Distribution of growth hormone-responsive cells in the mouse brain

Abstract

Growth hormone (GH) exerts important biological effects primarily related to growth and metabolism. However, the role of GH signaling in the brain is still elusive. To better understand GH functions in the brain, we mapped the distribution of GH-responsive cells and identified the receptors involved in GH central effects. For this purpose, mice received an acute intraperitoneal challenge with specific ligands of the GH receptor (mouse GH), prolactin receptor (prolactin) or both receptors (human GH), and their brains were subsequently processed immunohistochemically to detect the phosphorylated form of STAT5 (pSTAT5). GH induced pSTAT5 immunoreactivity in neurons, but not in astroglial cells of numerous brain regions, including the cerebral cortex, nucleus accumbens, hippocampus, septum and amygdala. The most prominent populations of GH-responsive neurons were located in hypothalamic areas, including several preoptic divisions, and the supraoptic, paraventricular, suprachiasmatic, periventricular, arcuate, ventromedial, dorsomedial, tuberal, posterior and ventral premammillary nuclei. Interestingly, many brainstem structures also exhibited GH-responsive cells. Experiments combining immunohistochemistry for pSTAT5 and in situ hybridization for GH and prolactin receptors revealed that human GH induced pSTAT5 in most, but not all, brain regions through both prolactin and GH receptors. Additionally, males and females exhibited a similar number of GH-responsive cells in forebrain structures known to be sexually dimorphic. In summary, we found GH-responsive cells primarily distributed in brain regions implicated in neurovegetative, emotional/motivational and cognitive functions. Our findings deepen the understanding of GH signaling in the brain and suggest that central GH signaling is likely more ample and complex than formerly recognized.

Hypothalamic growth hormone receptor (GHR) controls hepatic glucose production in nutrient-sensing leptin receptor (LepRb) expressing neurons

“…This suggests that central GH signaling might be involved in energy expenditure and glucose homeostasis through a central mechanism [10]. GH overexpression in the CNS results in hyperphagia-induced obesity, insulin resistance, and increased circulating GH levels [17].…”

“…Previous studies also indicate that leptin can modulate GH secretion and the GH response to GHRH [22]. LepRb neurons are widely distributed within the hypothalamic ARH, VMH, DMH, LHA, and some additional sites that also express GHR [10], [23]. Recent transcriptome analysis of LepRb expressing neurons revealed that the Ghr gene is strongly enriched in LepRb neurons [24].…”

“…In both human and mouse brain, GH and the GH receptor (GHR) are present in regions known to participate in the regulation of feeding behavior, energy balance, and glucose metabolism such as the hypothalamus, hippocampus, and amygdala [6], [7], [8], [9], [10]. Upon GHR activation, the signal transducer and activator of transcription 5 (Stat5) is recruited and regulates the transcription of genes directly controlled by GH [11], [12].…”

Tuning the brain for motherhood: prolactin-like central signalling in virgin, pregnant, and lactating female mice

“…Thus, pSTAT5 immunoreactivity observed in this group reveals signalling exclusively through the PRLR-l. Still, GH (Furigo et al 2016) or leptin could contribute to the pSTAT5-ir observed in pregnant females, although the high levels of PLs likely account for most (if not all) of the pSTAT5 immunolabelling observed. Regarding leptin, STAT3 is the main STAT member associated with the leptin receptor (Ladyman et al 2012), whereas STAT5 phosphorylation associated with leptin signalling has been reported only in the arcuate nucleus (Gong et al 2007;Mütze et al 2007) and has not been replicated in all studies (Vaisse et al 1996).…”

“…Regarding leptin, STAT3 is the main STAT member associated with the leptin receptor (Ladyman et al 2012), whereas STAT5 phosphorylation associated with leptin signalling has been reported only in the arcuate nucleus (Gong et al 2007;Mütze et al 2007) and has not been replicated in all studies (Vaisse et al 1996). As for GH, regions of the brain showing high levels of expression of GH receptors and responsiveness to GH (detected by pSTAT5-ir; Furigo et al 2016), such as the hippocampus and dentate gyrus (Burton et al 1992) or layers 2, 3, and 5, and especially, layer 6 of the cerebral cortex (Lobie et al 1993), show no pSTAT5 labelling in any of our mice, neither in virgin nor in pregnant or lactating females. This suggests that GH signalling in the brain is taking place through alternative pathways, e.g., those involving Src kinases (Waters 2015).…”