bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–10–11
seven papers selected by
Xiong Weng, University of Edinburgh
  1. Inheritance and selection of the mitochondrial genome.
  2. Golgi-derived vesicles containing PI(3,4)P2 drive mitochondrial fusion.
  3. Astrocytic PI3Kα controls synaptic plasticity and cognitive function via serine metabolism.
  4. A heritability-optimized method for functional prioritization of rare coding variants in complex traits.
  5. Human genetic evidence challenges NCOA1 as a monogenic obesity gene.
  6. Epigenetic insights into extreme longevity in the world's oldest terrestrial animal, Jonathan.
  7. PI3K is the dominant signalling pathway recruited by IRS proteins to mediate their effects on metabolism and growth.
  1. Nat Rev Genet. 2026 Oct 05.
    Inheritance and selection of the mitochondrial genome.
    Qin Xie, Harry E Walker, Michal Minczuk, Marcos R Chiaratti, Patrick F Chinnery.
      The functioning mitochondrial genome is essential for cellular energy production. Being strictly maternally inherited and possessing limited DNA repair capacity, mitochondrial DNA (mtDNA) replication errors tend to accumulate over time. If left unchecked, these errors can accumulate through the female germline over successive generations, potentially leading to species extinction. However, this outcome is not observed in most species, including humans, which implies the existence of mechanisms that counteract the progressive accumulation of deleterious mtDNA mutations. Recent technological advances are building a deeper understanding of the processes that preserve mtDNA integrity, including the molecular and cellular basis and timing of purifying selection. This new knowledge helps to explain how mtDNA can change rapidly over just a few generations, whilst remaining compatible with the independently inherited, evolving nuclear genome.
    DOI:  https://doi.org/10.1038/s41576-026-01019-0
  2. Science. 2026 Oct 08. 394(6820): eadx9628
    Golgi-derived vesicles containing PI(3,4)P2 drive mitochondrial fusion.
    Sho Aki, Mayuko Segawa, Vincent Anton, Suvagata R Chowdhury, Shun Nagashima, Isshin Shiiba, Dane M Wolf, Ikuko Koyama-Honda, Ayumu Sugiura, Joe Ganellin, Mark Johnson, Sakie Katsumura, Maki Sugaya, Yasunori Fujita, Koki Nakamura, Kazuaki Yoshioka, Hisamichi Naito, Yoh Takuwa, Ikuroh Ohsawa, Yusuke Hirabayashi, Shigeru Yanagi, Masahiro Morita, Tsuyoshi Osawa, Julien Prudent.
      Mitochondria are dynamic organelles that remodel their shape to regulate cell fate. Mitochondrial division involves interactions with the endoplasmic reticulum (ER), lysosomes, and trans-Golgi network-derived vesicles to facilitate membrane scission. How interorganelle contacts regulate mitochondrial membrane fusion remains largely unknown. Here, we identified a role for Golgi-derived vesicles enriched in phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] in regulating mitochondrial fusion. We found that these vesicles were recruited to ER- and mitofusin-marked fusion sites. Accordingly, loss of class II PI3-kinase isoforms α and β (PI3K-C2α and PI3K-C2β), which generate PI(3,4)P2, led to mitochondrial fragmentation resulting from impaired fusion. Furthermore, cardiomyocyte-specific PI3K-C2α and PI3K-C2β double-deletion mice exhibited mitochondrial fragmentation and heart failure. Thus, subpopulations of Golgi-derived vesicles carrying different phosphoinositides control mitochondrial membrane remodeling and homeostasis.
    DOI:  https://doi.org/10.1126/science.adx9628
  3. Nat Commun. 2026 09 04. pii: 10520. [Epub ahead of print]17(1):
    Astrocytic PI3Kα controls synaptic plasticity and cognitive function via serine metabolism.
    Alba Fernández-Rodrigo, Celia García-Vilela, Abel Eraso-Pichot, Irene B Maroto, María D G Moreno, Esperanza López-Merino, Silvia Gutiérrez-Eisman, Carla Sánchez-Castillo, Cristina Boers-Escuder, Eneko Merino-Casamayor, Mariona Graupera, Albert Quintana, María I Cuartero, Maite Solas, Giovanni Marsicano, José A Esteban.
