bims-obesme 2026-05-24 papers

Issue of 2026–05–24
five papers selected by
Xiong Weng, University of Edinburgh

Mol Med. 2026 May 18.

Gdf15 expression in thermogenic adipocytes regulates diet-induced weight gain in a sex-dependent manner.

Jayashree Jena, Ayushi Sood, Joshua Peterson, Luis Miguel García-Peña, Eric T Weatherford, Pritesh Patel, Shelly Roitershtein, David A Smith, Vamsi Challa, Randy J Seeley, Renata O Pereira.

BACKGROUND: Growth differentiation factor 15 (GDF15) is a stress-induced cytokine known to bind to its endogenous receptor GDNF-family α-like (GFRAL) in the hindbrain, thereby modulating energy homeostasis. In response to prolonged high-fat diet (HFD) feeding, Gdf15 expression is induced in various tissues, including liver and brown adipose tissue (BAT), leading to increased GDF15 serum levels. Although the liver is the primary source of circulating GDF15 during diet-induced obesity (DIO), other tissues are also required. We investigated whether BAT contributes to GDF15 circulating levels and if GDF15 induction in BAT regulates systemic metabolism during DIO.
METHODS: We generated mice with selective Gdf15 deletion in thermogenic adipocytes (KO) and subjected them to 12 weeks of HFD feeding to determine the role of BAT-derived GDF15 on systemic metabolic homeostasis in both male and female mice.
RESULTS: Unexpectedely, despite no changes in GDF15 serum levels in mice fed ad-libitum regardless of sex or genotype, female KO mice were resistant to DIO, had increased energy expenditure and improved mitochondrial fatty acid oxidation in BAT, which was prevented by ovariectomy. Conversely, male KO mice had increased body weight and adiposity upon HFD feeding, along with reduced respiratory capacity in BAT mitchondria, and increased markers of fibro-inflammation.
CONCLUSIONS: Together, our data reveal GDF15 induction in BAT is required to regulate weight gain in mice in a sex-dependent manner. Our results also suggest female sex hormones contribute to increase energy expenditure in female KO mice promoting leanness. Our study underscore the importance of rigorously addressing sex differences in GDF15 biology and pharmacology and suggests GDF15 might exert effects on energy balance and adiposity that are independent of signaling through GFRAL.

Keywords: Brown adipose tissue; GDF15; Obesity; Sex dimorphism

DOI: https://doi.org/10.1186/s10020-026-01505-5

Nat Commun. 2026 May 21.

Insulin receptorT1160 phosphorylation mediates renal cortical insulin resistance but not excess gluconeogenesis from glycerol.

Brandon T Hubbard, Yumin Ma, Rafael C Gaspar, Traci E LaMoia, Dongyan Zhang, Mario Kahn, Sylvie Dufour, Ali Nasiri, Gerald I Shulman.

Impaired suppression of endogenous glucose production (EGP) drives end-organ damage in insulin resistance and type 2 diabetes. Although the liver is traditionally thought to mediate dysregulated EGP, the role of the renal cortex is less understood. Here, we investigate if high-fat diet (HFD) induces renal cortical insulin resistance while assessing renal glucose production (RGP) and mitochondrial metabolism in male mice. HFD increases plasma membrane sn-1,2-DAGs, PKCε translocation, and Insulin Receptor Kinase (IRK)T1160 phosphorylation while blunting insulin-stimulated pyruvate oxidation and insulin signaling. In HFD mice, RGP is elevated 6.5-fold and accounts for 60% of EGP during hyperinsulinemia. Excess RGP is derived equally from glycerol and mitochondrial sources, chiefly pyruvate. Signaling and flux defects are abrogated in HFD-fed IRKT1150A knockin mice, except for glycerol-derived gluconeogenesis. Our findings implicate the sn-1,2-DAG → PKCε → IRKT1160 axis in renal cortical insulin resistance and highlight renal gluconeogenesis as a driver of dysregulated glucose homeostasis.

DOI: https://doi.org/10.1038/s41467-026-73016-0

Nat Genet. 2026 May 20.

Genome-wide associations of structural variants with human traits through imputation from long-read assemblies.

