Leptin, a hormone produced in white adipose tissue, acts in the brain to maintain body weight and blood glucose stability. Dysregulation of leptin or its receptor (LEPR) results in severe obesity and diabetes. Although intensive studies on leptin have transformed obesity and diabetes research, clinical applications of the molecule are still limited, at least in part owing to the complexity and our incomplete understanding of the underlying neural circuits. In our previous findings, we found that the hypothalamic AgRP(agouti-related peptide) neurons are the primary target for leptin to regulate both energy balance and glucose homeostasis. We show that CRISPR-mediated deletion of leptin receptor in AgRP neurons causes severe obesity and diabetes. 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 (Katp), respectively). However, the molecular signaling involved in leptin's regulation on Katp and GABA transmission are not clear. In current study, we employed the CRISPR technology, combined with electrophysiology to further identify that the Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway plays an important role in mediating leptin's action on GABA transmission. We also tested that leptin can directly activate KATP channel and by using two-photon excitation microscopy, we proved that this activation is modulated by ATP/ADP ratio.


J. Xu: None. C. Chien: None. X. Yi: None. C. Bartolome: None. D. Kong: Board Member; Spouse/Partner; Jersey Biosciences Inc. Board Member; Self; PRECIDIAG INC.


American Diabetes Association (1-19-PDF-159-R to J.X.)

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