Does the pituitary somatotrope play a primary role in regulating GH output in metabolic extremes?

Circulating growth hormone (GH) levels rise in response to nutrient deprivation and fall in states of nutrient excess. Because GH regulates carbohydrate, lipid, and protein metabolism, defining the mechanisms by which changes in metabolism alter GH secretion will aid in our understanding of the cause, progression, and treatment of metabolic diseases. This review will summarize what is currently known regarding the impact of systemic metabolic signals on GH‐axis function. In addition, ongoing studies using the Cre/loxP system to generate mouse models with selective somatotrope resistance to metabolic signals will be discussed, where these models will serve to enhance our understanding of the specific role the somatotrope plays in sensing the metabolic environment and adjusting GH output in metabolic extremes.

[1]  L. Suva,et al.  The somatotrope as a metabolic sensor: deletion of leptin receptors causes obesity. , 2010, Endocrinology.

[2]  V. Tolle,et al.  The Ghrelin/Obestatin Balance in the Physiological and Pathological Control of Growth Hormone Secretion, Body Composition and Food Intake , 2010, Journal of neuroendocrinology.

[3]  S. Radovick,et al.  Targeted deletion of somatotroph insulin-like growth factor-I signaling in a cell-specific knockout mouse model. , 2010, Molecular endocrinology.

[4]  R. Kineman,et al.  Metabolic regulation of ghrelin O-acyl transferase (GOAT) expression in the mouse hypothalamus, pituitary, and stomach , 2010, Molecular and Cellular Endocrinology.

[5]  A. Murphy,et al.  Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice , 2010, Proceedings of the National Academy of Sciences.

[6]  Maria Chmielnicka-Kopaczyk,et al.  Assessment of ghrelin, GHS-R, GH, and neurohormones in human fetal pituitary glands and central nervous system: an immunohistochemical study. , 2010, Folia histochemica et cytobiologica.

[7]  I. Robinson,et al.  Ghrelin Stimulation of Growth Hormone-Releasing Hormone Neurons Is Direct in the Arcuate Nucleus , 2010, PloS one.

[8]  M. Malagón,et al.  Identification and characterization of new functional truncated variants of somatostatin receptor subtype 5 in rodents , 2010, Cellular and Molecular Life Sciences.

[9]  J. Salles,et al.  LEPROT and LEPROTL1 cooperatively decrease hepatic growth hormone action in mice. , 2009, The Journal of clinical investigation.

[10]  M. Thorner,et al.  Impact of growth hormone receptor blockade on substrate metabolism during fasting in healthy subjects. , 2009, The Journal of clinical endocrinology and metabolism.

[11]  H. Vaudry,et al.  Resistin regulates pituitary somatotrope cell function through the activation of multiple signaling pathways. , 2009, Endocrinology.

[12]  I. Robinson,et al.  Regulation of rapid signal transducer and activator of transcription-5 phosphorylation in the resting cells of the growth plate and in the liver by growth hormone and feeding. , 2009, Endocrinology.

[13]  K. Hodate,et al.  Ghrelin differentially modulates the GH secretory response to GHRH between the fed and fasted states in sheep. , 2009, Domestic animal endocrinology.

[14]  M. Malagón,et al.  Understanding the Multifactorial Control of Growth Hormone Release by Somatotropes , 2009, Annals of the New York Academy of Sciences.

[15]  N. Møller,et al.  Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. , 2009, Endocrine reviews.

[16]  D. Taub,et al.  Reduction in hypophyseal growth hormone and prolactin expression due to deficiency in ghrelin receptor signaling is associated with Pit-1 suppression: Relevance to the immune system , 2008, Brain, Behavior, and Immunity.

[17]  R. Kineman,et al.  Severity of the catabolic condition differentially modulates hypothalamic expression of growth hormone-releasing hormone in the fasted mouse: potential role of neuropeptide Y and corticotropin-releasing hormone. , 2008, Endocrinology.