      Astrocytes modulate neuronal activity by gliotransmission and through metabolic regulation, yet the relationship between these functions remains poorly understood. Here we show that phosphatidylinositol 3-kinase (PI3K) signaling in astrocytes controls synaptic plasticity and memory by regulating cellular metabolism. Deletion of the p110α isoform of PI3K in hippocampal astrocytes impairs NMDA receptor activation during the induction of hippocampal long-term potentiation (LTP). This defect is rescued by either D-serine (co-agonist of synaptic NMDA receptors) or its precursor L-serine, indicating that PI3K regulates synaptic plasticity through serine availability. Indeed, deletion of p110α rewires astrocyte metabolism, reducing glycolytic flux while enhancing mitochondrial respiration. This, in turn, would limit L-serine biosynthesis through the phosphorylated pathway. Consistently, mice lacking astrocytic p110α display memory deficits that are rescued by in vivo L-serine administration. These findings identify astrocytic PI3K p110α as a key link between cellular metabolism, synaptic plasticity and cognition.
    DOI:  https://doi.org/10.1038/s41467-026-77319-0
  4. Nat Genet. 2026 Oct;58(10): 2502-2513
    A heritability-optimized method for functional prioritization of rare coding variants in complex traits.
    Keona Pang, Nazia Pathan, Ann Le, Alice Man, Josef Graf, Yanran Li, Guilherme L da Rocha, Elad Shemesh, Daria Grafodatskaya, Michael R Chong, Guillaume Paré.
      Population sequencing studies are uncovering millions of missense rare variants (RVs) implicated in the 'missing heritability' of complex diseases, yet distinguishing functional from neutral variation remains challenging. Here we present rare variant heritability-optimized scores (RovHer), a heritability-optimized method for inferring a variant's probability of being functional (that is, its contribution to trait variance). RovHer leverages exome-wide association statistics across 4,927,334 RVs and uses multivariate adaptive regression splines to integrate 75 variant- and gene-level features without a priori constraints. Across 21 traits in up to 357,086 UK Biobank European individuals, the top 1% of RovHer-prioritized missense RVs (m = 13,410) explained, on average, 16.1% of total RV heritability, a 10-fold gain over 7 alternative methods (average 1.5%; range 1.2-2.3%). RovHer's predictions are independent of allele frequency, generalize in a multi-ancestry replication and effectively identify high-risk carriers of severe clinical outcomes across 17 monogenic gene-trait pairs. Our tool showcases the value of missense RVs in population risk stratification.
    DOI:  https://doi.org/10.1038/s41588-026-02766-w
  5. Cell Rep Med. 2026 Oct 08. pii: S2666-3791(26)00523-9. [Epub ahead of print] 103106
    Human genetic evidence challenges NCOA1 as a monogenic obesity gene.
    Jérôme Delplanque, Audrey Leloire, Lauriane Le Collen, Hélène Loiselle, Bénédicte Toussaint, Emmanuel Vaillant, Frédéric Allegaert, Timothée Beke, Guillaume Charpentier, Sylvia Franc, Beverley Balkau, Michel Marre, Emma Henriques, Emmanuel Buse Falay, Mehdi Derhourhi, Philippe Froguel, Amélie Bonnefond.
      Obesity is a heterogeneous disease with a substantial genetic component. Rare pathogenic variants in genes of the leptin-melanocortin pathway can cause monogenic obesity and support targeted therapies such as setmelanotide, a melanocortin 4 receptor agonist. Pathogenic variants in NCOA1, encoding the nuclear receptor co-activator SRC-1, have recently been proposed as a cause of monogenic obesity through impaired leptin-induced POMC activation, leading to the inclusion of NCOA1 variant carriers in the EMANATE setmelanotide trial. However, despite biological rationale, the contribution of NCOA1 variants to human obesity remains elusive. Here, we assess NCOA1 variants with case-control analyses in adults and children from the RaDiO study, combined with in vitro assays and replication in the UK Biobank. We find no association between pathogenic NCOA1 variants and obesity or body mass index.
