Analysis of the adiponectin paradox in healthy older people

Analysis o he adiponec in pa adox in heal hy olde people Ca ina O. Walowski 1 , Ca in He pich 2,3,4 , Janna Ende le 1 , Wiebke B aun 1 , Ma cus Bo h 5 , Ma io Hasle 6 , Man ed J. Mülle 1 , K is ina No man 2,3,4,7 & Anja Bosy-Wes phal 1 * 1 Ins i u e o Human Nu i ion and Food Science, Ch is ian-Alb ech s-Uni e si y, Kiel, Ge many; 2 Ins i u e o Nu i ional Science, Uni e si y o Po sdam, Nu he al, Ge many; 3 Depa men o Ge ia ics and Medical Ge on ology, Cha i é Uni e si ä smedizin Be lin, Co po a e membe o F eie Uni e si ä Be lin and Humbold -Uni e si ä zu Be lin, Be lin, Ge many; 4 Depa men o Nu i ion and Ge on ology, Ge man Ins i u e o Human Nu i ion, Po sdam-Rehb ücke, Nu he al, Ge many; 5 Depa men o Radiology and Neu o adiology, Uni e si y Medical Cen e Schleswig-Hols ein, Kiel, Ge many; 6 Applied S a is ics, Facul y o Ag icul u al and Nu i ional Sciences, Ch is ian-Alb ech s- Uni e si y, Kiel, Ge many; 7 Ge man Cen e o Ca dio ascula Resea ch (DZHK), Pa ne Si e Be lin, Be lin, Ge many Abs ac Backg ound I emains unknown why adiponec in le els a e associa ed wi h poo physical unc ioning, skele al muscle mass and inc eased mo ali y in olde popula ions. Me hods In 190 heal hy adul s (59–86 yea s, BMI 17–37 kg/m 2 , 56.8% emale), whole body skele al muscle mass (no malized by heigh , SMI, kg/m 2 ), muscle and li e a we e de e mined by magne ic esonance imaging. Bone min- e al con en (BMC) and densi y (BMD) we e assessed by dual X- ay abso p iome y (n= 135). Le els o insulin-like g ow h ac o 1 (IGF-1), insulin, inflamma ion ma ke s, lep in and fib oblas g ow h ac o 21 we e measu ed as po en- ial de e minan s o he ela ionship be ween adiponec in and body composi ion. Resul s Highe adiponec in le els we e associa ed wi h a lowe SMI ( =0.23, P<0.01), BMC ( =0.17, P<0.05) and li e a ( =0.20, P<0.05) in he o al popula ion and wi h highe muscle a in women ( = 0.27, P<0.01). By con as , IGF-1 showed posi i e co ela ions wi h SMI ( = 0.33), BMD ( = 0.37) and BMC ( = 0.33) (all P<0.01) and a nega i e co ela ion wi h muscle a ( =0.17, P<0.05). IGF-1 was nega i ely associa ed wi h age ( =0.21, P<0.01) and wi h adiponec in ( =0.15, P<0.05). S epwise eg ession analyses e ealed ha IGF-1, insulin and lep in explained 18% o he a iance in SMI, and IGF-1, lep in and age explained 16% o he a iance in BMC, whe eas adiponec in did no con ibu e o hese models. Conclusions Associa ions be ween highe adiponec in le els and lowe muscle o bone mass in heal hy olde adul s may be explained by a dec ease in IGF-1 wi h inc easing adiponec in le els. Keywo ds Adiponec in pa adox; Olde adul s; Skele al muscle mass; Muscle quali y; Bone; Li e a Recei ed: 18 May 2022 ; Re ised: 4 Oc obe 2022 ; Accep ed: 25 Oc obe 2022 *Co espondence o: Anja Bosy-Wes phal, Ch is ian-Alb ech s-Uni e si ä zu Kiel, Ins i u ü Humane näh ung und Lebensmi elkunde, Düs e nb ooke Weg 17 , 24105 Kiel, Ge many. Email: [email p o ec ed]e In oduc ion Adiponec in is an abundan pep ide ho mone p ima ily sec e ed by adipose issue (AT), and o a lesse ex en by skel- e al muscle (SM) and bone ma ow adipocy es ( o a e iew, see Fazeli e al. 1 ). I is well-known o imp o ing insulin sen- si i i y as well as o an i-inflamma o y and an i-a he ogenic p ope ies ( o a e iew, see Robinson e al. 2 ). Se e al me a- bolic and ca dio ascula diso de s including ype 2 diabe es, me abolic synd ome ( o a e iew, see Di Chia a e al. 3 ), a he oscle osis 4 and non-alcoholic a y li e disease 5 a e hus accompanied by hypoadiponec inaemia. As a myokine, adiponec in ac s as a myogenic ac o h ough he pa icipa- ion in muscle di e en ia ion and issue egene a ion, and influencing he beha iou o muscle cells ( o a e iew, see Gambe i e al. 6 ). Accumula ing e idence also sugges s ha ORIGINAL ARTICLE © 2022 The Au ho s. Jou nal o Cachexia, Sa copenia and Muscle published by John Wiley & Sons L d on behal o Socie y on Sa copenia, Cachexia and Was ing Diso de s. This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion-NonComme