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Epigenetic control of variation and stochasticity in metabolic disease

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Panzeri, Ilaria, Pospisilik, John Andrew·2018·Molecular Metabolism
DOI 10.1016/j.molmet.2018.05.010PMC PMC6034039
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Abstract

BACKGROUND: The alarming rise of obesity and its associated comorbidities represents a medical burden and a major global health and economic issue. Understanding etiological mechanisms underpinning susceptibility and therapeutic response is of primary importance. Obesity, diabetes, and metabolic diseases are complex trait disorders with only partial genetic heritability, indicating important roles for environmental programing and epigenetic effects. SCOPE OF THE REVIEW: We will highlight some of the reasons for the scarce predictability of metabolic diseases. We will outline how genetic variants generate phenotypic variation in disease susceptibility across populations. We will then focus on recent conclusions about epigenetic mechanisms playing a fundamental role in increasing variability and subsequently disease triggering. MAJOR CONCLUSIONS: Currently, we are unable to predict or mechanistically define how "missing heritability" drives disease. Unravelling this black box of regulatory processes will allow us to move towards a truly personalized and precision medicine.

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  • A large part of phenotype variability across patients with the same ABCD1 genotype may be due to stochasticity.

    “Beyond identifiable causes, a large part of phenotype variability across patients with the same ABCD1 genotype may “simply” be due to stochasticity, a factor hitherto considered “noise” by Cartesian researchers.”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [132]

    The section “A role for true stochasticity, randomness, and noise?” describes substantial phenotypic variation in inbred rodents and attributes some variation to stochastic sources. It does not address patients with the same ABCD1 genotype or establish that stochasticity accounts for a large part of their phenotype variability. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Stochasticity rules all living cells through fluctuations in gene expression, molecular interactions, and metabolic fluxes, even systems governed by deterministic laws.

    “Actually, stochasticity rules all living cells through fluctuations in gene expression, molecular interactions, and metabolic fluxes, even systems governed by deterministic laws, such as monogenic genetics [131,132,133,134].”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [132]

    In “Mechanisms of non-Mendelian variation” (page unavailable), the paper says most cellular processes are susceptible to random variation through stochastic molecular interactions, and that transcription exhibits stochasticity. It does not specifically establish fluctuations in metabolic fluxes or the claim about systems governed by deterministic laws, such as monogenic genetics. “Rules all living cells” is also stronger than the paper’s qualified wording. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Authors
Panzeri, I., & Pospisilik, J. A.
Affiliations
Max Planck Institute of Immunobiology and Epigenetics (DE)
Corresponding author
Pospisilik, John Andrew
ORCID
Venue
Molecular Metabolism
Publisher
Elsevier BV
Published
2018-08
Volume
14
Pages
26-38
ISSN
2212-8778 (ISSN-L)
DOI
10.1016/j.molmet.2018.05.010
PMC
PMC6034039
OpenAlex
W2803754442
Cited by
50
References
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Citations by year
2026: 2 · 2025: 6 · 2024: 7 · 2023: 3 · 2022: 7 · 2021: 5 · 2020: 11 · 2019: 9
FWCI
0.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Metabolism (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
Keywords
epigenetics, obesity, metabolic disorders, diabetes mellitus, missing heritability, phenotypic variability, disease susceptibility, randomness, environmental programming, genetic variants, precision medicine
MeSH terms
Biological Variation, Population, Animals, Humans, Metabolic Diseases, Stochastic Processes, Epigenesis, Genetic

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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