bims-obesme 2026-11-08 papers

Issue of 2026–11–08
five papers selected by
Xiong Weng, University of Edinburgh

Cell Metab. 2026 Nov 03. pii: S1550-4131(26)00442-0. [Epub ahead of print]38(11): 2178-2198

Beyond singular effectors: The futile creatine cycle from molecular mechanism to integrated adipocyte thermogenesis.

Mohammed Faiz Hussain, Mina Ersin, Maria Delgado-Martin, Lawrence Kazak.

The discovery of uncoupling protein 1 (UCP1) established regulated mitochondrial proton leak as the canonical mechanism of adaptive thermogenesis. Yet, foundational studies showed that thermogenic activation can increase proton leak without fully dissipating the protonmotive force, providing a bioenergetic basis for ATP-dependent heat production through futile cycles involving creatine, lipids, and calcium. We focus on the futile creatine cycle (FCC), whose effectors, activation mechanism, structural regulation, and physiological function have been defined. Selective loss-of-function, reconstitution, and genetic interaction studies have established its contribution to thermogenesis and parallel action with UCP1. Such approaches determine whether disrupting a pathway reduces thermogenesis, whether restoring it recovers function, and how its contribution depends on other pathways. They establish physiological relevance beyond what maximal respiratory rates in reductionist systems alone can reveal. The FCC thus offers a reference point for connecting the biochemical mechanisms of other thermogenic cycles to their physiological contributions.

Keywords: UCP1-independent; adipose tissue; allosteric regulation; creatine; creatine kinase; futile cycle; genetics; oxidative phosphorylation; thermogenesis; tissue-nonspecific alkaline phosphatase

DOI: https://doi.org/10.1016/j.cmet.2026.10.005

Exp Mol Med. 2026 Nov 04.

IDH2 links mitochondrial α-ketoglutarate to epigenetic thermogenic activation in brown adipose tissue.

Soo-Young Park, Min-Hee Seo, Sulagna Mukherjee, Yong Hyun Jeon, Dae-Kyu Song, Byung-Chul Oh, Juro Sakai, Timothy F Osborne, Hye Ra Jung, Chang Hwa Jung, Jae-Ho Lee, Seung-Soon Im.

Brown adipose tissue (BAT) regulates energy expenditure, influencing metabolic health. This study aimed to highlight the role of isocitrate dehydrogenase 2 (IDH2), a mitochondrial enzyme essential for alpha-ketoglutarate (α-KG) production, in BAT differentiation and function. In global and BAT-specific IDH2 knockout (KO) mice, cold exposure reduced thermogenesis, induced BAT whitening, and abolished the cold-dependent induction of thermogenesis by reducing the expressions of key thermogenic genes. Lower α-KG levels in IDH2 KO BAT, a key cofactor for TET2-mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine in genomic DNA, decreased the nuclear factor erythroid-2-related factor 2 (NRF2)-dependent induction of BAT-enriched lncRNA 10 (lncBATE10). Reduced induction of thermogenesis in IDH2-deficient BAT impaired energy balance. α-KG supplementation partially restored TET2 function and thermogenic gene expression in IDH2 KO mice, indicating that IDH2-dependent α-KG production is an important contributor to the thermogenic response during cold exposure. Our study uncovers a previously unrecognized novel mechanism involving the IDH2-TET2-Nrf2-lncBATE10 regulatory axis, linking mitochondrial function to epigenetic BAT regulation.

DOI: https://doi.org/10.1038/s12276-026-01877-y

Nat Genet. 2026 Nov 03.

A framework for genome-wide characterization of DNA methylation and variant effect prediction.

Weiguang Mao, Kathleen M Chen, Christopher Y Park, Chandra L Theesfeld, Olga G Troyanskaya.

DNA methylation plays a critical role in many essential biological processes, including transcriptional regulation, genomic imprinting, chromosomal maintenance, genomic stability and development, and has phenotypic and disease impacts. However, genome-wide characterization of methylation patterns across cell types and tissues remains a major challenge. Here, to address this, we present a framework that enables systematic genome-wide analysis of methylation and sequence-based prediction of context-specific methylation effects of variants. Our data-driven discovery of methylation classes reveals context-dependent roles for methylation across tissues, cell types and regions of the genome. The framework also includes Wreath, a deep learning-based sequence model specifically designed to accurately predict the context-dependent impact of any genetic variant on methylation. These developments leverage a compendium that harmonizes disparate methylation profiles from disparate studies including over 90 tissues and cell types. Using Wreath, we systematically characterized the impact of noncoding pathogenic variants on tissue-specific methylation, generating mechanistic hypotheses for individual regulatory variants. We make the full framework, including the compendium, the methylation classes and the model, available for use by the community.

DOI: https://doi.org/10.1038/s41588-026-02807-4

Curr Med Sci. 2026 Oct 29.

Intervening in Adipocyte Senescence: Lipid Prodrugs as an Emerging Strategy for Metabolic Disease Treatment.

Xin-Ying Mo, Dan Huang, Si-Fei Han, Guang-Jie Tai, Ming Xu.

The accelerating aging of the global population has made aging and its related diseases major public health challenges in the 21st century. Adipose tissue is not only an energy reservoir but also a crucial endocrine organ and metabolic regulator. Its dysfunction is closely linked to aging and the development of multiple diseases. This review outlines the key characteristics of adipocyte senescence and discusses its pathological contributions to obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular diseases. It also summarizes current intervention strategies for adipocyte senescence, including senolytics, senomorphics, caloric restriction, physical exercise, and gene editing. We propose lipid prodrugs as promising adipose tissue delivery platforms that can be coupled with diverse therapeutic agents to increase the local concentration of drugs and minimize systemic toxicity. By utilizing the unique lipid metabolism of adipocytes, this strategy offers a new avenue for therapeutic intervention in adipocyte senescence and its associated metabolic disorders.

Keywords: Adipocyte senescence; Aging; Lipid prodrug delivery; Metabolic diseases; Obesity; Type 2 diabetes

DOI: https://doi.org/10.1007/s11596-026-00251-3

Nat Genet. 2026 Nov 02.

A catalog of transcriptome genetic regulation in a consanguineous Middle Eastern biobank.

Ancestry-specific genetic mapping of transcriptome regulation is pivotal for understanding genome function, especially in underrepresented consanguineous populations. Here we characterized 1,882 Qatar Biobank participants, integrating blood RNA sequencing, whole-genome sequencing and phenotypic data across 45 clinically relevant traits. We cataloged ~7 million significant quantitative trait loci (QTLs), both short and structural variants, impacting gene expression, isoform usage, splicing and allele-specific expression, uncovering 1,379 novel eGenes. Fine-mapping resolved 29,953 high-confidence, independent causal loci including 24% previously unreported as well as those with effect alleles showing significant divergence across global populations, while 1,371 were absent from public databases. Leveraging elevated autozygosity, we found that causal variants are depleted from runs of homozygosity, consistent with purifying selection, while recent autozygosity increased the burden of homozygous regulatory variants. We identified QTLs with recessive deleterious effects on 10 Mendelian disease genes and homozygous QTLs causing extreme outlier expression in 66 genes including dosage-sensitive ones. Colocalization analysis revealed 58 causal variants acting on 20 clinically relevant phenotypes, implicating novel genes including ATP6V0B and RQCD1 in metabolic and blood disorders. These findings establish this QTL catalog as a valuable Middle Eastern resource for genome interpretation and genomic medicine.

DOI: https://doi.org/10.1038/s41588-026-02785-7