bims-obesme 2026-06-28 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2026–06–28
six papers selected by
Xiong Weng, University of Edinburgh

Meta-analysis of DNA methylation aging signatures in 17 human tissues.
E4BP4 safeguards brown fat mitochondria from obesity-induced fragmentation via ceramide repression.
Adipocyte Myoglobin Is a Determinant of Energy Expenditure and a Potential Target to Limit Obesity.
Mitochondrial DNA heteroplasmy drives cortical neuronal disturbances in human organoids harbouring the common m.3243A>G mutation.
Plasma GDF15 affects long-term dementia risk and alters neuroimmune signaling.
Common human ALDH1B1 and ALDH2 variants increase neuroinflammatory response to a single ethanol dose in mice.

Nat Aging. 2026 Jun 26.

Meta-analysis of DNA methylation aging signatures in 17 human tissues.

Macsue Jacques, Kirsten Seale, Sarah Voisin, Anna Lysenko, Robin Grolaux, Bernadette Jones-Freeman, Severine Lamon, Mandhri Abeysooriya, Itamar Levinger, Carlie Bauer, Adam P Sharples, Aino Heikkinen, Elina Sillanpaa, Miina Ollikainen, Cassandra Smith, James R Broatch, Navabeh Zarekookandeh, Linn Gillberg, Ida Blom, Jesse R Poganik, Mahdi Moqri, Vadim N Gladyshev, Matthew Taper, Cassandra Malecki, Sean Lal, Nathalie Saurat, Steve Horvath, Andrew Teschendorff, Nir Eynon.

Epigenetic changes, in particular DNA methylation, accumulate with age across different tissues, but whether these changes follow consistent patterns across different organs remains poorly understood. Here we show, through a meta-analysis of more than 15,000 human methylation profiles spanning 17 tissues, that aging produces both conserved and tissue-specific epigenetic signatures. We identify systemic shifts in methylation levels, increases in methylation variability, and growing molecular disorder across tissues. Network analysis revealed tightly connected gene clusters that are not modified by beneficial interventions, alongside a more modifiable cluster linked to NAD+ metabolism, supporting NAD+ as a potential therapeutic target in aging. A gene encoding a cell-adhesion protein, PCDHGA1, emerged as a conserved hub across tissues, implicating cell-to-cell communication pathways in aging across multiple organs. Our methylation atlas therefore provides a resource for dissecting the molecular basis of human aging and for identifying potential biomarkers and translational therapies.

DOI: https://doi.org/10.1038/s43587-026-01164-5
EMBO Rep. 2026 Jun 22.

E4BP4 safeguards brown fat mitochondria from obesity-induced fragmentation via ceramide repression.

Fernando Valdivieso-Rivera, Vanessa O Furino, Carlos E Leher, Ariane M Zanesco, Monara Kaélle Cruz, Flavia C Gan, Adriana Leandra Santoro, Lara Regina-Ferreira, Giovanna Leite Santos, Tiago Gonçalves, Luiz Osório Leiria, Pedro M Moraes-Vieira, Roger Frigério Castilho, Shingo Kajimura, Marcelo A Mori, Licio A Velloso, Carlos H Sponton.

Brown adipose tissue (BAT) counteracts obesity-related metabolic dysfunction through both thermogenic and non-thermogenic means. However, substantial evidence indicates that obesity negatively affects BAT mitochondrial morphology and oxidative capacity, impairing systemic energy homeostasis. Motivated by this apparent contradiction, we investigate the relationship between obesity and mitochondrial dynamics, as the underlying mechanisms remain incompletely understood. Here, we identify E4BP4 as a transcriptional repressor that prevents obesity-induced mitochondrial fragmentation and oxidative dysfunction by inhibiting ceramide synthesis in brown fat. Specifically, E4BP4 interacts with PRDM16 to repress Cers6 mRNA expression and consequently reduces C16:0 ceramide levels by binding to a 65 kb upstream enhancer region of the Cers6 gene. Notably, the preservation of mitochondrial integrity in BAT by E4BP4 gain-of-function improves systemic glucose homeostasis, independent of weight loss. Collectively, our findings establish E4BP4 as a molecular safeguard against obesity-induced mitochondrial fragmentation and oxidative dysfunction, primarily by suppressing ceramide synthesis in brown fat.