cial-NoDe i s License, which pe mi s use and dis ibu ion in any medium, p o ided he o iginal wo k is p ope ly ci ed, he use is non-comme cial and no modifica ions o adap a ions a e made. Jou nal o Cachexia, Sa copenia and Muscle 2023; 14: 270–278 Published online 18 No embe 2022 in Wiley Online Lib a y (wileyonlinelib a y.com) DOI: 10.1002/jcsm.13127 adiponec in p omo es os eoblas ogenesis, while simul a- neously inhibi ing os eoclas ogenesis ( o a e iew, see Lewis e al. 7 ). I is he e o e causally enigma ic why adiponec in le els a e nega i ely associa ed wi h SM, muscle densi y, physical unc ioning 8 o bone mine al densi y (BMD) 9 among olde adul s. Adiponec in le els we e shown o inc ease wi h age 10 and a e e en associa ed wi h highe a es o ca dio as- cula and all-cause mo ali y in olde popula ions. 11 The so-called adiponec in pa adox he e o e sugges s ha adipo- nec in may no exe beneficial e ec s in olde adul s. Di e en explana ions o he adiponec in pa adox in olde people ha e been discussed including adiponec in esis ance, 12 compensa o y e ec s o adiponec in o subclin- ical pa hologies, impai ed enal unc ion and dec eased he- pa ic clea ance o adiponec in ( o a e iew, see Kalkman 13 ). In addi ion, adiponec in was p oposed o be a bioma ke o ad e se ca abolic p ocesses (i.e., a low SM due o sa copenia ela ed o aging, 8,14 o cachexia associa ed wi h ch onic in- flamma ion and p e-exis ing illness 15,16 ). I emains unknown i highe adiponec in le els in olde adul s a e a cause o a low muscle mass by media ing ca abolic p ocesses o a he a consequence o ca abolic p ocesses ha lead o a lowe SM. The ela ionship be ween adiponec in and de ailed body composi ion analysis he e o e needs o be in es iga ed in heal hy olde adul s wi hou ca abolic disease o impai ed e- nal unc ion. The aim o he p esen s udy was he e o e (i) o in es i- ga e he associa ion be ween adiponec in le els and SM (by whole body magne ic esonance imaging, (MRI)), muscle a and s eng h o bone mass and bone densi y in heal hy communi y-dwelling olde adul s and (ii) o iden i y po en ial endoc ine de e minan s o adiponec in le els. Me hods S udy popula ion The p esen s udy was conduc ed a he ‘Ge man Re e ence Cen e o Body Composi ion’(Ins i u e o Human Nu i ion and Food Science a he Uni e si y o Kiel, Ge many) be ween 2019 and 2020. Exclusion c i e ia we e oedema, acu e dis- eases, hea ailu e, enal ailu e, in ake o diu e ics, pa alysis (e.g., a e a s oke), neu odegene a i e diseases, umou s in ea men , ampu a ion o limbs, elec ical and me allic implan s, cu en alcohol abuse, no emo able pie cings and la ge a oos on he a ms o legs (because o possible in- e e ence wi h MRI examina ions) as well as medica ion, which could influence body composi ion. Subjec s we e e- c ui ed using no ice boa d pos ings and local ad e isemen s. W i en in o med consen was ob ained om each pa ici- pan . The s udy p o ocol was app o ed by he medical e hics commi ee o he Ch is ian-Alb ech s-Uni e si y o Kiel, Ge - many, and ollowed he guidelines based on he ‘Decla a ion o Helsinki’. The p ima y aim o he s udy was o alida e mea- su es o bioelec ical impedance analysis s. e e ence me hods in olde adul s. The ial was egis e ed a ClinicalT ials.go as NCT04028648. The s udy popula ion was expanded by a subg oup o 40 heal hy Caucasian olde pa ic- ipan s as desc ibed in de ail elsewhe e. 17 F om he included 190 pa icipan s, da a o 173 adul s we e analysed (da a om 15 pa icipan s we e excluded because o mo ion a e ac s o inco ec pa ien posi ioning in MRI. Fu he da a om wo subjec s we e excluded due o missing endoc ine pa ame e s). Body composi ion analysis Body weigh was measu ed o he nea es 0.01 kg by an elec- onic Tani a scale (Tani a, Tokyo, Japan) coupled o he BOD POD® Body Composi ion Sys em (Cosmed s l, Rome, I aly) wi h subjec s in unde wea . Heigh was de e mined wi hou shoes using a s adiome e (SECA, Modell 285, Hambu g, Ge many). Fa mass (FM) and a - ee mass (FFM) we e de- e mined ia ai -displacemen ple hysmog aphy (BOD POD® Cosmed s