    Keywords:  NCOA1; SRC1; functional genetics; melanocortin pathway; monogenic obesity; precision medicine
    DOI:  https://doi.org/10.1016/j.xcrm.2026.103106
  6. Sci Adv. 2026 Oct 09. 12(41): eadw8887
    Epigenetic insights into extreme longevity in the world's oldest terrestrial animal, Jonathan.
    Benjamin Vaisvil, Daniel P Schmitt, Angela Jones, Vinayak Kapatral, James M Ford, Madison L Taylor, Mathia Colwell, Jonathan Hollins, Sam Pascucci, Konstantin Weissenow, Burkhard Rost, Pascal Notin, Justin Gerlach, Thomas C Terwilliger, Li-Wei Hung, Lars Juhl Jensen, Kathlyn Reed, Todd R Robeck, Steve Horvath, Christopher Faulk, Yanjun Ma, Stephen W Clark.
      Aldabra giant tortoises (Aldabrachelys gigantea) are exceptionally long-lived. We sequenced the genome and methylome of Jonathan, a 194-year-old Aldabra, to explore the molecular basis of his longevity. Relative to other giant tortoises (A. gigantea and Chelonoidis abingdonii), Jonathan has unique gene variants in most aging pathways. Moreover, Jonathan has substantial DNA methylation and methylation entropy changes compared to four other Aldabras ranging in age from a 5-year-old juvenile to older adults. Notably, we found that lower-entropy regions in Jonathan's methylome were enriched for the promoters of genes involved in the mitochondrial electron transport chain, and RNA metabolism. This suggests that high-fidelity transcription of the genes in these pathways may be crucial for long-lived species. Our findings support a model for aging wherein the maintenance of low methylation entropy in gene promoters is coupled to efficient mitochondrial energy production, efficient RNA processing, and efficient genomic repair.
    DOI:  https://doi.org/10.1126/sciadv.adw8887
  7. Mol Metab. 2026 Oct 06. pii: S2212-8778(26)00134-1. [Epub ahead of print] 102450
    PI3K is the dominant signalling pathway recruited by IRS proteins to mediate their effects on metabolism and growth.
    Steven J Millership, Nadia Tyler-Rubinstein, Elaine E Irvine, Marika Charalambous, Agharul I Choudhury, Santiago Vernia, Peter Voshol, Antonio Vidal Puig, Lazaros C Foukas, Dominic J Withers.
       OBJECTIVES: Insulin and Igf1 have pleiotropic effects on development, growth and metabolism. The activated insulin and IGF1 receptors engage insulin receptor substrate (IRS) proteins, intracellular adaptor molecules that recruit multiple downstream signalling pathways, including PI3K and GRB2-RAS-MAPK. Global deletion of IRS1 or IRS2 in mice results in divergent effects on growth, metabolism, and ageing. However, the precise signalling pathways recruited by IRS1 or IRS2 to mediate their physiological effects in vivo have not been defined.
    METHODS: We generated knock-in mice in which either IRS1 or IRS2 was mutated to prevent downstream recruitment of PI3K or GRB2 and undertook phenotypic analysis of these animals.
    RESULTS: Knock-in mice unable to recruit PI3K to IRS1 (Irs1YnF) or to IRS2 (Irs2YnF) had limited or no compensation in IRS2 and IRS1 signalling respectively. Irs1YnF mice were growth restricted, with reduced adiposity and insulin resistance, but did not develop diabetes due to compensatory increase in β-cell mass. Irs2YnF mice were obese and insulin resistant and developed diabetes due to β-cell failure. In contrast knock-in mice unable to recruit GRB2 to IRS1 (Irs1Y891F) or to IRS2 (Irs2Y911F) displayed normal growth and metabolism.
    CONCLUSIONS: PI3K recruitment by either IRS1 or IRS2 is the primary signalling mediator of the effects of these adaptor molecules on growth and metabolism in mice, and suggest that the other signalling pathways recruited by IRS1 and IRS2, including GRB2, have minimal or redundant roles.
    Keywords:  Diabetes; GRB2; Growth; IRS; Insulin; PI3K
    DOI:  https://doi.org/10.1016/j.molmet.2026.102450
This page is being maintained by Thomas Krichel. It was last updated on 2026‒10‒11 at 14:13.