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C i ical Commen a y on “Gu - o-b ain signaling es ic s die a y
p o ein in ake du ing eco e y om ca abolic s a es”in Cell 2025
Au ho s: Yiheng Wang and Shu-Feng Zhou*
College o Chemical Enginee ing, Huaqiao Uni e si y, Xiamen, China
*Co espondence: [email p o ec ed]
INTRODUCTION
The s udy by Jaschke NP, e al.1 published in Cell (No 4, 2025) claims o unco e a gu -
o-b ain signaling pa hway ha selec i ely supp esses die a y p o ein in ake du ing
eco e y om ca abolic s a es. Acco ding o he au ho s, animals eco e ing om
as ing, in lamma ion, o glucoco icoid-induced ca abolism exhibi a ansien p o ein
a oidance go e ned by a specialized en e oendoc ine- agal-NTS-PVN pa hway. The
au ho s p opose ha his mechanism p o ec s he o ganism om “me abolic s ess”
imposed by ea ly p o ein e eeding.
The concep is s iking because i con adic s long-s anding physiological knowledge.
Classical nu i ion s udies show ha pos -ca abolic o ganisms ypically demons a e a
p o ein appe i e, seeking ni ogen eplenishmen and amino acids equi ed o issue
e-syn hesis. In con as , his pape claims ha p o ein in ake is es ic ed du ing
eco e y, and ha his es ic ion is ac i ely imposed by a speci ic gu –b ain ci cui .
Gi en i s concep ual boldness, he claims equi e excep ionally igo ous e idence. Ye ,
upon de ailed e alua ion o he da a ac oss main igu es, ex ended da a, and
supplemen a y igu es, we ind subs an ial me hodological weaknesses, in e p e i e
leaps, and missing con ols. Se e al da ase s suppo a gene al supp ession o eeding
a he han p o ein-speci ic a oidance. Ci cui speci ici y is inadequa ely demons a ed.
The pu po ed gu -de i ed pep ide emains uniden i ied and uncha ac e ized. The
physiological a ionale is specula i e and inconsis en wi h es ablished ca abolic
eco e y li e a u e.
This commen a y p o ides a comp ehensi e, igu e-by- igu e c i ique, e alua ing
echnical and concep ual sho comings ha collec i ely unde mine he s eng h o he
au ho s’ conclusions.
CONCEPTUAL CRITIQUE
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Be o e examining indi idual igu es, se e al o e a ching issues limi he in e p e abili y
o he en i e s udy:
1. P o ein a oidance s. gene al hypophagia
Many o he au ho s’ beha io al esul s show educed o al calo ic in ake a he han a
selec i e a oidance o p o ein. Wi hou de ailed pala abili y, ex u e, calo ic densi y,
and sickness-beha io con ols, di e ences in p o ein s. ca bohyd a e in ake may be
d i en by gene al malaise a he han nu ien -speci ic signaling.
2. “Ca abolic s a es” a e ea ed as in e changeable
The au ho s employ se e al un ela ed models:
• 24–48 h as ing
• Glucoco icoid ea men
• Hindlimb unloading
• LPS-induced sys emic in lamma ion
These models sha e li le mechanis ic o e lap. G ouping hem unde a single ca ego y
(“ca abolic s a es”) o e simpli ies complex me abolic and immunological changes.
3. Gu -de i ed signal is no iden i ied
Despi e claims o a gu pep ide media ing he e ec :
• No pep ide is pu i ied
• No ecep o is iden i ied
• No cell- ype–speci ic senso y mechanism is demons a ed
Wi hou molecula iden i y, he cen al mechanis ic claim emains specula i e.
4. Vagal and cen al ci cui s a e nonspeci ically labeled
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The au ho s ely hea ily on Phox2b-C e, AAV, c-Fos, and PRV acing—all o which su e
om:
• b oad opism
• mul isynap ic con amina ion
• lack o nu ien speci ici y
• absence o elec ophysiological alida ion
Ci cui speci ici y is he e o e unsubs an ia ed.
5. Physiological a ionale is inconsis en wi h known
biology
P o ein es ic ion du ing eco e y om ca abolism con adic s:
• ni ogen-balance li e a u e
• FGF21-d i en p o ein appe i e
• classical s a a ion- e eeding physiology
No biochemical o me abolic jus i ica ion is p o ided.