DOI: https://doi.org/10.1038/s44319-026-00826-0
Adv Sci (Weinh). 2026 Jun 25. e76191

Adipocyte Myoglobin Is a Determinant of Energy Expenditure and a Potential Target to Limit Obesity.

Christian Strehlau, Helen Broghammer, Claudia Gebhardt, Anne Hoffmann, Tobias Hagemann, Şeyma Midilli, Rachel S Zimmer, Kristin Schubert, Vasiliki Karagiannakou, Anastasia Georgiadi, Mario Ost, Martin Krüger, Lisa Roth, Kerstin Krause, Nora Klöting, Maria Keller, Martin Wabitsch, Rima Nuwayhid, Roland H Stimson, Michael Stumvoll, Matthias Blüher, Juliane Weiner, John T Heiker.

  Nutritional overflow and a positive energy balance are hallmarks of metabolic diseases including obesity and type 2 diabetes. Brown and beige adipocytes maintain systemic metabolic homeostasis by clearing and oxidizing energy-rich nutrients during thermogenic activation. Myoglobin (MB) is classically regarded as a muscle-associated oxygen-binding protein; however it is also expressed in brown and beige adipocytes, where it contributes to intracellular lipid handling and oxidative metabolism. Here, we report that loss of MB exclusively in adipose tissue (AT) lowers whole-body energy expenditure, impairs thermoregulation, and increases susceptibility to diet-induced obesity. AT-specific MB knockout (ATMBKO) mice exhibit elevated circulating triglycerides (TG) and fatty acids, indicating defective lipid clearance and utilization. Omics analyses reveal coordinated downregulation of oxidative phosphorylation, fatty acid metabolism, and myogenic programs. Conversely, restoration of MB in MB knockout (MBKO) mice improves metabolism in vivo. MB expression determines the capacity for mitochondrial fatty acid oxidation in brown adipocytes, whereas MB overexpression in primary human white adipocytes enhances thermogenic activity, confirming functional relevance of MB in human AT. Together, these findings establish MB as a key determinant of thermogenic lipid metabolism and energy expenditure in vivo and increasing adipocyte MB expression could increase energy expenditure and complement obesity treatment strategies.

Keywords:  brown adipose tissue; energy expenditure; lipid metabolism; metabolic disease; myoglobin; obesity; thermogenesis

DOI:  https://doi.org/10.1002/advs.76191
Nat Commun. 2026 Jun 21.

Mitochondrial DNA heteroplasmy drives cortical neuronal disturbances in human organoids harbouring the common m.3243A>G mutation.

Denisa Hathazi, Camilla Lyons, Daniel Lagos, Oliver Podmanicky, Mariana Zarate-Mendez, Yu Nie, Juliane S Müller, Kieren S J Allinson, Huw Naylor, Majlinda Lako, Ibrahim Elsharkawi, Irena Muffels, Eva Morava, Tamas Kozicz, Patrick Chinnery, András Lakatos, Rita Horvath.

Mitochondrial diseases frequently affect the brain leading to severe and disabling neurological symptoms. The heteroplasmic m.3243 A > G mutation in MT-TL1, encoding mt-tRNALeu, is responsible for ~80% of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), which is one of the most characteristic mitochondrial syndromes, leading to disability and early death. There are no animal models harbouring this mutation to provide precise mechanistic insights informing therapeutic interventions. Here, we generate a human iPSC-derived cerebral organoid slice model that recapitulates cortical architecture and mitochondrial pathology. Using biological assays and single-cell RNA sequencing, we uncover heteroplasmy-dependent transcriptional shifts and changes in key cellular processes in cortical neurons. Organoids with high heteroplasmy show a predominant impairment of deep-layer neurons triggered by mitochondrial stress, leading to axonal degeneration and apoptosis, similar to brain autopsy of a MELAS patient. Our findings provide insights into the vulnerability of long-range projection neurons in mitochondrial diseases, advancing our understanding of disease mechanisms with a view to potential therapeutic strategies.

