Uncoupling of metabolism and circadian activity is associated with an increased risk of various pathologies, including neurodegeneration. Recently, insulin and the closely related insulin-like growth factor I (IGF-I) were shown to entrain feeding patterns with circadian rhythms. Moreover, both hormones act centrally to modulate peripheral glucose metabolism; however, whereas central targets of insulin actions are intensely scrutinized, those mediating the actions of IGF-I remain undefined. We analyzed whether IGF-I targets orexin neurons in the lateral hypothalamus, as these neurons are involved in circadian rhythms and energy allocation, and are modulated by IGF-I. Mice with disrupted IGF-IR activity in orexin neurons show phase shifts in circadian feeding behavior, loss of circadian orexin expression, and gradually develop sex-dependent metabolic alterations. In addition, modulation by IGF-I of hepatic KLF transcription factors involved in peripheral glucose metabolism is mediated by orexin neurons. Thus, IGF-I entrains energy metabolism and circadian rhythms through hypothalamic orexin neurons.
bioRxiv Subject Collection: Neuroscience