Notch directly controls adult thyroid cell identity and function to regulate important aspects of whole-body metabolism Lluc Mosteiro, Chris Siebel Department of Discovery Oncology, Genentech (San Francisco, USA) The conserved Notch signaling pathway regulates cell fate decisions during development. Notch also regulates cell fate in adult tissues, for example through transdifferentiation of airway cells or by directing the differentiation fates of intestinal progenitors. We observed that mice treated with blocking antibodies targeting the Notch ligands JAG1 and JAG2 suffer extreme and rapid weight loss-without the intestinal goblet cell metaplasia previously associated with pan-Notch inhibition. Hypothesizing that one or more Notch-controlled cell fate switches might be the root cause of this observation, we found that Notch inhibition induces metabolic defects orchestrated by the thyroid. Notch blockade in adult mice induces hypothyroidism and reduces thyrocyte marker expression. The thyroid changes trigger hyperactivation of brown adipose tissue, which unexpectedly occurs with decreased body temperature and metabolic function. Exogenous administration of thyroid hormones partially rescues anti-JAG1/2-mediated metabolic defects. To ascertain cellular mechanisms in vitro, we discovered that Notch blockade also induces defects in the development of thyroid organoids, in a manner consistent with Notch determining thyroid cell fate. Single-cell transcriptomic studies of thyroids revealed three distinct thyrocyte subpopulations and provide a path to a molecular understanding of Notch-controlled thyroid cell identities. Together, these data support a model in which Notch-dependent control of thyroid cell fate and function induce a cascade of metabolic defects that contribute to the morbidity observed after pan-Notch inhibition, historically attributed to intestinal defects.