Genetic identification of leptin neural circuits in energy and glucose homeostases

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 stability(1,2). Dysregulations of leptin or its receptors (LepR) result in severe obesity and diabetes(3–5). Although intensive studies on leptin have transformed obesity and diabetes research(2,6), clinical applications of the molecule are still limited(7) which, at least in part, is due to the complexity and our incomplete understanding of the underlying neural circuits. The hypothalamic neurons expressing agouti-related peptide (AgRP) and proopiomelanocortin (POMC) were posited as the first-order leptin-responsive neurons. Selective deletion of LepR in these neurons with Cre-loxP system, however, failed to or marginally recapitulated obesity and diabetes in LepR-deficient Lepr(db/db) mice, suggesting that AgRP or POMC neurons are not directly required(8–10). The primary neural targets for leptin are thus still unclear. Here, we conduct a systematic, unbiased survey of leptin-responsive neurons in streptozotocin (STZ)-induced diabetic mice and exploit CRISPR/Cas9-mediated genetic ablation of LepR in vivo. Unexpectedly, we find that AgRP neurons but not POMC neurons integrate the primary action of leptin to regulate both energy balance and glucose homeostasis. Leptin deficiency disinhibits AgRP neurons, and their chemogenetic inhibition reverses both diabetic hyperphagia and hyperglycemia. In sharp contrast with prior studies, we show that CRISPR-mediated deletion of LepR in AgRP neurons causes severe obesity and diabetes, fatefully replicating the phenotype of Lepr(db/db) mice. We also uncover divergent mechanisms underlying leptin’s acute and chronic inhibition of AgRP neurons (i.e., presynaptic potentiation of GABAergic neurotransmission and postsynaptic activation of ATP-sensitive potassium channels, respectively). Our findings provide the framework underlying the neurobiological mechanisms of leptin and associated metabolic disorders.