l, Rome, I aly) as p e iously desc ibed. 18 FM was calcula ed using he equa ion by Si i e al. 19 FFM was calcu- la ed om he di e ence be ween body weigh and FM. On he basis o FM and FFM, FM-Index (FMI) and FFM-Index (FFMI) we e calcula ed as FM (kg)/heigh (m 2 ) and FFM (kg)/heigh (m 2 ). SM and AT we e measu ed using whole body MRI as de- sc ibed in de ail elsewhe e. 20 B iefly, subjec s we e examined in a supine posi ion wi h a ms ex ended abo e hei heads. Fo scans in abdominal and ho acic egions pa icipan s we e equi ed o hold hei b ea h. Images we e ob ained using a 1.5 T scanne (Magne om A an o, Siemens Medical Sys ems, E langen, Ge many) wi h a T1-weigh ed-g adien echo sequence ( epe i ion ime (TR): 157 ms; echo ime (TE): 4 ms o scans o a ms, legs and abdominal egion). The whole body was scanned om w is o ankle using con inuous axial images wi h a slice hickness o 8 mm and 2 mm in e slice gaps o a ms, legs and unk. Volumes o SM, subcu aneous adipose issue (SAT) and isce al adipose issue (VAT) we e manually segmen ed using SliceOma ic 4.3 so wa e (Tomo ision, Mon eal, Canada). VAT was e alu- a ed om he op o he li e o emo al heads. Volumes o o al SM (excluding head and neck muscles, hands and ee ), SAT and VAT we e de e mined om he sum o issue a eas (cm 2 ) mul iplied by he slice hickness. Tissue olumes we e hen con e ed in o masses using he assumed densi ies o 1.04 g cm 3 o SM and 0.92 g cm 3 o SAT and VAT. 21 SM was no malized o heigh squa ed o calcula e skele al mus- cle mass index (SMI, (kg)/heigh (m 2 )). In a subg oup o 135 subjec s, whole body bone mine al con en (BMC), BMD and T-Sco e we e quan ified using dual ene gy X- ay abso p iome y (DXA) (HOLOGIC Disco e y Analysis o he adiponec in pa adox in heal hy olde people 271 Jou nal o Cachexia, Sa copenia and Muscle 2023; 14: 270–278 DOI: 10.1002/jcsm.13127 1353921906009, 2023, 1, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1002/jcsm.13127 by Uni e si a sbiblio hek Kiel, Wiley Online Lib a y on [18/08/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License A (S/N 82686), Inc., Bed o d, MA, USA). Be o e daily measu e- men s, a spine phan om calib a ion was pe o med. Scans we e analysed using manu ac u e ’s so wa e ( e sion 12.6.1:3, Hologic, Inc.). Resul s we e summed up o bo h a ms and legs as well as he head. Li e a was de e mined by MRI (Magne om A an o, Sie- mens Medical Sys ems, E langen, Ge many) based on he wo-poin Dixon me hod wi h a olume ic in e pola ed b ea h-hold examina ion sequence as desc ibed in de ail elsewhe e. 22 B iefly, a T1-weigh ed g adien -echo sequence wi h in-phase and ou -o -phase imaging was conduc ed (TR: 10.4 ms; TE: 4.76 (in-phase) and 7.14 (opposed-phase) ms; flip angle, 10° ma ix, 80 × 128; and field o iew, 440 mm; slice hickness/in e slice gap: 5/1 mm; o al scan ime: 19 s). F om in-phase and opposed-phase images, he wa e - only (WO) and a -only (FO)-images we e calcula ed: WO:1 2in-phase þopposed-phaseðÞ(1) FO:1 2in-phase þopposed-phaseðÞ(2) WO and FO-images we e han analysed using ImageJ so - wa e (US NIH, Be hesda, MD, USA 22 ) o de e mine hepa ic a ac ion (HFF). In each o fi e adjacen HFF images, a sin- gle con inuous egion o in e es (ROI) was defined (20.62 × 20.62) and was placed in he li e pa enchyma, a oiding ascula s uc u es. The quan i y o li e a was a - e aged o he fi e HFF images and was de e mined as pe - cen age o he o al li e co e. In e muscula adipose issue (IMAT) in a single mid- high MRI slice and muscle a by he wo-poin Dixon me hod we e used o assess muscle quali y in 173 and 172 subjec s, espec i ely (Figu es 1and 2). IMAT was defined as isible AT be ween muscle g oups ha is loca ed wi hin a muscle and benea h he muscle as- cia. I was assessed in single c oss-sec ional MRI images a he le el o he mid- high. The midpoin o he high was de- fined as hal way be ween he emo al head and he ibial pla eau. Masses o IMAT we e manually de e mined by using a semi-au oma ic segmen a ion so wa e (SliceOma ic 4.3, Tomo ision, Mon eal, Canada). Muscle a was de e mined based on he Dixon me hod using ImageJ so wa e (US NIH, Be hesda, MD, USA 22 ). In lumba egion o mul ifidus and e ec o spinae muscles, a sin- gle con inuous ROI was defined (10.75 × 10.75) in each o fi e adjacen muscle a ac ion images and was placed in he same a ea o all epea ed measu emen s. Muscle a was quan ified as pe cen age o he o al muscle a ea and was a - e aged o he fi e muscle a ac ion images. All p ocedu es we e conduc ed by he same obse e . In 173 subjec s, hand g ip s eng h (HGS) was measu ed using a hyd aulic SAEHAN® handg ip dynamome e (SH5001, Masan, Sou h Ko ea). 