[18]  Eunhee Kim,et al.  Role of Glucocorticoids in Fasting-induced Changes in Hypothalamic and Pituitary Components of the Growth Hormone (GH)-axis. , 2008, The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology.

[19]  M. Eriksson,et al.  The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. , 2008, Cell metabolism.

[20]  M. Blüher,et al.  Autocrine IGF-1 Action in Adipocytes Controls Systemic IGF-1 Concentrations and Growth , 2008, Diabetes.

[21]  A. Morozov,et al.  Conditional Gene Expression and Targeting in Neuroscience Research , 2008, Current protocols in neuroscience.

[22]  M. Thorner,et al.  Evidence for acyl-ghrelin modulation of growth hormone release in the fed state. , 2008, The Journal of clinical endocrinology and metabolism.

[23]  B. Ciocchi,et al.  Relationships between desacylated and acylated ghrelin and insulin sensitivity in the metabolic syndrome. , 2007, The Journal of clinical endocrinology and metabolism.

[24]  M. Tschöp,et al.  Ghrelin, obesity and diabetes , 2007, Nature Clinical Practice Endocrinology &Metabolism.

[25]  R. Kineman,et al.  Evidence that ghrelin is as potent as growth hormone (GH)-releasing hormone (GHRH) in releasing GH from primary pituitary cell cultures of a nonhuman primate (Papio anubis), acting through intracellular signaling pathways distinct from GHRH. , 2007, Endocrinology.

[26]  C. Lobe,et al.  Reporter expression, induced by a growth hormone promoter-driven Cre recombinase (rGHp-Cre) transgene, questions the developmental relationship between somatotropes and lactotropes in the adult mouse pituitary gland. , 2007, Endocrinology.

[27]  S. Shalet,et al.  Defining Growth Hormone Status in Adults with Hypopituitarism , 2007, Hormone Research in Paediatrics.

[28]  R. Kineman,et al.  Effects of leptin replacement on hypothalamic-pituitary growth hormone axis function and circulating ghrelin levels in ob/ob mice. , 2007, American journal of physiology. Endocrinology and metabolism.

[29]  R. Kineman,et al.  Examination of the direct effects of metabolic factors on somatotrope function in a non-human primate model, Papio anubis. , 2006, Journal of molecular endocrinology.

[30]  S. Ferris,et al.  GH peak response to GHRH-arginine: relationship to insulin resistance and other cardiovascular risk factors in a population of adults aged 50–90 , 2006, Clinical endocrinology.

[31]  R. Kineman,et al.  Impact of obesity on the growth hormone axis: evidence for a direct inhibitory effect of hyperinsulinemia on pituitary function. , 2006, Endocrinology.

[32]  S. Park,et al.  Differential responses of the growth hormone axis in two rat models of streptozotocin-induced insulinopenic diabetes. , 2006, The Journal of endocrinology.

[33]  S. Bloom,et al.  Ghrelin does not stimulate food intake in patients with surgical procedures involving vagotomy. , 2005, The Journal of clinical endocrinology and metabolism.

[34]  Takahiro Sato,et al.  Molecular forms of hypothalamic ghrelin and its regulation by fasting and 2-deoxy-d-glucose administration. , 2005, Endocrinology.

[35]  J. Kamegai,et al.  Insulin-like growth factor-I down-regulates ghrelin receptor (growth hormone secretagogue receptor) expression in the rat pituitary , 2005, Regulatory Peptides.

[36]  F. Casanueva,et al.  The GHRH/GHRP-6 test for the diagnosis of GH deficiency in elderly or severely obese men. , 2005, European journal of endocrinology.

[37]  H. Nørrelund The metabolic role of growth hormone in humans with particular reference to fasting. , 2005, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[38]  K. Kangawa,et al.  Ghrelin: structure and function. , 2005, Physiological reviews.

[39]  Christina Wang,et al.  Influence of body mass index and gender on growth hormone (GH) responses to GH-releasing hormone plus arginine and insulin tolerance tests. , 2005, The Journal of clinical endocrinology and metabolism.

