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Female mice with low serum IGF\u20101 levels (LID mice) exhibit reduced spontaneous running compared to control females, an effect not seen in males. Reduced activity normalized after sustained systemic IGF\u20101 treatment. This observation led us to hypothesize that circulating IGF\u20101\u2014a key regulator of skeletal muscle and bone mass that crosses the blood\u2013brain barrier during physical activity\u2014may convey body vigor information to the brain. Since hypothalamic orexin neurons, which are involved in regulating physical activity, express IGF\u20101 receptors (IGF\u20101R) and are modulated by this growth factor, we hypothesized that these neurons might gauge circulating IGF\u20101 levels to modulate physical activity. Indeed, inactivation of IGF\u20101R in mouse orexin neurons (Firoc mice) was associated with less time spent in free running. These mice maintain physical fitness but display altered mood and are less sensitive to the rewarding actions of exercise. Further, in response to exercise, Firoc mice showed limited c\u2010fos activation of hypothalamic orexin neurons and monoaminergic neurons of the ventro\u2010tegmental area (VTA) in the brainstem. This area is involved in the rewarding component of exercise that seems to be modulated by IGF\u20101, as mice receiving systemic IGF\u20101 showed increased c\u2010fos expression in VTA neurons, while mice with reduced IGF\u20101R expression in VTA neurons showed no improved mood after exercise. Collectively, these results suggest that circulating IGF\u20101 is gauged by orexin neurons to modulate physical activity, and that VTA neurons convey the rewarding properties of exercise through direct actions of IGF\u20101 on them. Hence, serum IGF\u20101 may constitute an interoceptive signal acting on orexin\/VTA neurons to modulate physical activity according to physical vigor (muscle and bone mass).<\/jats:p>","DOI":"10.1096\/fba.2025-00226","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T09:25:46Z","timestamp":1768209946000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Interoceptive Information of Physical Vigor Through Circulating Insulin\u2010Like Growth Factor 1"],"prefix":"10.1096","volume":"8","author":[{"given":"Jonathan A.","family":"Zegarra\u2010Valdivia","sequence":"first","affiliation":[{"name":"Achucarro Basque Center for Neuroscience  Leioa Spain"},{"name":"Cajal Institute (CSIC)  Madrid Spain"},{"name":"Ciberned  Madrid Spain"},{"name":"Universidad Cient\u00edfica del Sur  Lima Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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