135 subjec s conduc ed he es in a s anding posi ion and 38 in a si ing posi ion and he elbow was flexed a 90 deg ees wi h he shoulde a ached o he o so. In 135 subjec s, HGS o he le and igh hand was de e mined h ee imes and he g ea es alue o he dominan hand was included in he analysis, whe eas in 38 subjec s, HGS was de e mined only wice. Endoc ine pa ame e s Se um and plasma blood samples we e aken om an an ecubi al ein a e >10 h o e nigh as . The subjec s we e ins uc ed o e ain om igo ous exe cise and alcohol in ake o 24 h p io o blood sampling. A e collec ion, se- Figu e 1 In e muscula adipose issue (IMAT) in a single mid- high magne ic esonance imaging (MRI) slice segmen ed in pu ple using SliceOma ic so wa e, acqui ed as axial T1-weigh ed g adien -echo sequence. Resul o o al IMAT was 9.30 g. 272 C.O. Walowski e al. Jou nal o Cachexia, Sa copenia and Muscle 2023; 14: 270–278 DOI: 10.1002/jcsm.13127 1353921906009, 2023, 1, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1002/jcsm.13127 by Uni e si a sbiblio hek Kiel, Wiley Online Lib a y on [18/08/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License um samples we e s o ed a oom empe a u e in an up igh posi ion o 30 min o comple e clo o ma ion. Plasma and se um we e ob ained by cen i uga ion a 2000 g o 10 min a 20°C and s o ed a 40°C. Sample analyses we e pe o med a he ‘Ge man Ins i u e o Human Nu i ion’, Po sdam-Rehb ücke, Depa men o Nu i ion and Ge on ol- ogy, Nu he al, Ge many and a labo a o y in Kiel, Ge many. In 172 subjec s, lep in (in a-assay CV: 4.2–7.6%, in e -assay CV: 4.4–6.7%; BioVendo , B no, Czech Republic), adiponec in (in a-assay CV: 2.8–3.9%, in e -assay CV: 5.9– 6.4%; Immundiagnos ik AG, Bensheim, Ge many) as well as insulin-like g ow h ac o 1 (IGF-1) (in a-assay CV: 5.1– 6.7%, in e -assay CV: 5.5–6.6%; BioVendo , B no, Czech Republic) we e measu ed by comme cial ELISA ki s. As adipo- nec in exp ession is egula ed by he hepa ic ho mone fib o- blas g ow h ac o 21 (FGF-21), also FGF-21 concen a ions we e quan ified by ELISA (in a-assay CV: 1.6–2.4%, in e -assay CV: 3.1–3.5%; BioVendo , B no, Czech Republic) in a subg oup o 135 subjec s. As inflamma o y pa ame e s, in e leukin 6 (IL-6) (in a-assay CV: 4.2–5.1%, in e -assay CV: 4.7–5.0%; BioVendo , B no, Czech Republic) was de e mined in 135 pa icipan s using comme cial ELISA ki , and high-sen- si i i y C- eac i e p o ein (hsCRP) (in a-assay CV: 0.73– 5.73%, in e -assay CV: 1.50–5.76%; BECKMAN COULTER, B ea, CA, USA) was measu ed using an immuno- u bidime ic es . Insulin was de e mined by chemi- luminescen mic opa icle immunoassay (in a-assay CV: 1.4– 2.1%, in e -assay CV: 1.5–2.2%; Abbo , Wiesbaden, Ge many). Inflamma ion was based on hsCRP >3 mg/L and ele a ed insulin le els we e se a >25.0 mU/L. S a is ical analysis S a is ical analyses we e pe o med using SPSS s a is ical so - wa e (SPSS 28.0, Inc., Chicago, IL, USA). All da a a e gi en as means ±SD. Di e ences be ween independen samples we e analysed using unpai ed - es . E alua ion o no mali y was pe o med using he Shapi o–Wilk es and esidual analysis. Pea son’s and Spea man’s co ela ion coe ficien s we e calcu- la ed o iden i y bi a ia e associa ions be ween and wi hin body composi ion, endoc ine and unc ional pa ame e s. Pa - ial co ela ions we e used o adjus o a ious con ounde s. S epwise mul iple eg ession analyses we e pe o med o as- sess ac o s independen ly associa ed wi h SMI, BMC and lumba muscle a . All es s we e