Insulin-like growth factor-1 acts as a zeitgeber on hypothalamic circadian clock gene expression via glycogen synthase kinase-3β signaling

Abstract

Brain and muscle ARNT-like protein-1 (BMAL-1) is an important component of the cellular circadian clock. Proteins such as epidermal (EGF) or nerve growth factor (NGF) affect the cellular clock via extracellular signal-regulated kinases-1/2 (ERK-1/2) in NIH3T3 or neuronal stem cells, but no such data are available for the insulin-like growth factor-1 (IGF-1). The hypothalamus expresses receptors for all three growth factors, acts as a central circadian pacemaker, and releases hormones in a circadian fashion. However, little is known about growth factor-induced modulation of clock gene activity in hypothalamic cells. Here, we investigated effects of IGF-1, EGF, or NGF on the promoter in two hypothalamic cell lines. We found that only IGF-1 but not EGF or NGF enhanced activity of the promoter. Inhibition of ERK-1/2 activity did not affect IGF-1-induced promoter activation and all three growth factors similarly phosphorylated ERK-1/2, questioning a role for ERK-1/2 in controlling promoter activity. Of note, only IGF-1 induced sustained phosphorylation of glycogen synthase kinase-3β (GSK-3β). Moreover, the GSK-3β inhibitor lithium or siRNA-mediated GSK-3β knockdown diminished the effects of IGF-1 on the promoter. When IGF-1 was used in the context of temperature cycles entraining hypothalamic clock gene expression to a 24-h rhythm, it shifted the phase of promoter activity, indicating that IGF-1 functions as a zeitgeber for cellular hypothalamic circadian clocks. Our results reveal that IGF-1 regulates clock gene expression and that GSK-3β but not ERK-1/2 is required for the IGF-1-mediated regulation of the promoter in hypothalamic cells.

Association of Insulin-like Growth Factor 1 Concentrations with Risk for and Prognosis of Amyotrophic Lateral Sclerosis – Results from the ALS Registry Swabia

“…Interestingly growth hormone secretion was dysregulated in both patients and mouse models of ALS 28 . Results from experimental studies indicate a circadian control of IGF-I production 29,30 . In our study the time of blood www.nature.com/scientificreports www.nature.com/scientificreports/ sampling was in median about 1.5 hours earlier in ALS cases than in control subjects, with large overlap in the distribution.…”

Adult survival is reduced when endogenous period deviates from 24h in a non-human primate (Microcebus murinus), depending on sex and season

“…Interestingly, the winter-like IGF-1 rates are also predictive of survival (Aujard et al, 2010). It could thus be worthwhile to combine data from tau and IGF-1 in this species, as it is known that circadian rhythms and IGF-1 are closely related (Breit et al, 2018; Crosby et al, 2019).…”

Insulin-Like Growth Factor I Modulates Sleep Through Hypothalamic Orexin Neurons

“…ECG segments of 5 minutes were analyzed with this software using the Fast Fourier Transform algorithm to obtain the power spectra. The mean power density was calculated for 5 different frequency bands that constitute the global ECG: delta band (0.3-5 Hz), theta band (5-8 Hz), alpha band (8-12 Hz), beta band (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) Hz), and gamma band . The total power of the five frequency bands was considered 100%, and the percentage of each frequency band was calculated for the 60 minutes.…”

“…Indeed, circulating IGF-I enters into the brain in response to physical activity 24 , through an activity-dependent process 25 . Furthermore, recent evidence indicates that circulating IGF-I shows a circadian pattern and is a circadian entrain cue 26,27 , affecting hypothalamic clock genes 28 .…”