FIGURE-BY-FIGURE CRITIQUE (MAIN FIGURES 1–7)
Below we c i ique each main igu e indi idually.
Figu e 1 – Beha io al E idence o P o ein A oidance
Au ho s’claim:
Du ing eco e y om ca abolic s a es, animals a oid p o ein bu no ca bohyd a es.
C i ique:
1. To al calo ic in ake d ops, sugges ing gene alized hypophagia.
2. Pala abili y di e ences a e no con olled; p o ein pelle s usually di e in
ex u e, ha dness, and odo .
3. Ci cadian eeding pa e ns a e no ma ched.
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4. Lack o baseline p e e ence compa isons be o e ca abolic induc ion.
5. No mic os uc u e licking analysis o dis inguish as e s. pos -inges i e e ec s.
6. Some ca abolic models (e.g., LPS) induce sickness beha io , con ounding
p e e ence esul s.
Conclusion: E idence o selec i e p o ein a oidance is weak and con ounded.
Figu e 2 – Iden i ica ion o a Pu a i e Gu Senso Popula ion
Au ho s’claim:
A subse o duodenal en e oendoc ine cells (EECs) is ac i a ed by p o ein in ake du ing
ca abolic eco e y.
C i ique:
1. c-Fos s aining in gu epi helium is un eliable, con ounded by mechanical
s imula ion o eeding.
2. scRNA-seq is unde powe ed ( ewe han ~400 EECs analyzed), esul ing in
uns able clus e ing.
3. No single-amino-acid sensing da a—no leucine, a ginine, alanine speci ici y
assays.
4. No in i o demons a ion ha hese cells di ec ly espond o p o eins o amino
acids.
5. No gene ic ma ke s dis inguish his “p o ein- esponsi e sub ype” om known
EEC classes.
Conclusion: Da a do no con incingly iden i y a nu i ionally specialized EEC popula ion.
Figu e 3 – Vagal Media ion o P o ein A oidance
Au ho s’ claim:
Vagal a e en s a e equi ed o ansmi he gu -de i ed p o ein-a oidance signal.
C i ique:
1. Vago omy causes majo physiological dis u bances (gas ic emp ying, mo ili y
changes) ha con ound nu ien choice assays.
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2. Phox2b-C e exp ession is no selec i e o agal a e en s.
3. Chemogene ic manipula ion lacks alida ion (no immunos aining, no
elec ophysiology).
4. Beha io al escue expe imen s con ounded: CNO doses inconsis en , o de o
p e e ence es ing unclea .
5. No di ec demons a ion ha agal ibe s hemsel es espond o p o ein s imuli.
Conclusion: Vagal in ol emen is plausible bu no demons a ed wi h speci ici y.
Figu e 4 – Hypo halamic In eg a ion Node (PVN)
Au ho s’ claim:
PVN neu ons in eg a e agal in o ma ion and supp ess p o ein in ake.
C i ique:
1. PVN c-Fos ac i a ion is non-speci ic; PVN esponds o s ess, no el y, and
osmola i y changes.
2. PRV acing is mul isynap ic and p one o non-speci ic in ec ion.
3. Op ogene ic ac i a ion supp esses all eeding, no jus p o ein in ake.
4. No elec ophysiological e idence o agal- o-PVN monosynap ic connec i i y.
5. No cell- ype iden i ica ion (e.g., CRH+, TRH+, oxy ocin neu ons).
Conclusion: PVN ec ui men is no nu ien -speci ic and is o e in e p e ed.
Figu e 5 – Sec e ed Gu -De i ed Signal
Au ho s’ claim:
A sec e ed pep ide om ca abolic EECs supp esses p o ein in ake.
C i ique:
1. No pep ide is iden i ied—LC–MS/MS da a no adequa e; no pu i ica ion o
ecep o assays pe o med.
2. Condi ioned medium con ains many signaling molecules; he e ec may be
nonspeci ic.
3. AAV o e exp ession o he candida e ac o lacks quan i ica ion and localiza ion.
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4. No demons a ion ha he condi ioned medium ac i a es agal neu ons.
5. No dose- esponse cu es, ime cou ses, o in i o pep ide injec ions.
Conclusion: Majo mechanis ic gap; he gu -de i ed signal emains unknown.
