article published yes Rachel J. Perry author Jon M. Resch author Amelia May Barnett Douglass author de5f6fda-80fb-11ef-996f-a8c4ecd8e2890000-0001-5398-6473 Joseph C. Madara author Aviva Rabin-Court author Hakan Kucukdereli author Chen Wu author Joongyu D. Song author Bradford B. Lowell author Gerald I. Shulman author Leptin informs the brain about sufficiency of fuel stores. When insufficient, leptin levels fall, triggering compensatory increases in appetite. Falling leptin is first sensed by hypothalamic neurons, which then initiate adaptive responses. With regard to hunger, it is thought that leptin-sensing neurons work entirely via circuits within the central nervous system (CNS). Very unexpectedly, however, we now show this is not the case. Instead, stimulation of hunger requires an intervening endocrine step, namely activation of the hypothalamic–pituitary–adrenocortical (HPA) axis. Increased corticosterone then activates AgRP neurons to fully increase hunger. Importantly, this is true for 2 forms of low leptin-induced hunger, fasting and poorly controlled type 1 diabetes. Hypoglycemia, which also stimulates hunger by activating CNS neurons, albeit independently of leptin, similarly recruits and requires this pathway by which HPA axis activity stimulates AgRP neurons. Thus, HPA axis regulation of AgRP neurons is a previously underappreciated step in homeostatic regulation of hunger. National Academy of Sciences2019 eng 0027-8424 1091-6490 3121353310.1073/pnas.1901795116 1162713670-13679 yes R.J. Perry, J.M. Resch, A.M. Douglass, J.C. Madara, A. Rabin-Court, H. Kucukdereli, C. Wu, J.D. Song, B.B. Lowell, G.I. Shulman, Proceedings of the National Academy of Sciences 116 (2019) 13670–13679. Perry RJ, Resch JM, Douglass AM, et al. Leptin’s hunger-suppressing effects are mediated by the hypothalamic–pituitary–adrenocortical axis in rodents. <i>Proceedings of the National Academy of Sciences</i>. 2019;116(27):13670-13679. doi:<a href="https://doi.org/10.1073/pnas.1901795116">10.1073/pnas.1901795116</a> Perry, R. J., Resch, J. M., Douglass, A. M., Madara, J. C., Rabin-Court, A., Kucukdereli, H., … Shulman, G. I. (2019). Leptin’s hunger-suppressing effects are mediated by the hypothalamic–pituitary–adrenocortical axis in rodents. <i>Proceedings of the National Academy of Sciences</i>. National Academy of Sciences. <a href="https://doi.org/10.1073/pnas.1901795116">https://doi.org/10.1073/pnas.1901795116</a> R. J. Perry <i>et al.</i>, “Leptin’s hunger-suppressing effects are mediated by the hypothalamic–pituitary–adrenocortical axis in rodents,” <i>Proceedings of the National Academy of Sciences</i>, vol. 116, no. 27. National Academy of Sciences, pp. 13670–13679, 2019. Perry RJ, Resch JM, Douglass AM, Madara JC, Rabin-Court A, Kucukdereli H, Wu C, Song JD, Lowell BB, Shulman GI. 2019. Leptin’s hunger-suppressing effects are mediated by the hypothalamic–pituitary–adrenocortical axis in rodents. Proceedings of the National Academy of Sciences. 116(27), 13670–13679. Perry, Rachel J., et al. “Leptin’s Hunger-Suppressing Effects Are Mediated by the Hypothalamic–Pituitary–Adrenocortical Axis in Rodents.” <i>Proceedings of the National Academy of Sciences</i>, vol. 116, no. 27, National Academy of Sciences, 2019, pp. 13670–79, doi:<a href="https://doi.org/10.1073/pnas.1901795116">10.1073/pnas.1901795116</a>. Perry, Rachel J., Jon M. Resch, Amelia M. Douglass, Joseph C. Madara, Aviva Rabin-Court, Hakan Kucukdereli, Chen Wu, Joongyu D. Song, Bradford B. Lowell, and Gerald I. Shulman. “Leptin’s Hunger-Suppressing Effects Are Mediated by the Hypothalamic–Pituitary–Adrenocortical Axis in Rodents.” <i>Proceedings of the National Academy of Sciences</i>. National Academy of Sciences, 2019. <a href="https://doi.org/10.1073/pnas.1901795116">https://doi.org/10.1073/pnas.1901795116</a>. 194732025-04-03T12:30:19Z2025-07-10T11:51:42Z