DOI: https://doi.org/10.1038/s41467-026-74103-y
Sci Adv. 2026 Jun 26. 12(26): eaec7614

Plasma GDF15 affects long-term dementia risk and alters neuroimmune signaling.

Cassandra O Blew, Michael R Duggan, Dimitrios Tsitsipatis, Gabriela T Gomez, Zulema Rodriguez-Hernandez, Luke C Pilling, Jingsha Chen, Eva Jacobsen, Heather E Dark, Yifei Lu, Shannon M Drouin, Cassandra M Joynes, Minhao Yao, Murat Bilgel, Abhay Moghekar, Qu Tian, Julián Candia, Mary Kaileh, Aditi Gupta, Krystyna Mazan-Mamczarz, Myriam Gorospe, Alexey Lyashkov, Yevgeniya Lukyanenko, Mika Kivimaki, Philipp Frank, Lori L Jennings, Valborg Gudmundsdottir, Vilmundur Gudnason, Lenore J Launer, Naoto Kaneko, Shintaro Kato, Makio Furuichi, Masaki Shibayama, Masahisa Katsuno, Keita Hiraga, Yukiko Nishita, Rei Otsuka, James R Pike, Mary R Rooney, Pascal Schlosser, Yuhan Cui, Guray Erus, Christos Davatzikos, Rebecca F Gottesman, Iwao Waga, Priya Palta, Christie Ballantyne, Michael Griswold, Zhonghua Liu, Luigi Ferrucci, Allison B Herman, Keenan A Walker.

Growth/differentiation factor-15 (GDF15) is a secreted cytokine strongly associated with dementia risk. However, the extent to which GDF15 represents a biomarker and driver of dementia risk remains unclear. Across multiple cohorts, we demonstrated that plasma GDF15 is associated with greater dementia risk over 15- to 25-year follow-up periods when measured in midlife, with stronger associations observed for vascular, compared to Alzheimer's disease (AD), dementia. Two-sample Mendelian randomization supported plasma GDF15's mechanistic role in AD and related dementias, while cohort studies linked it to cerebral small vessel disease, neurodegeneration, phosphorylated tau, and a cerebrospinal fluid proteomic signature indicative of neuroimmune activation. Exposure of cultured myeloid cells to recombinant GDF15 altered biological pathways that we subsequently demonstrated are predictive of dementia risk, including interferon/antiviral responses. These findings support circulating GDF15's role as an early biomarker-particularly for vascular dementia and neuroinflammation-and identify the mechanisms by which it may drive dementia risk.

DOI: https://doi.org/10.1126/sciadv.aec7614
Sci Adv. 2026 Jun 26. 12(26): eaec6309

Common human ALDH1B1 and ALDH2 variants increase neuroinflammatory response to a single ethanol dose in mice.

Takuya Seike, Ruda Prestes E Albuquerque, Julio Cesar Batista Ferreira, Che-Hong Chen, Daria Mochly-Rosen.

Unlike the well-documented effects of aldehyde dehydrogenase 2 (ALDH2) hypoactive variants, the impact of hypoactive ALDH1B1 has yet to be elucidated. Using the Global Human Genome Aggregation Database, we identified 38 ALDH1B1 variants, common (>0.1% allele frequency) to different human genetic ancestral groups. Some missense ALDH1B1 human variants are notably less active and less stable, and three variants represent a complete loss of function (LoF) due to early stop codon. Since these inactive variants are common among humans, we studied the impact of carrying both ALDH1B1 LoF and ALDH2 inactive variant in mice. Double knock-in (DKI) mice carrying ALDH1B1G193fs and ALDH2*2E504K exhibited elevated neuroinjury markers. Following a single ethanol gavage (2 grams per kilogram), DKI mice showed exacerbated intoxication and significantly higher levels of neuroinjury markers, including elevated amyloid-β and ptau217 compared to WT or single-mutant mice. Our study highlights a potential impact of common hypoactive mitochondrial ALDH enzymes on human health, especially among those that consume alcohol.

DOI: https://doi.org/10.1126/sciadv.aec6309