wo-sided and le el o sig- nificance was se a P<0.05. Resul s In o al, 173 olde adul s (101 women and 72 men) aged 59– 86 yea s wi h a BMI be ween 18 and 37 kg/m 2 we e included in he s udy. Desc ip i e cha ac e is ics a e summa ized in Table 1. Men we e significan ly olde and had a highe BMI, FFMI, SM, SMI, IMAT, VAT, HGS as well as BMC, BMD and T-Sco e compa ed wi h women. Acco ding o WHO c i e ia, 26.6% o women and 30.6% o men we e o e weigh o obese. In a subpopula ion o 135 subjec s wi h DXA esul s, he p e alence o a educed muscle mass was 7.40% acco d- ing o he ecommended FFMI h esholds o he ‘Global Lead- e ship Ini ia i e on Malnu i ion’(FFMI cu -o s: <15 and <17 kg/m 2 in women and men, espec i ely 23 ). Po en ial endoc ine de e minan s o adiponec in le els a e summa ized in Table 2. Adiponec in le els we e lowe in men compa ed wi h women. Insulin and IGF-1 le els we e highe and lep in le els we e lowe in men compa ed wi h women. P e alence o ele a ed hsCRP and insulin le els we e 20.2% and 2.3%, espec i ely. Co ela ions be ween adiponec in o IGF-1 le els and body composi ion pa ame e s a e p esen ed in Table 3.In Figu e 2 Lumba muscle a in he egion o mul ifidus and e ec o spinae muscles wi h a yellow 10.75 × 10.75 egion o in e es (ROI) de e mined using ImageJ so wa e, acqui ed as axial T1-weigh ed g adien -echo Dixon sequence. Resul o he pe cen age o muscle a was 9.54%. Analysis o he adiponec in pa adox in heal hy olde people 273 Jou nal o Cachexia, Sa copenia and Muscle 2023; 14: 270–278 DOI: 10.1002/jcsm.13127 1353921906009, 2023, 1, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1002/jcsm.13127 by Uni e si a sbiblio hek Kiel, Wiley Online Lib a y on [18/08/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License acco dance wi h he adiponec in pa adox, highe adiponec in le els we e associa ed wi h a lowe SMI and BMC in he o al s udy popula ion. No co ela ion was obse ed be ween adi- ponec in and HGS. Lowe adiponec in le els we e associa ed wi h a highe BMI ( =0.34, P<0.01) and FMI in men and wi h g ea e VAT in he o al popula ion. The associa ion be- ween adiponec in and SMI emained significan a e adjus - men o VAT ( =0.16, P<0.04). No ela ionships be ween adiponec in and FGF-21, lep in, IL-6 o hsCRP and insulin we e ound. In con as o adiponec in, IGF-1 le els we e posi i ely as- socia ed wi h SMI in he o al popula ion and in he sub- g oups o men and women. Fu he mo e, IGF-1 concen a- ions we e co ela ed wi h BMC, BMD and T-Sco e in he o al popula ion and BMD and T-Sco e in women. IGF-1 le els we e also posi i ely associa ed wi h HGS ( = 0.31, P<0.05, all; = 0.35, P<0.01, men) and nega i ely wi h age ( =0.21, P<0.01, all; =0.20, P<0.05, women; =0.33, P<0.01, men) and adiponec in le els ( =0.15, P<0.05). To es , i he pa adoxical associa ion be ween highe adiponec in and lowe SMI could be ex- plained by lowe IGF-1 le els wi h highe age, pa ial co ela- ion analysis be ween adiponec in and SMI adjus ed o IGF-1 was pe o med. The nega i e co ela ion be ween SMI and adiponec in in he o al s udy popula ion pe sis ed, bu was sligh ly weakened ( =0.20, P= 0.01). S epwise eg ession analyses wi h SMI o BMC as depen- den a iables and adiponec in, IGF-1, insulin, IL-6, hsCRP, lep in and age ( o SMI) and adiponec in, IGF-1, IL-6, lep in and age ( o BMC), espec i ely as independen a iables we e pe o med (Table 4). Insulin, IGF-1 and lep in explained 18.4% o he a iance in SMI. A e conside ing sex as u he Table 1 Cha ac e is ics o he s udy popula ion All subjec s Women Men n173 101 72 Age (yea s) 70.7 ± 5.3 70.0 ± 4.9* 71.7 ± 5.7 Heigh (m) 1.68 ± 0.10 1.62 ± 0.06*** 1.77 ± 0.1 Weigh (kg) 73.3 ± 15.2 65.1 ± 11.0*** 84.7 ± 12.7 BMI (kg/m 2 ) 25.7 ± 3.8 24.9 ± 4.0*** 27.0 ± 3.2 FMI (kg/m 2 ) 9.2 ± 3.4 9.9 ± 3.6*** 8.1 ± 2.7 SAT (kg) 17.4 ± 6.5 18.8 ± 6.8*** 15.5 ± 5.5 VAT (kg) 2.2 ± 1.6 1.4 ± 0.9*** 3.3 ± 1.7 FFMI (kg/m 2 ) 16.6 ± 2.3 15.0 ± 1.2*** 18.8 ± 1.2 SM (kg) 22.2 ± 5.9 18.0 ± 2.5*** 28.0 ± 4.1 SMI (kg/m 2 ) 7.7 ± 1.4 6.9 ± 0.8*** 8.9 ± 1.1 BMC (kg) 2.07 ± 0.54 1.71 ± 0.27*** 