[40]  H. Orskov,et al.  Fasting unmasks a strong inverse association between ghrelin and cortisol in serum: studies in obese and normal-weight subjects. , 2005, The Journal of clinical endocrinology and metabolism.

[41]  J. Frystyk Free insulin-like growth factors -- measurements and relationships to growth hormone secretion and glucose homeostasis. , 2004, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[42]  R. Kineman,et al.  The role of pituitary ghrelin in growth hormone (GH) secretion: GH-releasing hormone-dependent regulation of pituitary ghrelin gene expression and peptide content. , 2004, Endocrinology.

[43]  M. Malagón,et al.  Homologous and heterologous regulation of pituitary receptors for ghrelin and growth hormone-releasing hormone. , 2004, Endocrinology.

[44]  J. Elashoff,et al.  Body mass index determines evoked growth hormone (GH) responsiveness in normal healthy male subjects: diagnostic caveat for adult GH deficiency. , 2004, The Journal of clinical endocrinology and metabolism.

[45]  B. Lowell,et al.  Leptin Receptor Signaling in POMC Neurons Is Required for Normal Body Weight Homeostasis , 2004, Neuron.

[46]  M. Tschöp,et al.  Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. , 2004, Endocrine reviews.

[47]  A. Giustina,et al.  Leptin Stimulates Growth Hormone Secretion via a Direct Pituitary Effect Combined with a Decreased Somatostatin Tone in a Median Eminence-Pituitary Perifusion Study , 2004, Neuroendocrinology.

[48]  R. Kineman,et al.  Fasting-induced changes in the hypothalamic-pituitary-GH axis in the absence of GH expression: lessons from the spontaneous dwarf rat. , 2004, The Journal of endocrinology.

[49]  F. Casanueva,et al.  Intracellular signaling mechanisms mediating ghrelin-stimulated growth hormone release in somatotropes. , 2003, Endocrinology.

[50]  R. Kineman,et al.  Role of Glucocorticoids in the Regulation of Pituitary Somatostatin Receptor Subtype (sst1–sst5) mRNA Levels: Evidence for Direct and Somatostatin-Mediated Effects , 2003, Neuroendocrinology.

[51]  F. Casanueva,et al.  Comparison between insulin tolerance test, growth hormone (GH)-releasing hormone (GHRH), GHRH plus acipimox and GHRH plus GH-releasing peptide-6 for the diagnosis of adult GH deficiency in normal subjects, obese and hypopituitary patients. , 2003, European journal of endocrinology.

[52]  F. Cavagnini,et al.  Nutritional status in the neuroendocrine control of growth hormone secretion: the model of anorexia nervosa , 2003, Frontiers in Neuroendocrinology.

[53]  Min-Seon Kim,et al.  Changes in ghrelin and ghrelin receptor expression according to feeding status , 2003, Neuroreport.

[54]  F. Oesch,et al.  Of mice and models: improved animal models for biomedical research. , 2002, Physiological genomics.

[55]  F. Golley,et al.  Structure and Function , 2002, Science's STKE.

[56]  M. Edery,et al.  Impairment of Liver GH Receptor Signaling by Fasting. , 2002, Endocrinology.

[57]  M. Matsubara,et al.  Regulational Effect of Ghrelin on Growth Hormone Secretion from Perifused Rat Anterior Pituitary Cells , 2002, Journal of neuroendocrinology.

[58]  H. Pijl,et al.  Altered neuroregulation of GH secretion in viscerally obese premenopausal women. , 2001, The Journal of clinical endocrinology and metabolism.

[59]  J. Kamegai,et al.  Regulation of the ghrelin gene: growth hormone-releasing hormone upregulates ghrelin mRNA in the pituitary. , 2001, Endocrinology.

[60]  S. Grottoli,et al.  Effects of 36 hour fasting on GH/IGF-I axis and metabolic parameters in patients with simple obesity. Comparison with normal subjects and hypopituitary patients with severe GH deficiency , 2001, International Journal of Obesity.

