The Sim1 transcription factor acts as another key regulatory gene of the PVN, encoding a protein that also regulates AVP, TRH, and OT expression, as well as CRH and somatostatin (Michaud et al., 1998). Sim1 knock-out mice show severe loss of AVP, TRH, CRH, OT, and somatostatin neurons and rarely survive to adulthood (Michaud, 2001), while heterozygous mice display early obesity, hyperinsulinemia, hyperphagia, and hyperleptinemia, phenotypes that are associated with PVN neurosecretory neurons (Michaud, 2001). Here, TRH is linked to obesity due to melanocortin 4 receptor deficiency.