Liver-Derived IGF-I Regulates GH Secretion at the Pituitary Level in Mice

Wallenius, Kristina; Sjögren, Klara; Peng, Xiao; Park, Seungjoon; Wallenius, Ville; Liu, Jun Li; Umaerus, M.; Wennbo, Håkan; Isaksson, Olle; Frohman, Lawrence A.; Kineman, Rhonda D.; Ohlsson, Claes; Jansson, John Olov

doi:10.1210/endo.142.11.8478

Cited by 74 publications

(34 citation statements)

References 50 publications

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“…These results, taken together with the current observations, suggest that even under normal conditions, regulation of GH, GHRH-R and GHS-R expression is under direct tonic inhibition by low circulating levels of free IGF-I. This notion is consistent with the observation that circulating GH and pituitary GHRH-R and GHS-R mRNA levels are elevated in liverspecific IGF-I knockout mice, where circulating IGF-I levels are less than 10% of normal controls, while hypothalamic GHRH or SST expression do not differ from controls (Sjogren et al 1999, Yakar et al 1999, Wallenius et al 2002. It has also been hypothesized that suppression of free IGF-I levels observed following fasting and increases in free IGF-I reported in obesity may play a role in the reciprocal changes in GH output in these extreme metabolic conditions (for review, see Frystyk 2004).…”

Section: Direct Effects Of Igf-i and Insulinsupporting

confidence: 86%

Examination of the direct effects of metabolic factors on somatotrope function in a non-human primate model, Papio anubis

Luque¹,

Gahete²,

Valentine³

et al. 2006

Journal of Molecular Endocrinology

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In humans, circulating GH levels are increased in catabolic states and suppressed in obesity. In both extremes, normalization of the metabolic environment normalizes GH release, leading to the conclusion that changes in metabolic hormones and/or metabolites promote changes in GH synthesis and release. Metabolic regulation of GH secretion can be mediated centrally by modulation of hypothalamic GHRH and somatostatin input to the pituitary and/or by direct regulation of pituitary somatotrope function. Although data are available showing glucocorticoids, free fatty acids (FFA), IGF-I, and insulin have direct effects on rat somatotrope function, little information is available regarding the direct pituitary effects of these metabolic factors in primates. Therefore, this study examined the effects of glucocorticoids (dexamethasone (0.1-100 nM) and hydrocortisone (10 nM)), FFA (oleic and linoleic acid, 100 and 400 mM each), IGF-I (0.5-50 nM), and insulin (0.5-50 nM) on GH release and GH, GHRH-receptor (GHRH-R) and ghrelin-receptor (GHS-R) mRNA levels, in primary pituitary cell cultures of baboons (Papio anubis) after 24 h treatment. A commercial ELISA kit was used to determine the amount of GH released into the media, while quantitative real-time reverse transcription-PCR was used to determine mRNA levels. To design species-specific primers for baboon GH, GHRH-R, GHS-R, insulin receptor (INSR), IGF-I receptor (IGF-IR), pituitary-specific transcription factor-1 (Pit-1), and cyclophilin A (used as a housekeeping gene) cDNA, sequence data for each baboon transcript were obtained and this data were submitted to Genbank. Glucocorticoids, FFA, insulin and IGF-I treatment did not significantly alter the expression of Pit-1, a transcription factor essential for normal somatotrope development and function. However, as previously reported in the rat, glucocorticoids increased, while FFA, IGF-I and insulin decreased GH release in baboon pituitary cell cultures, where changes in GH release were reflected by comparable changes in GH mRNA levels. In addition, glucocorticoids increased, while FFA, IGF-I and insulin decreased the expression of the GH stimulatory receptors, GHRH-R and GHS-R, without significantly altering cyclophilin A mRNA levels. A role of insulin/INSR pathway, independent of IGF-I, in regulating pituitary function is supported by the fact that (1) IGF-I and insulin significantly suppressed somatotrope function at doses (0.5 and 5 nM respectively) not anticipated to activate their respective receptors, and (2) the baboon pituitary expresses INSR mRNA at levels comparable to or greater than that of tissues commonly considered as insulin sensitive (i.e. liver, skeletal muscle, and fat). Taken together, these results demonstrate that metabolic factors can directly modulate primate somatotrope function through regulating GH synthesis and release, as well as mediating the expression of receptors important in central (GHRH) and systemic (ghrelin) regulation of GH secretion.

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Section: Direct Effects Of Igf-i and Insulinsupporting

confidence: 86%

Examination of the direct effects of metabolic factors on somatotrope function in a non-human primate model, Papio anubis

Luque¹,

Gahete²,

Valentine³

et al. 2006

Journal of Molecular Endocrinology

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“…However, in the adult rGhp-Cre transgenic mice, only 10% of lactotrophs are derived from somatotrophs (Luque et al 2007). In this study, GH cells in IGF1KO mice were already increased at day 10 because of the absence of the IGF1 negative feedback loop that suppressed GH production (Wallenius et al 2001). An increase of GH cells may be due to the mass differentiation of progenitor cells to GH cells, therefore, it may result in suppression of PRL cell differentiation in IGF1KO mice because PRL cells and GH cells are derived from the same origin.…”

Section: Discussionmentioning

confidence: 51%

“…Circulating IGF1 produced in the liver acts as a mediator of GH action and regulates systemic growth (D'Ercole et al 1984). In the regulation of GH synthesis and release, IGF1 specifically inhibits GH gene transcription and secretion by negative feedback mechanisms (Wallenius et al 2001). Therefore, high blood GH levels are induced by severe IGF1 deficiency (Lembo et al 1996).…”

