Hypothalamic POMC neurons regulate intestinal glucose absorption via a gut-brain circuit

  • Nat Commun. 2026 Jun 11. doi: 10.1038/s41467-026-74170-1.
Hyo Sun Lim  #  1 ,  Se Hee Min  #  2 ,  Hyo Jin Kim  #  3 ,  Chae Beom Park  1 ,  Seong Jun Kim  1 ,  Mun Gyeom Kim  1 ,  Ji Su Kim  1 ,  Jun Young Byun  1 ,  Se Eun Park  1 ,  Myeong Ju Kim  1 ,  So Yeon Jeong  1 ,  Jin A An  2 ,  Seokbeom Seo  3 ,  Joomi Park  3 ,  Yeji Kim  3 ,  Ji Ye Kim  3 ,  Sang Ju Lee  4 ,  Seog-Young Kim  5 ,  Xin Yi Yeo  6 ,  Edra London  7 ,  Jong-Woo Shon  8 ,  Gil Myoung Kang  3 ,  Sangyong Jung  6 ,  Min-Seon Kim  9
Affiliations
  • 1. Department of Biomedical Science, University of Ulsan College of Medicine, Seoul, South Korea.
  • 2. Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea.
  • 3. Asan Institute for Life Science, Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea.
  • 4. Department of Nuclear Medicine, Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea.
  • 5. Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, South Korea.
  • 6. Department of Medical Science, CHA University College of Medicine, Seongnam, South Korea.
  • 7. Section on Cellular and Synaptic Physiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
  • 8. Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
  • 9. Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea. [email protected].
  • # Contributed equally.
PMID: 42277019 DOI: 10.1038/s41467-026-74170-1
Abstract

Hypothalamic proopiomelanocortin (POMC)-producing neurons are essential for maintaining energy balance and glucose homeostasis. We show that cAMP-dependent protein kinase A (PKA) signaling in these neurons is activated postprandially and upon the administration of glucagon-like peptide-1-based antiobesity/antidiabetic agents. To investigate the metabolic regulatory role of PKA signaling in hypothalamic POMC neurons, we generated mice with POMC-specific constitutive PKA activation by depleting the PKA regulatory subunit Prkar1a. These mice developed obesity due to PKA activation in pituitary corticotrophs and hypercortisolism. Despite increased Insulin resistance, these Animals exhibited a marked improvement in glucose tolerance, attributable to reduced intestinal glucose absorption and increased fecal glucose excretion. Mechanistically, PKA activation in hypothalamic POMC neurons stimulated upper gut innervating-vagal motor neurons, leading to a suppression of sodium/glucose cotransporter-1 (SGLT1)-dependent intestinal glucose absorption. Our findings indicate that the POMC PKA signaling-vagal-gut SGLT1 axis may be a potential target for antidiabetic treatment in individuals with Insulin resistance.

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