[61]  T. Unterman,et al.  Gene- and Activation-specific Mechanisms for Insulin Inhibition of Basal and Glucocorticoid-induced Insulin-like Growth Factor Binding Protein-1 and Phosphoenolpyruvate Carboxykinase Transcription , 2001, The Journal of Biological Chemistry.

[62]  I. Clarke,et al.  Chronic food-restriction alters the expression of somatostatin and growth hormone-releasing hormone in the ovariectomised ewe. , 2001, The Journal of endocrinology.

[63]  E. Ravussin,et al.  Circulating ghrelin levels are decreased in human obesity. , 2001, Diabetes.

[64]  M. Nakazato,et al.  Central effects of a novel acylated peptide, ghrelin, on growth hormone release in rats. , 2000, Biochemical and biophysical research communications.

[65]  S. Grottoli,et al.  The GH/IGF-I axis in obesity: influence of neuroendocrine and metabolic factors , 2000, International Journal of Obesity.

[66]  R. Kineman,et al.  Glucocorticoids Regulate Pituitary Growth Hormone Secretagogue Receptor Gene Expression , 2000, Journal of neuroendocrinology.

[67]  J. Kamegai,et al.  Effect of insulin-like growth factor-I on growth hormone-releasing factor receptor expression in primary rat anterior pituitary cell culture , 1999, Neuroscience Letters.

[68]  H. Kaji,et al.  Leptin stimulates basal and GHRH-induced GH release from cultured rat anterior pituitary cells in vitro. , 1999, The Kobe journal of medical sciences.

[69]  A. Caumo,et al.  Elevated insulin levels contribute to the reduced growth hormone (GH) response to GH-releasing hormone in obese subjects. , 1999, Metabolism: clinical and experimental.

[70]  R. Kineman,et al.  Growth hormone (GH)-releasing hormone (GHRH) and the GH secretagogue (GHS), L692,585, differentially modulate rat pituitary GHS receptor and GHRH receptor messenger ribonucleic acid levels. , 1999, Endocrinology.

[71]  Charles R. Gerfen,et al.  Current Protocols In Neuroscience , 1999 .

[72]  F. Cavagnini,et al.  Growth hormone in obesity , 1999, International Journal of Obesity.

[73]  C. Kahn,et al.  A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. , 1998, Molecular cell.

[74]  E. Müller,et al.  Growth hormone responses to growth hormone-releasing hormone and hexarelin in fed and fasted dogs: effect of somatostatin infusion or pretreatment with pirenzepine. , 1998, The Journal of endocrinology.

[75]  K. Mayo,et al.  Glucocorticoids regulate pituitary growth hormone-releasing hormone receptor messenger ribonucleic acid expression. , 1997, Endocrinology.

[76]  H. Orskov,et al.  Abdominal adiposity rather than age and sex predicts mass and regularity of GH secretion in healthy adults. , 1997, The American journal of physiology.

[77]  R. Kineman,et al.  Homologous down-regulation of growth hormone-releasing hormone receptor messenger ribonucleic acid levels. , 1997, Endocrinology.

[78]  H. Sugihara,et al.  Increased pituitary growth hormone-releasing factor (GRF) receptor messenger ribonucleic acid expression in food-deprived rats , 1996, Brain Research.

[79]  J. Takahara,et al.  Dexamethasone Increases Growth Hormone (GH)‐Releasing Hormone (GRH) Receptor mRNA Levels in Cultured Rat Anterior Pituitary Cells , 1996, Journal of neuroendocrinology.

[80]  D. Cocchi,et al.  Characterization of the hypothalamo-pituitary-IGF-I axis in rats made obese by overfeeding. , 1996, The Journal of endocrinology.

[81]  C. Barb,et al.  Glucose and free fatty acid modulation of growth hormone and luteinizing hormone secretion by cultured porcine pituitary cells. , 1995, Journal of animal science.

[82]  M. Berelowitz,et al.  Pituitary and hypothalamic somatostatin receptor subtype messenger ribonucleic acid expression in the food-deprived and diabetic rat. , 1994, Endocrinology.

