bims-ciryme Biomed News
on Circadian rhythms and metabolism
Issue of 2025–08–03
two papers selected by
Gabriela Da Silva Xavier, University of Birmingham
  1. Rare variants in BMAL1 are associated with a neurodevelopmental syndrome.
  2. Regulation of hedonic feeding rhythms by circadian clocks in leptin-receptive neurons.
  1. Proc Natl Acad Sci U S A. 2025 Aug 05. 122(31): e2427085122
    Rare variants in BMAL1 are associated with a neurodevelopmental syndrome.
    Vishnu Anand Cuddapah, Dechun Chen, Bumsik Cho, Rebecca Moore, Mohnish Suri, Hana Safraou, Frederic Tran-Mau-Them, Ashley Wilson, Jacqueline Odgis, Atteeq U Rehman, Carol Saunders, Shiva Ganesan, Vaidehi Jobanputra, Stephen W Scherer, Ingo Helbig, Amita Sehgal.
      Through international gene-matching efforts, we identified 10 individuals with ultrarare heterozygous variants, including 5 de novo variants, in BMAL1, a core component of the molecular clock. Instead of an isolated circadian phenotype seen with disease-causing variants in other molecular clock genes, all individuals carrying BMAL1 variants surprisingly share a clinical syndrome manifest as developmental delay and autism spectrum disorder, with variably penetrant sleep disturbances, seizures, and marfanoid habitus. Variants were functionally tested in cultured cells using a Per2-promoter driven luciferase reporter and revealed both loss-of-function and gain-of-function changes in circadian rhythms. The tested BMAL1 variants disrupted PER2 mRNA cycling, but did not cause significant shifts in cellular localization or binding with CLOCK. Conserved variants were further tested in Drosophila, which confirmed variant-dependent effects on behavioral rhythms. Remarkably, flies expressing variant cycle, the ortholog of BMAL1, also demonstrated deficits in short- and long-term memory, reminiscent of the highly prevalent developmental delay observed in our cohort. We suggest that ultrarare variants in the BMAL1 core clock gene contribute to a neurodevelopmental disorder.
    Keywords:  BMAL1; Drosophila; circadian rhythms; developmental delay; neurodevelopmental disorder
    DOI:  https://doi.org/10.1073/pnas.2427085122
  2. Mol Metab. 2025 Jul 24. pii: S2212-8778(25)00128-0. [Epub ahead of print] 102221
    Regulation of hedonic feeding rhythms by circadian clocks in leptin-receptive neurons.
    Jazmin Osorio-Mendoza, Jana-Thabea Kiehn, Sarah Stenger, Keno O Heinen, Laura Griewahn, Christiane E Koch, Undine Haferkamp, Violetta Pilorz, Johanna L Barclay, Parth Joshi, Lisbeth Harder, Olaf Jöhren, Peter Kühnen, Gregor Eichele, Henrik Oster.
      The circadian clock anticipates daily repetitive events to adapt physiological processes. In mammals, the circadian system consists of a master clock in the suprachiasmatic nucleus (SCN), which synchronizes subordinate tissue clocks, including extra-SCN central nervous system (CNS) clocks involved in functions such as sleep and appetite regulation. Appetite is controlled by both homeostatic and non-homeostatic (hedonic) circuits. Homeostatic appetite addresses energy needs, while hedonic feeding targets cravings for palatable, calorie-dense foods. The adipokine leptin is a major appetite regulator, interacting with the circadian clock. Although leptin's role in satiation through its action in the mediobasal hypothalamus (MBH) is well established, its involvement in the circadian regulation of feeding remains poorly understood. We hypothesized that circadian gating of leptin signaling in the CNS controls homeostatic and hedonic appetite across the day. To test this, we analyzed food intake rhythms in mice with a loss of leptin (ob/ob mice) or clock function (Per1/2 or Bmal1 KO) and in mice with specific disruption of leptin circadian gating in the CNS (ObRb.Bmal1). We found that in leptin-deficient mice hedonic appetite increases specifically in the early rest phase. In contrast, clock-deficient Per1/2 mutant mice exhibit blunted rhythms in both hedonic and homeostatic appetite control. Finally, when clock function is disrupted in leptin-sensitive neurons only, mice display a lower sensitivity to palatable food, along with reduced initial weight gain and adipose hypertrophy under obesogenic diet conditions. Together, our data describe a local clock-controlled central leptin gating mechanism that modulates hedonic food intake rhythms and impacts metabolic homeostasis.
    Keywords:  circadian clock; feeding rhythms; hedonic appetite; leptin receptor
    DOI:  https://doi.org/10.1016/j.molmet.2025.102221
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