Section: Introductionmentioning

confidence: 99%

The role of IGF1 on the differentiation of prolactin secreting cells in the mouse anterior pituitary

Hikake¹,

Hayashi²,

Iguchi³

et al. 2009

Journal of Endocrinology

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IGF1 knockout (IGF1KO) mice show a reduced number of prolactin (PRL) producing cells (PRL cells); however, the role of IGF1 in PRL cell proliferation and differentiation in immature mice is unclear. In this study, ontogenic changes in the percentages of PRL cells, GH producing cells (GH cells), and 5-bromo-2 0 -deoxyuridine (BrdU)-labeled cells in the anterior pituitary of male IGF1KO mice during the postnatal period were investigated. The percentage of PRL cells in IGF1KO mice was significantly lower at day 20 compared with that in wild-type (WT) mice, while GH cells in IGF1KO mice were significantly increased from day 10. From days 5 to 20, the percentage of BrdU-labeled cells in WT and IGF1KO mice was similar. PRL cells and GH cells are thought to originate from the same progenitor cells, therefore, PRL cells in IGF1KO mice are not able to differentiate because progenitor cells have already committed to be GH cells. However, IGF1, 17b-estradiol (E 2 ), epidermal growth factor (EGF), or IGF1 plus E 2 treatments increased the PRL cell number in the pituitaries in vitro of 10-day-old WT and IGF1KO mice. This fact suggests that these factors are involved in PRL cell proliferation and differentiation. In addition, the increase of PRL cells in IGF1KO mice stimulated by E 2 or EGF was less than that of WT mice. Thus, IGF1 plays a crucial role in PRL cell proliferation and differentiation in mouse pituitaries by regulating the differentiation of progenitor cells and mediating the actions of E 2 and EGF.

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“…The fasting-induced increase in GHRH sensitivity is associated with an increase in pituitary GHRH receptor (GHRH-R) mRNA and an increase in pituitary GHRH binding (Sugihara et al 1996), with a concomitant decline in pituitary SRIF receptor expression and ligand binding (Bruno et al 1994). The rise in GHRH-R mRNA may be mediated by the reduction in GH/IGF-I negative feedback since IGF-I has been shown to suppress directly GHRH-R mRNA levels in primary pituitary cell cultures (Sugihara et al 1999), and we have observed an increase in GHRH-R mRNA in rats with isolated GH deficiency (spontaneous dwarf rats (SDR)) (Kamegai et al 1998a) and in mice with reduced circulating IGF-I (liver-specific IGF-I knockout mice) (Wallenius et al 2002). In order to test whether fastinginduced fall in GH/IGF-I is responsible for fastinginduced changes in pituitary receptor expression, we compared the hypothalamic/pituitary response to fasting in normal rats and GH-deficient SDR.…”

Section: Introductionmentioning

confidence: 90%

Fasting-induced changes in the hypothalamic-pituitary-GH axis in the absence of GH expression: lessons from the spontaneous dwarf rat

Park

Sohn²,

Kineman³

2004

Journal of Endocrinology

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Fasting results in a reciprocal shift in hypothalamic neuropeptide Y (NPY) and GH-releasing hormone (GHRH) expression in the adult male rat. It is hypothesized that the fasting-induced rise in NPY is responsible for the GHRH decline and subsequent attenuation of pulsatile GH release. Fasting also leads to a decrease in circulating IGF-I, attributed to both reduced GH release and peripheral GH resistance. Although pituitary GH output is suppressed in the fasted rat, we report herein that pituitary GHRH receptor (GHRH-R) and GH secretagogue receptor (GHS-R) mRNA levels are increased, while pituitary expression of the somatostatin receptor subtype 2 (sst2) and 5 (sst5) is decreased, as determined by real-time reverse transcription (RT)-PCR. A shift in the expression of pituitary receptor subtypes to favor GH synthesis and release may be due, at least in part, to a decline in GH/IGF-I negative feedback. In order to test this hypothesis, we compared hypothalamic and pituitary response to fasting (72 h) in normal male rats and rats with isolated GH deficiency (spontaneous dwarf rats (SDR)). Circulating GH levels were undetectable in SDR, and IGF-I levels were less than 10% of normal controls. Fasting stimulated NPY mRNA levels in SDR; however, the rise in NPY mRNA levels was not accompanied by a fall in GHRH mRNA, as observed in fasted normal rats. In fact, GHRH mRNA levels paradoxically rose in the fasted SDR to 135% of fed controls. At the pituitary level, fasting did not alter sst2 and sst5 mRNA levels in SDR but did stimulate the expression of GHRH-R and GHS-R to 165% and 149% of fed controls, respectively. These results demonstrate that the fasting-induced changes in pituitary expression of sst2 and sst5, but not GHRH-R and GHS-R, are GH/IGF-I dependent. In addition, these results argue against the theory that the negative association of NPY and GHRH expression observed following fasting represents a simple cause-and-effect relationship and suggest that GH, either directly or indirectly, mediates the effects of fasting on hypothalamic GHRH expression.

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Liver-Derived IGF-I Regulates GH Secretion at the Pituitary Level in Mice

Cited by 74 publications

References 50 publications

Examination of the direct effects of metabolic factors on somatotrope function in a non-human primate model, Papio anubis

Examination of the direct effects of metabolic factors on somatotrope function in a non-human primate model, Papio anubis

The role of IGF1 on the differentiation of prolactin secreting cells in the mouse anterior pituitary

Fasting-induced changes in the hypothalamic-pituitary-GH axis in the absence of GH expression: lessons from the spontaneous dwarf rat

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