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Genetic identification of leptin neural circuits in energy and glucose homeostases

Author

Listed:
  • Jie Xu

    (Tufts University School of Medicine)

  • Christopher L. Bartolome

    (Tufts University School of Medicine
    Tufts University Sackler School of Graduate Biomedical Sciences)

  • Cho Shing Low

    (Tufts University School of Medicine
    Tufts University Sackler School of Graduate Biomedical Sciences)

  • Xinchi Yi

    (Tufts University School of Medicine)

  • Cheng-Hao Chien

    (Tufts University School of Medicine)

  • Peng Wang

    (Tufts University School of Medicine)

  • Dong Kong

    (Tufts University School of Medicine
    Tufts University Sackler School of Graduate Biomedical Sciences
    Tufts University Sackler School of Graduate Biomedical Sciences)

Abstract

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 diabetes3–5. 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 vivo8–10. 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.

Suggested Citation

  • Jie Xu & Christopher L. Bartolome & Cho Shing Low & Xinchi Yi & Cheng-Hao Chien & Peng Wang & Dong Kong, 2018. "Genetic identification of leptin neural circuits in energy and glucose homeostases," Nature, Nature, vol. 556(7702), pages 505-509, April.
  • Handle: RePEc:nat:nature:v:556:y:2018:i:7702:d:10.1038_s41586-018-0049-7
    DOI: 10.1038/s41586-018-0049-7
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    Cited by:

    1. Yi Huang & Anyongqi Wang & Wenjiang Zhou & Baoguo Li & Linshan Zhang & Agata M. Rudolf & Zengguang Jin & Catherine Hambly & Guanlin Wang & John R. Speakman, 2024. "Maternal dietary fat during lactation shapes single nucleus transcriptomic profile of postnatal offspring hypothalamus in a sexually dimorphic manner in mice," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Sheng Qiu & Qinan Wu & Hao Wang & Dongfang Liu & Chen Chen & Zhiming Zhu & Hongting Zheng & Gangyi Yang & Ling Li & Mengliu Yang, 2024. "AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Myung Chung & Katsutoshi Imanaka & Ziyan Huang & Akiyuki Watarai & Mu-Yun Wang & Kentaro Tao & Hirotaka Ejima & Tomomi Aida & Guoping Feng & Teruhiro Okuyama, 2024. "Conditional knockout of Shank3 in the ventral CA1 by quantitative in vivo genome-editing impairs social memory in mice," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Frankie D. Heyward & Nan Liu & Christopher Jacobs & Natalia L. S. Machado & Rachael Ivison & Aykut Uner & Harini Srinivasan & Suraj J. Patel & Anton Gulko & Tyler Sermersheim & Linus Tsai & Evan D. Ro, 2024. "AgRP neuron cis-regulatory analysis across hunger states reveals that IRF3 mediates leptin’s acute effects," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Hongli Li & Yuanzhong Xu & Yanyan Jiang & Zhiying Jiang & Joshua Otiz-Guzman & Jessie C. Morrill & Jing Cai & Zhengmei Mao & Yong Xu & Benjamin R. Arenkiel & Cheng Huang & Qingchun Tong, 2023. "The melanocortin action is biased toward protection from weight loss in mice," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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