Journal Article

Genetic identification of leptin neural circuits in energy and glucose homeostases

Yi, Xinchi, Wang, Peng, Xu, Jie, Bartolome, Christopher L., Low, Cho Shing, Kong, Dong, Chien, Cheng-Hao

2018

Overview

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 . Dysregulation of leptin or its receptors (LEPR) results 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 , 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 Lepr db/db mice, suggesting that AGRP or POMC neurons are not directly required for the effects of leptin in vivo 8 – 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 Lepr db/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. A subset of neurons in the hypothalamus is identified as the primary site of action for regulating energy balance and glucose homeostasis by leptin.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
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