Leptin, a hormone produced in white adipose tissue, acts in the brain to communicate fuel status, suppress appetite following a meal, promote energy expenditure and maintain blood glucose stability1,2. Dysregulation of leptin or its receptors (LEPR) results in severe obesity and diabetes3,4,5. Although intensive studies on leptin have transformed obesity and diabetes research2,6, clinical applications of the molecule are still limited7, at least in part owing to the complexity and our incomplete understanding of the underlying neural circuits. The hypothalamic neurons that express agouti-related peptide (AGRP) and pro-opiomelanocortin (POMC) have been hypothesized to be the main first-order, leptin-responsive neurons. Selective deletion of LEPR in these neurons with the Cre–loxP system, however, has previously failed to recapitulate, or only marginally recapitulated, the obesity and diabetes that are seen in LEPR-deficient Leprdb/db mice, suggesting that AGRP or POMC neurons are not directly required for the effects of leptin in vivo8,9,10. The primary neural targets of leptin are therefore still unclear. Here we conduct a systematic, unbiased survey of leptin-responsive neurons in streptozotocin-induced diabetic mice and exploit CRISPR–Cas9-mediated genetic ablation of LEPR in vivo. Unexpectedly, we find that AGRP neurons but not POMC neurons are required for the primary action of leptin to regulate both energy balance and glucose homeostasis. Leptin deficiency disinhibits AGRP neurons, and chemogenetic inhibition of these neurons reverses both diabetic hyperphagia and hyperglycaemia. In sharp contrast to previous studies, we show that CRISPR-mediated deletion of LEPR in AGRP neurons causes severe obesity and diabetes, faithfully replicating the phenotype of Leprdb/db mice. We also uncover divergent mechanisms of acute and chronic inhibition of AGRP neurons by leptin (presynaptic potentiation of GABA (γ-aminobutyric acid) neurotransmission and postsynaptic activation of ATP-sensitive potassium channels, respectively). Our findings identify the underlying basis of the neurobiological effects of leptin and associated metabolic disorders.
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We thank all members of the Kong laboratory for helpful discussions and comments on the manuscript; F. Zhang for providing pX330 plasmid and Rosa26-LSL-Cas9-GFP mice; Tufts CNR for confocal imaging (supported by NIH/NINDS P30 NS047243); Boston Children’s Hospital Viral Core for AAV virus packaging (supported by NIH/NEI P30 EY012196-17); the Adipose Tissue Biology and Nutrient Metabolism Core and A. Greenberg for help with body mass and oxygen consumption measurement (supported by NIH/NIDDK P30 DK046200-26); BIDMC-FNL and G. Blackburn for equipment support; and P. Haydon and M. Rios for reading the manuscript. This research is supported by the following grants: to C.L.B., NINDS T32NS061764-09; to C.-H.C., AHA-Postdoctoral Fellowship 17POST33661185; to D.K., NIH/NIDDK K01 DK094943, R01 DK108797, NINDS R21 NS097922, BNORC Transgenic core, BNORC P&F grant, BNORC small grant program (NIDDK P30 DK046200) and Charles Hood Foundation Award.
Nature thanks R. Palmiter and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Current Diabetes Reports (2018)