Independent phenotypic plasticity axes define distinct obesity sub-types.
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
received:
03
05
2022
accepted:
29
07
2022
pubmed:
14
9
2022
medline:
28
9
2022
entrez:
13
9
2022
Statut:
ppublish
Résumé
Studies in genetically 'identical' individuals indicate that as much as 50% of complex trait variation cannot be traced to genetics or to the environment. The mechanisms that generate this 'unexplained' phenotypic variation (UPV) remain largely unknown. Here, we identify neuronatin (NNAT) as a conserved factor that buffers against UPV. We find that Nnat deficiency in isogenic mice triggers the emergence of a bi-stable polyphenism, where littermates emerge into adulthood either 'normal' or 'overgrown'. Mechanistically, this is mediated by an insulin-dependent overgrowth that arises from histone deacetylase (HDAC)-dependent β-cell hyperproliferation. A multi-dimensional analysis of monozygotic twin discordance reveals the existence of two patterns of human UPV, one of which (Type B) phenocopies the NNAT-buffered polyphenism identified in mice. Specifically, Type-B monozygotic co-twins exhibit coordinated increases in fat and lean mass across the body; decreased NNAT expression; increased HDAC-responsive gene signatures; and clinical outcomes linked to insulinemia. Critically, the Type-B UPV signature stratifies both childhood and adult cohorts into four metabolic states, including two phenotypically and molecularly distinct types of obesity.
Identifiants
pubmed: 36097183
doi: 10.1038/s42255-022-00629-2
pii: 10.1038/s42255-022-00629-2
pmc: PMC9499872
doi:
Substances chimiques
Insulin
0
Membrane Proteins
0
Nerve Tissue Proteins
0
Histone Deacetylases
EC 3.5.1.98
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1150-1165Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : R01 HG012444
Pays : United States
Organisme : NHGRI NIH HHS
ID : R21 HG011964
Pays : United States
Organisme : Medical Research Council
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Investigateurs
Timothy Triche
(T)
Adelheid Lempradl
(A)
Zachary J DeBruine
(ZJ)
Emily Wolfrum
(E)
Zachary Madaj
(Z)
Tim Gruber
(T)
Brooke Grimaldi
(B)
Andrea Parham
(A)
Mitchell J McDonald
(MJ)
Joseph H Nadeau
(JH)
Ildiko Polyak
(I)
Carmen Khoo
(C)
Christine Lary
(C)
Peter D Gluckman
(PD)
Neerja Karnani
(N)
David Carey
(D)
Ruth J F Loos
(RJF)
Gabriel Seifert
(G)
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2022. The Author(s).
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