An infrared thermal image of two mouse littermates following CRISPR-mediated genome editing of leptin signaling reveals surprises. Leptin, a fat hormone identified over 20 years ago, acts in the brain to maintain body weight and blood glucose balance, preventing the development of both obesity and diabetes. Despite years of study, clinical treatment of metabolic diseases with leptin is still limited due to incomplete understanding of leptin's signaling in the brain. Neuroscientists at Tufts University School of Medicine exploited CRISPR technology and performed a series of experiments to map the neural circuitry of leptin in mice. Surprisingly, they found that genetic disruption of leptin receptors in the hypothalamic AgRP neurons -- a group of neurons widely regarded as inessential for leptin's direct effects based on earlier research -- caused severe obesity and diabetes in those mice (top) compared with their control littermates (bottom). This discovery suggests that AgRP neurons are in fact the primary target of leptin to regulate body weight and blood glucose in the brain. The research also revealed distinct complex mechanisms underlying leptin's regulation of AgRP neurons, by promoting presynaptic GABA release and by opening postsynaptic ATP-sensitive potassium channels. The research, published in the journal Nature on April 18, 2018, online in advance of print, will support future work to develop therapies for obesity and diabetes.