Interoceptive Information of Physical Vigor Through Circulating Insulin‐Like Growth Factor 1

ABSTRACT The brain relies on interoceptive feedback signals to regulate bodily functions. Female mice with low serum IGF‐1 levels (LID mice) exhibit reduced spontaneous running compared to control females, an effect not seen in males. Reduced activity normalized after sustained systemic IGF‐1 treatment. This observation led us to hypothesize that circulating IGF‐1—a key regulator of skeletal muscle and bone mass that crosses the blood–brain barrier during physical activity—may convey body vigor information to the brain. Since hypothalamic orexin neurons, which are involved in regulating physical activity, express IGF‐1 receptors (IGF‐1R) and are modulated by this growth factor, we hypothesized that these neurons might gauge circulating IGF‐1 levels to modulate physical activity. Indeed, inactivation of IGF‐1R 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‐fos activation of hypothalamic orexin neurons and monoaminergic neurons of the ventro‐tegmental area (VTA) in the brainstem. This area is involved in the rewarding component of exercise that seems to be modulated by IGF‐1, as mice receiving systemic IGF‐1 showed increased c‐fos expression in VTA neurons, while mice with reduced IGF‐1R expression in VTA neurons showed no improved mood after exercise. Collectively, these results suggest that circulating IGF‐1 is gauged by orexin neurons to modulate physical activity, and that VTA neurons convey the rewarding properties of exercise through direct actions of IGF‐1 on them. Hence, serum IGF‐1 may constitute an interoceptive signal acting on orexin/VTA neurons to modulate physical activity according to physical vigor (muscle and bone mass).