Cereblon regulates food intake by suppressing SIM1/ARNT2 action in the paraventricular nucleus of the hypothalamus

Cereblon regulates food intake by suppressing SIM1/ARNT2 action in the paraventricular nucleus of the hypothalamus | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Cereblon regulates food intake by suppressing SIM1/ARNT2 action in the paraventricular nucleus of the hypothalamus Jaemin Lee, Soojeong Kim, Doo Kyung Kim, Gülcan Kartal, Seho Jeong, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9206791/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Hypothalamic circuits maintain body weight by coordinating energy intake and expenditure. We identify CRBN, a substrate receptor of the CUL4A E3 ubiquitin ligase complex, as a central regulator of feeding within the paraventricular nucleus (PVN). Genetic deletion or pharmacological inhibition of CRBN reduced food intake and weight gain under high-fat feeding, phenotypes recapitulated by neural but not adipose-specific deletion. CRBN is enriched in Sim1-expressing PVN neurons, where gain-of-function promotes hyperphagia and loss-of-function suppresses feeding. Mechanistically, CRBN interacts with the SIM1/ARNT2 transcriptional complex, promoting its ubiquitination and degradation, thereby limiting anorexigenic transcriptional activity, which was reversed by thalidomide. CRBN inhibition alleviated hyperphagic obesity in Sim1 haploinsufficient mice. Comparative transcriptomic analysis revealed opposing gene-set enrichment profiles in Crbn knockout and Sim1 heterozygous PVNs, supporting CRBN as a nutrient-responsive negative regulator of SIM1/ARNT2 signaling. These findings establish a CRBN-dependent axis linking nutritional excess to hypothalamic control of appetite. Biological sciences/Physiology/Metabolism/Feeding behaviour/Hypothalamus Biological sciences/Physiology/Metabolism/Feeding behaviour/Obesity Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Supplementaryinformation.pdf Supplementary Information Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9206791","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":611417254,"identity":"aaa6cf6a-d3a5-4b1b-910a-b0e9ce9ec2ee","order_by":0,"name":"Jaemin 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