Anti-inflammatory effects of hunger are transmitted to the periphery via projection-specific AgRP circuits
Michelle L. Klima,
Kayla A. Kruger,
Nitsan Goldstein,
Santiago Pulido,
Aloysius Y.T. Low,
Charles-Antoine Assenmacher,
Amber L. Alhadeff,
J. Nicholas Betley
Affiliations
Michelle L. Klima
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA
Kayla A. Kruger
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
Nitsan Goldstein
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA
Santiago Pulido
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
Aloysius Y.T. Low
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
Charles-Antoine Assenmacher
Comparative Pathology Core, Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
Amber L. Alhadeff
Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA; Monell Chemical Senses Center, Philadelphia, PA 19104, USA; Corresponding author
J. Nicholas Betley
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
Summary: Caloric restriction has anti-inflammatory effects. However, the coordinated physiological actions that lead to reduced inflammation in a state of caloric deficit (hunger) are largely unknown. Using a mouse model of injury-induced peripheral inflammation, we find that food deprivation reduces edema, temperature, and cytokine responses that occur after injury. The magnitude of the anti-inflammatory effect that occurs during hunger is more robust than that of non-steroidal anti-inflammatory drugs. The effects of hunger are recapitulated centrally by activity in nutrient-sensing hypothalamic agouti-related protein (AgRP)-expressing neurons. We find that AgRP neurons projecting to the paraventricular nucleus of the hypothalamus rapidly and robustly reduce inflammation and mediate the majority of hunger’s anti-inflammatory effects. Intact vagal efferent signaling is required for the anti-inflammatory action of hunger, revealing a brain-to-periphery pathway for this reduction in inflammation. Taken together, these data begin to unravel a potent anti-inflammatory pathway engaged by hypothalamic AgRP neurons to reduce inflammation.