2.61 ± 0.35 BMD (g/cm 2 ) 1.00 ± 0.14 0.92 ± 0.10*** 1.12 ± 0.10 T-Sco e 1.5 ± 1.2 2.1 ± 1.1*** 0.7 ± 1.0 Li e a (%) 8.4 ± 4.2 8.1 ± 4.5 8.8 ± 3.8 Lumba muscle a (%) 9.5 ± 3.7 9.3 ± 3.8 9.6 ± 3.7 IMAT single mid- high (g) 4.5 ± 2.3 3.4 ± 2.1*** 5.4 ± 2.3 HGS (kg) 31.9 ± 10.3 25.0 ± 5.0*** 41.4 ± 7.9 Abb e ia ions: BMC, bone mine al con en ; BMD, bone mine al densi y; BMI, body mass index; FFMI, a - ee mass index; FMI, a mass index; HGS, hand g ip s eng h; IMAT, in e muscula adipose issue; SAT, subcu aneous adipose issue; SM, skele al muscle; SMI, skele al muscle mass index; VAT, isce al adipose issue. No e: Values a e means ± SD; n, no. o subjec s. * P<0.05. *** P<0.001 sex di e ences by - es , wo-sided. Table 2 Adiponec in le els and i s po en ial endoc ine de e minan s All subjec s Women Men n173 101 72 Adiponec in (mg/L) 19.8 ± 16.4 22.8 ± 19.3** 15.5 ± 9.8 IGF-1 (μg/L) 151.3 ± 56.8 140.3 ± 52.5** 166.7 ± 59.4 FGF-21 (pg/mL) 212.2 ± 212.2 233.5 ± 255.3 180.3 ± 117.3 Lep in (ng/mL) 11.2 ± 11.0 14.2 ± 12.7*** 6.6 ± 5.5 IL-6 (pg/mL) 10.11 ± 24.52 6.72 ± 6.47 15.20 ± 37.58 hsCRP (mg/L) 2.31 ± 3.07 2.12 ± 2.60 2.58 ± 3.63 Insulin (μU/L) 9.8 ± 6.1 8.9 ± 4.3* 10.9 ± 7.8 Abb e ia ions: FGF-21, fib oblas g ow h ac o 21; hsCRP, high-sensi i i y C- eac i e p o ein; IGF-1, insulin-like g ow h ac o 1; IL-6, in- e leukin 6. No e: Values a e means ± SD; n, no. o subjec s. * P<0.05. ** P<0.01. *** P<0.001 sex di e ences by - es , wo-sided. 274 C.O. Walowski e al. Jou nal o Cachexia, Sa copenia and Muscle 2023; 14: 270–278 DOI: 10.1002/jcsm.13127 1353921906009, 2023, 1, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1002/jcsm.13127 by Uni e si a sbiblio hek Kiel, Wiley Online Lib a y on [18/08/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License co a ia e, sex and insulin oge he explained 65.1% o he a iance in SMI. IGF-1, lep in and age explained 16.4% o he a iance in BMC. A e addi ional adjus men o sex, only sex was en e ed in he equa ion and explained 68.5% o he a iance in BMC. A e excluding subjec s wi h ele a ed hsCRP le els, he nega i e associa ion be ween adiponec in concen a- ions and BMC in he o al popula ion was no longe signi - ican (P= 0.08), whe eas nega i e co ela ions be ween adiponec in le els and insulin ( =0.18, P<0.05), BMI ( =0.18, P<0.05) and HGS ( =0.18, P<0.05) could be obse ed. The nega i e associa ion be ween IGF-1 and adiponec in le els in he o al popula ion pe sis ed ( =0.18, P<0.05). Conce ning ec opic a , highe adiponec in le els we e as- socia ed wi h lowe li e a in he o al s udy popula ion and in he subg oup o men, whe eas adiponec in le els we e pa adoxically posi i ely co ela ed wi h lumba muscle a in women (Table 3). By con as , IGF-1 showed nega i e co ela ions wi h lumba muscle a in women and in he o al s udy popula ion. The nega i e associa ion be ween adiponec in and lumba muscle a in women weakened a e adjus men o IGF-1 ( = 0.19, P= 0.05). S epwise e- g ession analysis wi h lumba muscle a as he dependen a iable and adiponec in, IGF-1, lep in, insulin, IL-6, hsCRP, FMI and age as independen a iables, e ealed ha only FMI and IGF-1 independen ly explained 34.3% o he a i- ance (Table 4). Insulin, lep in, IL-6 and hsCRP we e posi i ely co ela ed wi h ec opic a deposi ion in li e and muscle, whe eas highe FGF-21 le els we e posi i ely co ela ed wi h li e a con en . Fu he mo e, ec opic li e and muscle a showed consis en posi i e associa ions wi h FMI and VAT anging be- ween = 0.31 and = 0.61 (all P<0.05). Table 3 Co ela ions be ween adiponec in o IGF-1 and body composi ion pa ame e s All subjec s Women Men Adiponec in (mg/L) IGF-1 (μg/L) Adiponec in (mg/L) IGF-1 (μg/L) Adiponec in (mg/L) IGF-1 (μg/L) SMI (kg/m 2 )0.23** 0.33** - 0.22* - 0.39** BMC (kg) 0.17* 0.33** ---- BMD (g/cm 2 ) - 0.37** - 0.22* - - T-Sco e - 0.34** - 0.22* - - FMI (kg/m 2 ) ----0.32** - VAT (kg) 0.21** ----- Li e a (%) 0.20* - - - 0.26* - Lumba muscle a (%) - 0.17* 0.27** 0.30** - - IMAT single mid- high (g) ------ Abb e ia ions: BMC, bone mine al con en ; BMD, bone mine al