Cellular mechanisms of metabolic sensing by human hypothalamic neurons (360G-Wellcome-211221_Z_18_Z)

Obesity is a major public health problem, but its molecular mechanisms are poorly understood, frustrating efforts to develop broadly effective treatments. Obesity is characterised by abnormal energy homeostasis, which is regulated in large part by hypothalamic melanocortin neurons. The activity of melanocortin neurons is in turn regulated by circulating nutrients and hormones (e.g. leptin), but the mechanisms by which they sense and integrate these metabolic signals have been difficult to study using traditional model systems. Functional human melanocortin neurons derived from pluripotent stem cells provide an unprecedented opportunity to illuminate and therapeutically harness the molecular mechanisms by which human melanocortin neurons sense metabolic signals to regulate energy homeostasis. In particular, they enable a detailed characterisation of leptin signalling and direct testing of hypothesised mechanisms of leptin resistance. At a cellular level, the role of primary cilia in sensing and integrating leptin and other metabolic signals can be studied. Third, the synergistic action of different metabolic signals in vitro will be used to predict effective anti-obesity therapies in vivo. Together these studies will shed light on obesity disease mechanisms and facilitate the development of effective anti-obesity treatments.