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

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.