densi y; FMI, a mass index; IGF-1, insulin-like g ow h ac o 1; IMAT, in e muscula adipose issue; SMI, skele al muscle mass index; VAT, isce al adipose issue. * P<0.05. ** P<0.01. Table 4 S epwise mul iple eg ession analyses wi h SMI, BMC and lumba muscle a as dependen a iables Dependen a iables and p edic o s βcoe ficien R 2 SEE P- alue VIF SMI (kg/m 2 ) Model a S ep 1: insulin (μU/L) 0.073 0.101 0.018 <0.001 1.135 S ep 2: IGF-1 (μg/L) 0.005 0.150 0.002 0.015 1.053 S ep 3: lep in (ng/mL) 0.023 0.184 0.010 0.021 1.104 BMC (kg) Model b S ep 1: IGF-1 (μg/L) 3.232 0.098 0.794 <0.001 1.044 S ep 2: lep in (ng/mL) 8.500 0.135 3.715 0.024 1.009 S ep 3: age (y) 16.918 0.164 7.949 0.035 1.040 Lumba muscle a (%) Model c S ep 1: FMI (kg/m 2 ) 0.56 0.296 0.100 0.100 1.020 S ep 2: IGF-1 (μg/L) 0.02 0.343 0.007 0.007 1.020 Abb e ia ions: BMC, bone mine al con en ; FMI, a mass index; IGF-1, insulin-like g ow h ac o 1; SEE, s anda d e o o es ima ion; SMI, skele al muscle mass index; VIF, a iance infla ion ac o . a Model: independen a iables: adiponec in, IGF-1, insulin, IL-6, hsCRP, lep in and age. b Model: independen a iables: adiponec in, IGF-1, lep in, IL-6 and age. c Model: independen a iables: adiponec in, IGF-1, lep in, insulin, IL-6, hsCRP, FMI and age. Analysis o he adiponec in pa adox in heal hy olde people 275 Jou nal o Cachexia, Sa copenia and Muscle 2023; 14: 270–278 DOI: 10.1002/jcsm.13127 1353921906009, 2023, 1, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1002/jcsm.13127 by Uni e si a sbiblio hek Kiel, Wiley Online Lib a y on [18/08/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License Discussion Ou da a confi m he adiponec in pa adox in olde adul s wi hou inflamma o y diseases. Highe adiponec in le els we e associa ed wi h lowe SMI and BMC in he o al s udy popula ion and highe lumba muscle a in women. These obse a ions may explain he posi i e associa ion be ween adiponec in and mo ali y ha was ound in p e ious s udies e en independen o como bid condi ions like his o y o cance , 8 hype ension, diabe es, ca dio ascula disease, con- ges i e hea ailu e 8,24 and ch onic kidney disease. 24 Howe e , adiponec in may no be causally ela ed o an unheal hy body composi ion because o he nega i e associ- a ion be ween adiponec in and IGF-1. IGF-1 has well-known anabolic e ec s on muscle and bone ( o a e iew, see Goma asca e al. 25 ). In line wi h ou hypo hesis, s epwise mul iple eg ession analyses e ealed ha adiponec in was no significan p edic o o SMI, BMC and lumba muscle a when conside ing IGF-1 as a dependen a iable (Table 4). Simila o ou esul s in heal hy people, adiponec in le els we e nega i ely ela ed o se um IGF-1 in ac omegaly 26 as well as in men wi h ype 2 diabe es. 27 This co ela ion was independen o BMI, 26,27 enal unc ion and age, 27 sugges ing ha IGF-1 migh inhibi he exp ession o adiponec in. In i o expe imen s in cul u ed 3T3-L1 adipocy es ha e indeed shown dec eased adiponec in mRNA le els by IGF-1 o insulin 28 and a s udy in a s demons a ed ha in usion o ecombinan human IGF-1 dec eased plasma le els o adiponec in. 29 By con as , IGF-1 supplemen a ion in pa ien s wi h g ow h ho mone deficiency did no a ec se um adipo- nec in le els. 30 In ou s udy, IGF-1 le els we e nega i ely co ela ed wi h age and may he e o e explain highe adiponec in le els in an olde popula ion. The nega i e associa ion be ween adipo- nec in and IGF-1 in pa ien s wi h ype 2 diabe es 27 may be due o impai ed insulin sec e ion and hus lowe IGF-1 le els in hese pa ien s, 31 whe eas in pa ien s wi h ac omegaly, o e p oduc ion o IGF-1 may con ibu e o lowe adiponec in concen a ions. The e was a lack o associa ion be ween adi- ponec in and IGF-1 le els in pa ien s wi h mo bid obesi y a - e weigh loss induced by ba ia ic su ge y 32 whe eas in young women wi h non-diabe ic obesi y a posi i e associa- ion be ween IGF-1 and adiponec in was ound. 33 In he la e s udy, a significan nega i e co ela ion be ween IGF-1 and CRP was obse ed indica ing ha inflamma ion may be causal o he posi i e associa ion be