucose nd insulin levels when the vgus nerve ws lted (Fig. 4, ). hd no effect on glycemi (Fig. 4) ut led to decrese in plsm insulin levels in control mice (Fig. 4). Leptin serum levels were lso significntly reduced Light phse Light phse Drk phse Drk phse Fig. 3 decresed glucose oxidtion in Ptg OE mice. Control (white rs) nd Ptg OE (lck rs) mice underwent or shm surgery (). After surgery, mice were fed n HFD for 1 weeks. ( c) Resting energy expenditure (), respirtory exchnge rtio (RER) () nd glucose oxidtion rte (c) during the light nd drk phses. p <.5 vs control mice sujected to the sme surgicl procedure; p<.5, shm-operted vs mice of the sme genotype in -control mice compred with shm-control mice (Fig. 4c), nd locked the decrese in serum leptin induced y heptic glycogen (Fig. 4c). The vgus nerve contriutes to glucose homeostsis in Ptg OE mice Ptg OE mice showed improved glucose tolernce compred with controls (Fig. 5), nd olished this effect (Fig. 5). These oservtions demonstrte tht liver glycogen regultes glucose metolism through the vgus nerve. Discussion Here, we studied the involvement of the heptic rnch of the vgus nerve in regulting food intke nd glucose homeostsis in Ptg OE mice, which ccumulte high levels of glycogen in the liver. These mice showed reduced food intke nd reversl of glucose intolernce when fed HFD [23]. We demonstrted tht olishes the effect of glycogen ccumultion on food intke. In contrst, -control mice te the sme mount of food s shm-control nimls when fed HFD. This finding is in line with oservtions mde in previous studies of rts [25, 26] ndmice[27]. It is noteworthy tht lthough oth groups nd shm-control mice hd similr food intkes, they did not weigh the sme. This finding suggests tht cuses decrese in ody weight nd promotes resistnce to diet-induced oesity. Thus, loss of the nerve connection itself hd n impct on ody weight independent of glycogen ccumultion, s descried y two recent studies in rts [28] nd mice[27]. Consistent with their reduced ody weight, our mice hd decrese in sucutneous ft mss, smller dipocytes nd lower levels of leptin in plsm. Similr results hve een reported in vrious studies [2, 27 29]. Tken together, these oservtions reinforce the notion tht reduces ody weight nd induces resistnce to diet-induced oesity. In n ttempt to explin the metolic chnges oserved fter, we exmined whole ody energy expenditure. -Ptg OE mice hd n increse in energy expenditure, which, together with their lower food intke, could explin the lower ody weight of this group. Energy expenditure lso differed etween -control mice nd shm-control mice, in ccordnce with the findings of Go et l [27]. These uthors reported n increse in energy expenditure during the drk phse in mice compred with shm-operted mice, concluding tht this increse my ccount for the reduction in ody weight of the former. Moreover, Ptg OE mice oxidised more glucose thn control mice, nd olished this effect. These findings indicte tht neuronl signls through the heptic vgus nerve re lso involved in regulting crohydrte oxidtion in these mice. As previously descried, PTG overexpression resulted in n increse in liver glycogen. Consistent with previous results [3],
Dietologi (217) 6:176 183 181 Fig. 4 Effect of on lood metolite levels. Control (white rs) nd Ptg OE (lck rs) mice underwent or shm surgery (). After surgery, mice were fednhfdfor1weeks. () Blood glucose, () plsm insulin nd (c) plsm leptin concentrtions were mesured. p <.5 vs control mice sujected to the sme surgicl procedure; p<.5, shm-operted vs mice of the sme genotype Blood glucose (mmol/l) c 1 8 6 4 2 3 Plsm insulin (pmol/l) 6 4 2 Plsm leptin (ng/ml) 2 1 did not ffect liver glycogen levels. Moreover, our results demonstrted tht Ptg OE mice fed HFD hd higher ATP levels compred with control mice, nd tht did not interfere with heptic ATP levels, s previously reported [8]. Fsted Ptg OE mice ctivted glycolysis (indicted y the increse in lctte nd Pklr mrna levels), suggesting tht this mechnism could e one wy in which Ptg OE mice mintin ATP levels in the liver. ATP is key metolite tht triggers food intke through the vgus nerve [6, 31]. It hs een hypothesised tht n incresing ATP concentrtion in the heptocytes inhiits the firing of heptic vgl fferents, inhiits ctivtion of the nucleus trctus solitrius, nd suppresses the ppetite [32]. Since sectioning the heptic vgus elimintes most of these responses, it is presumed tht ATP levels in the heptocyte re