Hypothalamic PNOC/NPY neurons constitute mediators of leptin-controlled energy homeostasis

Cell. 2025 Jun 26;188(13):3550-3566.e22. doi: 10.1016/j.cell.2025.04.001. Epub 2025 Apr 23.

Abstract

Leptin acts in the brain to suppress appetite, yet the responsible neurocircuitries underlying leptin's anorectic effect are incompletely defined. Prepronociceptin (PNOC)-expressing neurons mediate diet-induced hyperphagia and weight gain in mice. Here, we show that leptin regulates appetite and body weight via PNOC neurons, and that loss of leptin receptor (Lepr) expression in PNOC-expressing neurons in the arcuate nucleus of the hypothalamus (ARC) causes hyperphagia and obesity. Restoring Lepr expression in PNOC neurons on a Lepr-null obese background substantially reduces body weight. Lepr inactivation in PNOC neurons increases neuropeptide Y (Npy) expression in a subset of hypothalamic PNOC neurons that do not express agouti-related peptide (Agrp). Selective chemogenetic activation of PNOC/NPY neurons promotes feeding to the same extent as activating all PNOCARC neurons, and overexpression of Npy in PNOCARC neurons promotes hyperphagia and obesity. Thus, we introduce PNOC/NPYARC neurons as an additional critical mediator of leptin action and as a promising target for obesity therapeutics.

Keywords: AgRP; NPY; PNOC; POMC; energy homeostasis; food intake; hypothalamus; leptin; neurocircuits; nociceptin; obesity.

MeSH terms

  • Agouti-Related Protein / metabolism
  • Animals
  • Arcuate Nucleus of Hypothalamus / metabolism
  • Energy Metabolism*
  • Homeostasis
  • Hyperphagia / metabolism
  • Hypothalamus* / cytology
  • Hypothalamus* / metabolism
  • Leptin* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons* / metabolism
  • Neuropeptide Y* / metabolism
  • Obesity / metabolism
  • Protein Precursors* / metabolism
  • Receptors, Leptin / genetics
  • Receptors, Leptin / metabolism

Substances

  • Leptin
  • Neuropeptide Y
  • Receptors, Leptin
  • Protein Precursors
  • Agouti-Related Protein