ween IGF-1 and adipo- nec in because inflamma ion may impai he exp ession o bo h ho mones 33–35 ( o a e iew, see Ki k e al. 36 ). In con as o he associa ion be ween IGF-1 and muscle mass, muscle a o bone mass, o he bes o ou knowledge he e is no di ec causal e ec o IGF-1 on VAT o li e a . The e o e, he plausible nega i e co ela ions be ween adipo- nec in and VAT ( o al popula ion), FMI and li e a (especially in men) we e e iden in ou hea hy olde popula ion (Table 3). An al e na i e explana ion o he adiponec in pa adox is ha highe adiponec in le els in people wi h a lowe SM may be in e p e ed as a s a a ion signal (i.e. as a conse- quence o poo nu i ional s a us 37 o his o y o weigh loss among olde people 8 ). In line wi h his a gumen , weigh loss leads o an inc ease in adiponec in le els no only in people wi h obesi y 32 bu also in heal hy lean subjec s. 38 In he p es- en s udy, pa ial co ela ion be ween adiponec in and SMI adjus ed o IGF-1 e ealed, ha he nega i e co ela ion be ween SMI and adiponec in was only sligh ly weakened. Because ou da a a e c oss-sec ional, we canno exclude he possibili y ha a low SMI is causal o highe adiponec in le els. Adiponec in is also sec e ed by myocy es, he e o e he impac o ene gy a ailabili y on his e ec needs o be in es iga ed. The in e p e a ion o highe adiponec in le els as a s a a ion signal is howe e unlikely in a heal hy non-malnou ished s udy popula ion o communi y-dwelling olde people. The p esen s udy has se e al s eng hs. Fi s , he sample o olde communi y-dwelling Caucasians was heal hy, hus con ounde s caused by disease can be excluded. In addi ion, he popula ion was well cha ac e ized using whole body MRI, which is conside ed as he gold s anda d me hod o assessmen o SM and muscle a . Body composi ion was complemen ed wi h HGS as a unc ional pa ame e . Ne e - heless, ou findings should be conside ed in he con ex o some limi a ions. Fi s , adiponec in ci cula es in blood in mul- iple iso o ms wi h di e en physiologic unc ions. 39,40 As only o al adiponec in concen a ions we e measu ed, he e - ec s o he di e en iso o ms canno be examined. Finally, ou esul s need o be confi med using a longi udinal s udy design. Fo example, nu i ion in e en ions migh a ec ad- iponec in le els media ed by IGF-1. I has been demons a ed ha IGF-1 le els dec ease in esponse o as ing and sho - e m calo ic es ic ion o p o ein es ic ion 41 ( o a e- iew, see Thissen e al. 42 ). The e ec o p o ein supplemen a- ion in heal hy olde people on adiponec in le els emains o be in es iga ed. In conclusion, ou esul s sugges ha adiponec in is no causally ela ed o impai ed mass and unc ion o he musculoskele al sys em in heal hy olde people bu he as- socia ions a e media ed by an age- ela ed decline in IGF-1 le els ha con ibu e o an inc ease in adiponec in. These esul s suppo he hypo hesis o a unc ional in e play be ween IGF-1 and adiponec in ha had been p oposed by O ù e al. 43 Acknowledgemen s The s udy p o ocol was app o ed by he medical e hics com- mi ee o he Ch is ian-Alb ech s-Uni e si y o Kiel, Ge many, and ollowed he guidelines based on he ‘Decla a ion o Hel- 276 C.O. Walowski e al. Jou nal o Cachexia, Sa copenia and Muscle 2023; 14: 270–278 DOI: 10.1002/jcsm.13127 1353921906009, 2023, 1, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1002/jcsm.13127 by Uni e si a sbiblio hek Kiel, Wiley Online Lib a y on [18/08/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License sinki’. W i en in o med consen was ob ained om each pa - icipan . The au ho s ce i y ha hey comply wi h he e hical guidelines o au ho ship and publishing in he Jou nal o Ca- chexia, Sa copenia and Muscle. 44 This wo k was suppo ed by a g an o seca gmbh & co.kg., Ge many (2019/2020) and he Danone Ins i u e-Nu i ion o Heal h, Ge many (2013/14). We hank B i a Jux and he Clinic o Diagnos ic Radiology, Uni e si y medical Cen e Schleswig-Hols ein, Kiel (Ge many) o he help wi h MRI scanning. Open Access unding enabled and o ganized by P ojek DEAL. 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