Insulin‐like growth factor I modulates sleep through hypothalamic orexin neurons

Abstract

Although sleep disturbances are common co-morbidities of metabolic diseases, the underlying processes linking both are not yet fully defined. Changes in the duration of sleep are paralleled by changes in the levels of insulin-like growth factor-I (IGF-I), an anabolic hormone that shows a circadian pattern in the circulation and activitydependent entrance in the brain. However, the specific role, if any, of IGF-I in this universal homeostatic process remains poorly understood. We now report that the activity of orexin neurons, a discrete cell population in the lateral hypothalamus that is involved in the circadian sleep/wake cycle and arousal, is modulated by IGF-I. Furthermore, mice with blunted IGF-I receptor activity in orexin neurons have lower levels of orexin in the hypothalamus, show altered electro-corticographic patterns with predominant slow wave activity, and reduced onset-sleep latency. Collectively, these results extend the role in the brain of this pleiotropic growth factor to shaping sleep architecture through the regulation of orexin neurons. We speculate that poor sleep quality associated to diverse conditions may be related to disturbed brain IGF-I input to orexin neurons.

Insulin-Like Growth Factor I Couples Metabolism With Circadian Activity Through Hypothalamic Orexin Neurons

“…Hence, alterations in orexin function could be a consequence of IGF-I dysregulation due to aging, diet, or pathology. These results indicate that IGF-I regulates orexin neurons, and consequently circadian rhythm and metabolism, extending and confirming our previous observations about the central actions of IGF-I on mood, metabolism, and wellness 27,46 .…”

“…This confirms and extends previous observations that IGF-I entrains feeding and circadian rhythms 16 , pointing to orexin neurons as a site of food/light entrainment by IGF-I. Indeed, hypothalamic orexin neurons regulate sleep/wake rhythms 12,27,34 and feeding behavior 32 , and have been described as food-entrained oscilators 35 , as orexin knockout mice display reduced food anticipatory activity 36 . Conceivably, the circadian activity of IGF-I 37 may signal orexin neurons to help maintain metabolic homeostasis since blockage of IGF-I favors the development of metabolic disorders.…”

“…Certainly, the circadian activity of IGF-I shows a trough at the end of the resting phase, before the surge in orexin levels 38 . Together with the observation that circadian variation of hypothalamic orexin is disturbed in Firoc mice, these data suggest that IGF-I signaling onto orexin neurons is important for the regulation of orexin expression, as previously suggested 27 .…”

“…To analyze the role of IGF-I on orexin neurons we inactivated its receptor (IGF-IR) in these neurons (Firoc mice), as described 27 . Since we previously observed that Firoc mice have reduced levels of hypothalamic orexin 27 and levels of this neuropeptide shows a circadian rhythm 29 , we determined whether its circadian fluctuations were also altered in Firoc mice. We measured mRNA levels at ZT8 (inactive phase) and ZT12 (the beginning of the active phase) and found a significant attenuation of the orexin peak at the latter time (Figure 1A).…”

“…In turn, hypothalamic orexin neurons are involved in glucose sensing 23 and metabolism 23 , feeding behavior 25 , and overall energy balance 25 , and their impairment are linked to obesity 26 . Orexin neurons are directly modulated by IGF-I 27 and diverse humoral signals, including glucose and insulin 28 .…”