Glucose-sensing glucagon-like peptide-1 receptor neurons in the dorsomedial hypothalamus regulate glucose metabolism

  • Sci Adv. 2022 Jun 10;8(23):eabn5345. doi: 10.1126/sciadv.abn5345.
Zhaohuan Huang  1  2 ,  Ling Liu  1  2 ,  Jian Zhang  3 ,  Kristie Conde  4  5 ,  Jay Phansalkar  4  5 ,  Zhongzhong Li  1 ,  Lei Yao  3 ,  Zihui Xu  4  5 ,  Wei Wang  6 ,  Jiangning Zhou  3 ,  Guoqiang Bi  2  3 ,  Feng Wu  1  2 ,  Randy J Seeley  7 ,  Michael M Scott  8 ,  Cheng Zhan  9  10  11 ,  Zhiping P Pang  4  5 ,  Ji Liu  1  2  3
Affiliations
  • 1. National Engineering Laboratory for Brain-inspired Intelligence Technology and Application, School of Information Science and Technology, University of Science and Technology of China, Anhui, China.
  • 2. Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China.
  • 3. CAS Key Laboratory of Brain Function and Diseases, Life Science School, University of Science and Technology of China, Anhui, China.
  • 4. Child Health Institute of New Jersey, Rutgers University Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
  • 5. Department of Neuroscience and Cell Biology, Rutgers University Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
  • 6. Department of Endocrinology and Laboratory for Diabetes, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui, China.
  • 7. Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
  • 8. Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
  • 9. Department of Hematology, The First Affiliated Hospital, Life Science School, University of Science and Technology of China, Anhui, China.
  • 10. National Institute of Biological Sciences, Beijing 102206, China.
  • 11. Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 100084, China.
PMID: 35675406 DOI: 10.1126/sciadv.abn5345
Abstract

Glucagon-like peptide-1 (GLP-1) regulates energy homeostasis via activation of the GLP-1 receptors (GLP-1Rs) in the central nervous system. However, the mechanism by which the central GLP-1 signal controls blood glucose levels, especially in different nutrient states, remains unclear. Here, we defined a population of glucose-sensing GLP-1R neurons in the dorsomedial hypothalamic nucleus (DMH), by which endogenous GLP-1 decreases glucose levels via the cross-talk between the hypothalamus and pancreas. Specifically, we illustrated the sufficiency and necessity of DMHGLP-1R in glucose regulation. The activation of the DMHGLP-1R neurons is mediated by a cAMP-PKA-dependent inhibition of a delayed rectifier potassium current. We also dissected a descending control of DMHGLP-1R -dorsal motor nucleus of the vagus nerve (DMV)-pancreas activity that can regulate glucose levels by increasing Insulin release. Thus, our results illustrate how central GLP-1 action in the DMH can induce a nutrient state-dependent reduction in blood glucose level.

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