Hypothalamic AgRP neurons exert top-down control on systemic TNF-α release during endotoxemia

Mehdi Boudjadja, Isabella Culotta, Gabriela C De Paula, Erika Harno, Jenna Hunter, João Paulo Cavalcanti-de-Albuquerque, Simon M Luckman, Matthew Hepworth, Anne White, Gabriella Aviello, Giuseppe D'Agostino

Research output: Contribution to journalArticlepeer-review


Loss of appetite and negative energy balance are common features of endotoxemia in all animals and are thought to have protective roles by reducing nutrient availability to host and pathogen metabolism. Accordingly, fasting and caloric restriction have well-established anti-inflammatory properties. However, in response to reduced nutrient availability at the cellular and organ levels, negative energy balance also recruits distinct energy-sensing brain circuits, but it is not known whether these neuronal systems have a role in its anti-inflammatory effects. Here, we report that hypothalamic AgRP neurons-a critical neuronal population for the central representation of negative energy balance-have parallel immunoregulatory functions. We found that when endotoxemia occurs in fasted mice, the activity of AgRP neurons remains sustained, but this activity does not influence feeding behavior and endotoxemic anorexia. Furthermore, we found that endotoxemia acutely desensitizes AgRP neurons, which also become refractory to inhibitory signals. Mimicking this sustained AgRP neuron activity in fed mice by chemogenetic activation-a manipulation known to recapitulate core behavioral features of fasting-results in reduced acute tumor necrosis factor alpha (TNF-α) release during endotoxemia. Mechanistically, we found that endogenous glucocorticoids play an important role: glucocorticoid receptor deletion from AgRP neurons prevents their endotoxemia-induced desensitization, and importantly, it counteracts the fasting-induced suppression of TNF-α release, resulting in prolonged sickness. Together, these findings provide evidence directly linking AgRP neuron activity to the acute response during endotoxemia, suggesting that these neurons are a functional component of the immunoregulatory effects associated with negative energy balance and catabolic metabolism.

Original languageEnglish
Pages (from-to)4699-4706.e4
JournalCurrent biology
Issue number21
Early online date23 Sept 2022
Publication statusPublished - 7 Nov 2022


  • NPY
  • appetite
  • arcuate nucleus
  • energy balance
  • fasting
  • glucocorticoids
  • hypothalamus
  • inflammation
  • sickness behavior


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