The endocrine system is a key regulator of uncoupling protein (UCP) abundance and function through the life cycle and is particularly important at birth. Cortisol, leptin and tri-iodothyronine (T₃), appear to differentially regulate UCPs in large and small mammals. The regulation of UCPs by these hormones during the transition from fetal to neonatal life is crucial for survival. Adrenalectomised fetal sheep have reduced UCP1 protein in brown adipose tissue (BAT); conversely cortisol infusion raises UCP1. The manipulation of fetal plasma cortisol also causes parallel changes in plasma T₃, both of which are positively related to UCP1 abundance. This suggests that an intact adrenal gland is essential for the up-regulation of UCP1 at birth, due to cortisol in combination with T₃. Postnatally, cortisol, leptin and T₃ decline rapidly, an adaptation followed by the loss of UCP1. Rodent studies demonstrate that leptin administration increases body temperature and UCP1 activity. Acute or chronic leptin administration to young sheep causes maintenance of body temperature and loss of UCP1 as well as tissue specific effects on UCP2 expression in the pancreas and lung. Acute leptin administration decreases UCP2, whereas chronic administration has the opposite effect in BAT. Chronic administration of T₃ or a b3 adrenoceptor (ZD) agonist to piglets demonstrates genotype specific responses in subcutaneous AT with T₃ reducing UCP3 and ZD increasing UCP2 with no effect on UCP3 thereby contrasting with rodent studies. The divergent responses of UCPs to endocrine mediators between species and ages suggest a varied role in promoting normal temperature regulation, metabolism and development.