bims-ciryme 2026-10-04 papers

Science. 2026 Oct;394(6819): eadz4797

Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling.

Iuliia Karavaeva, Astrid Linde Basse, Samuel A J Trammell, Mohammed Faiz Hussain, Lasse Kruse Markussen, Jesper F Havelund, Marie Sophie Isidor, Adam Chatoff, Andrea Andress Huacachino, Hannah J Richter, Meghna Birla, Sabina Chubanava, Yann Deleye, Rini Arianti, David Tandio, Sarah E Utzon, Zafir Kaiser, Yachen Shen, Ditte Neess, Hannes Embring, Dilip Menon, Olivia J Conway, Frederike Sass, Fabian Finger, Lidia Argemi-Muntadas, Tao Ma, Elahu G Sustarsic, Cecilie Kynding Kristensen, Rebecca L McIntyre, Genesee J Martinez, Anna Sofie Husted, Matthew J Emmett, Zachary A Kipp, Mikkel Frost, Mark P Jedrychowski, Michel van Weeghel, Homa Majd, Ekaterina Zhuravleva, Robert W McGarrah, Kaja Plucińska, Mohit K Midha, Andreas Prokesch, Paul Cohen, James G Granneman, Patrick Seale, Riekelt H Houtkooper, Jacob B Hansen, Steven P Gygi, Thue W Schwartz, Matthew P Gillum, Terry D Hinds, Raymond E Soccio, Phillip J White, Edmund R S Kunji, Thomas Moritz, Jonas T Treebak, Endre Kristóf, Susanne Mandrup, Brice Emanuelli, Nathaniel W Snyder, Daniel J Fazakerley, Lawrence Kazak, Nils J Færgeman, Mitchell A Lazar, Zachary Gerhart-Hines.

Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature, but how these diverse signals are molecularly integrated remains unknown. We showed that these cues converge on the orphan mitochondrial transporter SLC25A34 to orchestrate lipid cycling. During the sleep phase, the adipocyte clock suppresses Slc25a34 expression through the REV-ERB transcriptional repressors. Entering the active phase, consuming lipid-rich diets, or exposure to cold abolishes REV-ERB repression, and lipolytic signals stimulate Slc25a34 transcription through the peroxisome proliferator-activated receptors. SLC25A34 is proposed to import oxaloacetate into mitochondria, dually supporting the tricarboxylic acid cycle and cytosolic acetyl-coenzyme A (acetyl-CoA) production. Elevated cytosolic acetyl-CoA then fuels the synthesis of lipids and promotes the transcription of genes enhancing mitochondrial oxidation. Thus, SLC25A34 confers circadian, dietary, and temperature control of adipocyte lipid metabolism.

DOI: https://doi.org/10.1126/science.adz4797

Mol Ecol. 2026 Oct;35(19): e70554

Natural Variation in Drosophila melanogaster Clock PolyQ Length: Geographic Gradients and Functional Properties.

Maya Yair, Bettina Fishman, Martin Kapun, Eran Tauber.

Natural variation in circadian clock genes provides a powerful framework for understanding how organisms respond to environmental heterogeneity. The Clock (Clk) gene encodes a core transcriptional regulator of circadian rhythms and contains a polymorphic polyglutamine (polyQ) tract whose evolutionary significance remains unclear. Here, we integrate population genomic, behavioural, and molecular analyses to investigate the functional and geographic patterns of Clk polyQ variation in Drosophila melanogaster. Using data from 127 European populations, we identify 11 Clk polyQ alleles and find that their frequencies are geographically structured, most consistently along an east-west gradient: the Q25 and Q27 alleles show robust clines in longitude and in a bioclimatic axis of continentality, whereas latitudinal and altitudinal trends are weaker. Behavioural assays of near-isogenic lines revealed that polyQ length modulates circadian function under thermal challenge: most alleles maintained stable free-running periods across temperatures, whereas the intermediate-length Q25 allele showed the strongest, though modest, temperature sensitivity. Circadian phase showed pronounced allele-specific sensitivity to elevated temperature in laboratory assays, although phase variation did not display a consistent relationship with geographic variables. At the molecular level, luciferase reporter assays showed that longer polyQ alleles exhibited higher transcriptional activity, linking polyQ length to CLK-mediated gene expression. Together, these results demonstrate that natural variation in Clk polyQ length has measurable functional consequences for circadian regulation and is geographically structured in patterns consistent with underlying climatic variation, highlighting the potential for low-complexity regions to modulate clock function in a context-dependent manner across environmental gradients.