Figu e 6 – Neu ophysiology o he Vagal–NTS Pa hway
Au ho s’ claim:
P o ein inges ion ac i a es a speci ic NTS popula ion ia agal inpu .
C i ique:
1. Vagal ibe eco dings lack amino acid speci ici y; no single-AA uning cu es.
2. Mechanical dis ension e ec s no con olled.
3. Calcium imaging in NTS p one o mo ion a i ac s; insu icien con ols.
4. NTS ac i a ion o e laps wi h GLP-1R+ cells—nonspeci ic sa ie y ci cui y.
5. No causal link o p o ein supp ession demons a ed.
Conclusion: NTS ac i a ion is no p o ein-speci ic.
Figu e 7 – Ci cui Manipula ion (Op o/Chemo) Al e s Feeding
Au ho s’ claim:
Ac i a ing o inhibi ing he ci cui modula es p o ein in ake.
C i ique:
1. Op ogene ic ac i a ion o PVN educes all eeding, no selec i ely p o ein eeding.
2. No ca bohyd a e/ a in ake da a unde iden ical manipula ions.
3. Locomo o , anxie y, and sickness-beha io con ols insu icien .
4. Inhibi o y manipula ions show inconsis en beha io al e ec s.
5. Vi al exp ession he e ogenei y no quan i ied.
Conclusion: Manipula ion esul s consis en wi h global sa ie y, no p o ein-speci ic
egula ion.
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EXTENDED DATA FIGURES ED1–ED15
Below we p o ide a concise c i ique o each Ex ended Da a igu e.
ED1 – Valida ion o Ca abolic Models
• Models a e physiologically dis inc and canno be g ouped oge he .
• No amino-acid p o iling, ni ogen balance, o co icos e one le els measu ed.
ED2 – Pala abili y Con ols
• Only minimal lickome e da a; no ex u e, ha dness, o ene gy densi y ma ching.
• P o ein pelle s isibly di e en .
ED3 – O ganoid EEC Cha ac e iza ion
• EEC di e en ia ion ma ke s incomple e; o ganoids lack physiological con ex .
ED4 – scRNA-seq Clus e ing
• High mi ochond ial gene pe cen ages; clus e s uns able; ba ch e ec s
unadd essed.
ED5 – Vagal Fibe Labeling
• Phox2b-C e no selec i e; acing o e ly b oad.
ED6 – Amino-Acid S imula ion Panel
• Only AA mix u es es ed; no indi idual amino acid es s.
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ED7 – NTS Neu opep ide Exp ession
• Bulk qPCR insu icien ; no cell- ype esolu ion.
ED8 – Op ogene ic Valida ion
• No elec ophysiological con i ma ion o opsin unc ionali y.
ED9 – Beha io al Con ol Assays
• Ac i i y sco ing unde powe ed; sickness beha io no quan i ied.
ED10 – Sho -Te m “Ch onic” Manipula ions
• 48 hou s oo sho o e alua e ca abolic eco e y.
• No me abolic, endoc ine, o ni ogen-balance co ela es.
ED11 – Ho monal P o iling
• Missing key ca abolic ho mones (FGF21, IGF-1, GH, u ea).
• Inconsis en sampling imes.
ED12 – Gu Mo phology
• Desc ip i e only; no quan i ica ion o illi, c yp s, o EEC densi y.
ED13 – Vagal Elec ophysiology Con ols
• No aw signal me ics; spike so ing unclea .
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ED14 – Vi al Tool Speci ici y
• AAV opism b oad; C e-lines leaky; no colocaliza ion quan i ica ion.
ED15 – Longi udinal Beha io
• No ni ogen balance; high a iabili y; beha io al en ainmen con ounded.
SUPPLEMENTARY FIGURES S1–S12
S1 – Die Composi ion Tables
• Amino acid p o iles missing; ibe and mois u e di e be ween die s.
S2 – Addi ional Lickome e Da a
• Bu s s uc u e, sa ia ion cu es missing.
S3 – scRNA-seq QC Me ics
• Poo lib a y complexi y; excessi e mi ochond ial gene exp ession.
S4 – Vi al Con ols
• No in lamma ion sco ing; GFP oxici y unadd essed.
S5 – Addi ional NTS Imaging