conveyed to the CNS vi vgl nerves. Therefore, liver glycogen, through mintining heptic ATP levels, contriuted to decresing ppetite nd this effect ws triggered y the vgus nerve. In rts, it hs een shown tht sensory vgl fires do not provide sustntil direct innervtion of heptocytes, ut rther with portl trids in proximity to rnches of the heptic rtery, portl vein nd ile ducts [33]. However, neurontomicl dt for the vgus in mice re limited. In fct, severl reports in mice descrie metolic informtion in the liver eing trnsmitted to the rin vi the heptic vgus [2, 34 36]. Nonetheless, we cnnot exclude the possiility tht the mechnism descried in our study depends on sensors locted in the portl region. Another fctor tht could complicte the interprettion of the dt is tht cutting the common heptic vgl rnch denervtes not only the liver ut lso prts of the gstrointestinl trct [33]. Despite these neurontomicl difficulties, the evidence presented here highlight the liver s powerful metolic sensor, nd crucil link in the rin regultion of energy metolism [37]. There is link etween the CNS nd heptic glucose production [38] tht involves the heptic rnch of the vgus; Blood glucose (mmol/l) 3 2 1 15 3 6 12 Time (min) Fig. 5 The vgus nerve contriutes to glucose homeostsis in Ptg OE mice. Control nd Ptg OE mice underwent or shm surgery. After surgery, mice were fed n HFD for 1 weeks. () GTT curve for glucose fter 8 weeks on n HFD for control-shm (white circles nd dshed line), Ptg OE -shm (lck circles nd solid line), control- (lck squres AUC GTT glucose (mmol/l min) 3 2 1 nd solid line) nd Ptg OE - (lck tringles nd solid line) () AUC for glucose in control (white rs) nd Ptg OE (lck rs) mice. p<.5 vs control mice sujected to the sme surgicl procedure; p<.5, shm-operted vs mice of the sme genotype
182 Dietologi (217) 6:176 183 however, this link is efferent, not fferent [4]. Moreover, intct vgl fferent fires re required for glucocorticoid-induced glucose intolernce [34]. Ptg OE mice showed n improvement in HFD-induced glucose intolernce, which ws olished y. This oservtion indictes tht n intct vgus nerve is required for HFD-induced glucose intolernce. This notion is consistent with recent study in dogs indicting tht heptic glycogen regultes hypoglycemic counter-regultion vi liver rin xis [39]. In our model system, lowered insulin without chnging glucose levels, indicting incresed insulin sensitivity. In rts, hs een reported to induce insulin resistnce [4, 41]. However, in dexmethsone-treted mice, resulted in greter insulin responsiveness during insulin tolernce testing compred with shm surgery, nd this effect persisted for t lest 3 months fter the surgery [34]. Thus, in models in which insulin resistnce is lredy present, for exmple, s induced y glucocorticoids [34] or in young nimls fed HFD [29], seems to increse insulin sensitivity. Rther thn eing direct consequence of liver denervtion [8], our findings support the hypothesis tht neurl signl to the CNS is involved in the inhiition of food intke cused y liver glycogen ccumultion. Therefore, we conclude tht liver glycogen ccumultion triggers liver rin neuronl network to regulte food intke nd glucose homeostsis. Acknowledgements The uthors thnk M. Grcí Roch, A. Adrover, E. Vez, N. Pln nd A. Berenguer, ll from the Institute of Reserch in Biomedicine (IRB Brcelon) nd stff of the Scientific nd Technologicl Services of the University of Brcelon for technicl ssistnce. Dt vilility The dt re ville on request from the uthors. Funding This study ws supported y grnts from the Spnish MINECO (SAF214 54525-P), Fundció Mrtó de TV3 (21613-1) nd CIBERDEM (Instituto de Slud Crlos III, Spnish Ministry of Science nd Innovtion). None of the supporting gencies hd ny role in performing the work or in writing the mnuscript. Dulity of interest sttement The uthors declre tht there is no dulity of interest ssocited with this mnuscript. Contriution sttement IL-S, JJG nd RF-R conceived the study nd designed ll experiments; JJG directed the study; IL-S nd RF-R nlysed the dt; IL-S, JD nd JJG interpreted the dt; IL-S nd RF-R wrote the mnuscript. All uthors pproved the finl version of the mnuscript to e pulished. JJG is responsile for the integrity of the work s whole. References 1. Izumid Y, Yhgi N, Tkeuchi Y et l (213) Glycogen shortge during fsting triggers liver-rin-dipose neurocircuitry to fcilitte ft utiliztion. Nt Commun 4:2316 2. 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