Keywords: Drosophila melanogaster ; Clock gene; circadian rhythm; climatic adaptation; geographic cline; natural variation; polyglutamine polymorphism; temperature compensation

DOI: https://doi.org/10.1111/mec.70554

Nat Commun. 2026 08 31. pii: 10342. [Epub ahead of print]17(1):

Single-cell profiling identifies obesity-disrupted brain glucose sensing.

Jenny M Brown, Marie A Bentsen, Anja Moltke Jørgensen, Thomas Svava Nielsen, Dylan M Belmont-Rausch, Din Selmanovic, Oksana Dmytriyeva, Charlotte Høy Kruse, Nadia N Aalling, Dana C Schwalbe, Oliver Knights Møller, John N Campbell, Anna Secher, Michael W Schwartz, Tune H Pers.

Neuronal nutrient sensing in the hypothalamus and brainstem is thought to regulate energy and glucose homeostasis, yet how these brain regions respond to elevated adiposity or blood glucose remains unclear. We performed single-nucleus RNA-sequencing on 75,787 cells from the arcuate nucleus, ventromedial hypothalamus, and dorsal vagal complex of control diet- and high-fat diet (HFD)-fed male mice following intravenous glucose or saline infusion. HFD broadly altered gene expression across cell types, including Th/Slc6a3, Agrp, Ghrh, and Trh/Cxcl12 neurons. In control diet-fed mice, hyperglycemia triggered transcriptional responses conserved across brain regions in astrocytes and oligodendrocytes, and a response in Ghrh neurons, consistent with reduced neuronal activity. The transcriptional responses to hyperglycemia were largely absent or reversed after HFD. Genes enriched in both mouse and human GHRH neurons were located in loci genetically linked to human glycemic traits. These findings point to the brain's intrinsic capacity to sense hyperglycemia and suggest that this detection system is profoundly impaired in obesity.

DOI: https://doi.org/10.1038/s41467-026-77116-9

EMBO Rep. 2026 Sep 30.

FBXL21 regulates diurnal proteostasis in skeletal muscle by targeting DNAJB6 and client proteins.

Ji Ye Lim, Jaebok Wi, Marvin Wirianto, Chorong Han, Sun Young Kim, Jane Nguyen, Sehyun Jung, Kristin Eckel-Mahan, Sung Yun Jung, Karyn A Esser, Zheng Chen, Seung-Hee Yoo.

Circadian regulation of proteostasis, a key determinant of muscle health, remains poorly understood. Here, we identify DNAJB6, an Hsp40 (DnaJ) co-chaperone, as a substrate of the circadian E3 ligase FBXL21. FBXL21 mediates the ubiquitination-dependent proteasomal degradation of both DNAJB6 and its client proteins, including Desmin. In contrast, myopathy-causing mutations of DNAJB6 confer resistance to FBXL21-directed degradation. Fbxl21 KO C2C12 cells display aberrant Desmin accumulation, and show aggravated cytoplasmic accumulation of TDP-43, another DNAJB6 client protein, in response to heat shock. Under timed exercise as a physiological stressor, WT mice display robust diurnal rhythms in the levels of stress granule markers (G3BP1 and FUS) and TDP-43 as a function of exercise timing. In contrast, the Fbxl21 hypomorph Psttm mutant mice show elevated expression of these proteins without exercise, which is exacerbated under exercise-induced stress conditions. Importantly, these abnormalities are rescued by skeletal muscle-specific FBXL21 expression. Our study elucidates a novel diurnal regulatory mechanism of skeletal muscle proteostasis via FBXL21 as a chaperone-linked E3 ligase, highlighting the FBXL21-DNAJB6 axis as a potential therapeutic target for myopathies.

DOI: https://doi.org/10.1038/s44319-026-00922-1