Wei-Yang Bai, Shuli Liu, Zhongqu Duan, Ji-Jian Yang, Jie Chen, Junren Hou, Lianfeng Wu, Nan Li, Ting Qi, Jian Yang.

Structural variants (SVs) are a major type of genetic variation, yet their role in human traits remains largely uncharacterized, primarily due to challenges in genotyping them on a genome-wide scale in large cohorts. Here we identified 171,233 high-quality, genome-wide SVs from 482 haplotype-resolved genome assemblies derived from PacBio HiFi long-read sequencing of 241 individuals. We developed a reference panel and a web application (ImputeSV) to impute these SVs from single-nucleotide polymorphism (SNP) data and demonstrated high imputation accuracy at both the individual and cohort levels. Using this tool, we imputed 54,578 common SVs (minor allele frequencies (MAFs) ≥1%) in 456,643 UK Biobank (UKB) participants of European ancestry. Through analysis of UKB data and simulations, we estimated that SVs contributed to at least 4.7% of the common genetic variation for complex traits. Genome-wide association analyses of SVs for 2,624 UKB traits identified 17,335 SV-trait associations, including 958 unlikely to be driven by small genetic variants. Our study demonstrates the power of using long-read assemblies for imputing SVs from SNPs, unveils the role of SVs in complex trait variation and provides a catalog of SV associations in the UKB.

DOI: https://doi.org/10.1038/s41588-026-02612-z

Nat Genet. 2026 May 20.

Non-Mendelian inheritance of DNA methylation patterns in mice.

Adam Davidovich, Danila Cuomo, Hang Su, Sandeep Kambhampati, Qingqing Gong, Alexandra Naron, Rakel Tryggvadottir, Leonard McMillan, Kasper D Hansen, David W Threadgill, Andrew P Feinberg.

Epigenetic mechanisms such as genomic imprinting demonstrate that molecular inheritance can deviate from typical Mendelian patterns. Despite this, the intergenerational inheritance of DNA methylation remains poorly understood. Here we developed a genome-wide approach to study epigenetic inheritance in mice using long-read nanopore sequencing. Using this approach in both liver and muscle, we found that ~93% of autosomal epigenetic inheritance patterns followed Mendel's laws, primarily driven by cis-acting methylation quantitative trait loci. However, we also identified extensive non-Mendelian inheritance, including emergent epigenetic inheritance patterns, widespread sex-specific DNA methylation patterns localized to the liver, and five seemingly new autosomal and X-linked imprinted genes. Notably, we also report an example of naturally occurring intergenerational paramutation, confirmed over strain-specific transposable elements within Capn11 and highly likely at Vps37c. Overall, an unexpectedly high ~7% of autosomal epigenetic inheritance patterns identified were non-Mendelian, highlighting the importance of epigenetic information in the analysis of inherited traits and disorders.

DOI: https://doi.org/10.1038/s41588-026-02604-z

Autophagy. 2026 May 19.

Feedback loops between DNMT1 and autophagy as well as senescence promotes organ aging and canities.

Lu Li, Xinyue Mao, Linda Xiaoyan Li, Huaping Xiao, Zhenkun Lou, Hongbo Liu, Julie Xia Zhou, Li Yao, Xiaogang Li.

Alternations of DNA methylation occur in aging, which is regulated by DNA methyltransferases (DNMTs). In this study, we show that even though the transcription of DNMT1, the only enzyme that maintains DNA methylation in the mammalian genome, is reported to be decreased in an age-dependent manner, the decrease of Dnmt1 mRNA does not result in a decrease of its protein. Instead, DNMT1 protein is increased in aged mouse tissues, which is responsible for the methylation of genes related to macroautophagy/autophagy, senescence repression, and melanin synthesis and transport in aged organs, resulting in a decline of autophagy, an increase of senescence in those organs, and a decrease in melanin production in hair follicles (canities) in response to ionizing radiation (IR). Genetic deletion and inhibition of DNMT1 can reverse these processes. The interaction of DNMT1 with ATG7 through its CXXC domain is essential for its degradation, and treatment with senolytics also downregulates DNMT1 in aged organs, supporting two feedback loops between them.

Keywords: ATG7; DNA methylation; hair graying; long-lived; melanin synthesis; senolytics

DOI: https://doi.org/10.1080/15548627.2026.2677185