[83]  A. Giustina,et al.  Growth hormone neuroregulation in diabetes mellitus , 1994, Trends in Endocrinology & Metabolism.

[84]  L. Frohman,et al.  Differential effects of central and peripheral administration of growth hormone (GH) and insulin-like growth factor on hypothalamic GH-releasing hormone and somatostatin gene expression in GH-deficient dwarf rats. , 1993, Endocrinology.

[85]  E. Arvat,et al.  Repetitive GHRH Administration Fails to Increase the Response to GHRH in Obese Subjects , 1993, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[86]  O. Serri,et al.  Effects of acute and prolonged glucose excess on growth hormone release by cultured rat anterior pituitary cells. , 1991, Neuroendocrinology.

[87]  D. Porte,et al.  Localization of type I insulin-like growth factor receptor messenger RNA in the adult rat brain by in situ hybridization. , 1991, Molecular endocrinology.

[88]  F. Bloom,et al.  Pituitary hyperplasia and gigantism in mice caused by a cholera toxin transgene , 1991, Nature.

[89]  R. Moxley,et al.  Distribution of insulin receptor-like immunoreactivity in the rat forebrain , 1989, Neuroscience.

[90]  B. Burguera,et al.  Activation of cholinergic neurotransmission by pyridostigmine reverses the inhibitory effect of hyperglycemia on growth hormone (GH) releasing hormone-induced GH secretion in man: does acute hyperglycemia act through hypothalamic release of somatostatin? , 1989, Neuroendocrinology.

[91]  G. Tannenbaum,et al.  Paradoxical enhancement of pituitary growth hormone (GH) responsiveness to GH-releasing factor in the face of high somatostatin tone. , 1989, Endocrinology.

[92]  C. Pert,et al.  Receptors for insulin-like growth factors I and II: autoradiographic localization in rat brain and comparison to receptors for insulin. , 1988, Endocrinology.

[93]  R. Palmiter,et al.  Dwarf mice produced by genetic ablation of growth hormone-expressing cells. , 1988, Genes & development.

[94]  M. Itoh Immunoreactive somatostatin in the hypothalamus and other regions of the rat brain: effects of insulin, glucose, alpha- or beta-blocker and L-dopa. , 1979, Endocrinologia japonica.

[95]  J. Martin,et al.  Ultradian growth hormone rhythm in the rat: effects of feeding, hyperglycemia, and insulin-induced hypoglycemia. , 1976, Endocrinology.

[96]  R. Kineman,et al.  Somatostatin and its receptors contribute in a tissue-specific manner to the sex-dependent metabolic (fed/fasting) control of growth hormone axis in mice. , 2011, American journal of physiology. Endocrinology and metabolism.

[97]  S. Kliewer,et al.  Fibroblast growth factor 21: from pharmacology to physiology. , 2010, The American journal of clinical nutrition.

[98]  M. Goldstein,et al.  Fibroblast growth factor-21 may mediate growth hormone resistance in anorexia nervosa. , 2010, The Journal of clinical endocrinology and metabolism.

[99]  K. Cianflone,et al.  Association of acylated and nonacylated ghrelin with insulin sensitivity in overweight and obese postmenopausal women. , 2007, The Journal of clinical endocrinology and metabolism.

[100]  M. Malagón,et al.  Regulation of pituitary cell function by adiponectin. , 2007, Endocrinology.

[101]  A. Bianchi,et al.  Growth hormone secretion and leptin in morbid obesity before and after biliopancreatic diversion: relationships with insulin and body composition. , 2004, The Journal of clinical endocrinology and metabolism.

[102]  M. Nakazato,et al.  Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. , 2002, The Journal of clinical endocrinology and metabolism.

[103]  S. Grottoli,et al.  Effects of recombinant human insulin-like growth factor I administration on the growth hormone (gh) response to GH-releasing hormone in obesity. , 2001, The Journal of clinical endocrinology and metabolism.

[104]  H. Yamamoto,et al.  IGF-I receptor signalling: lessons from the somatotroph. , 1996, Recent progress in hormone research.

[105]  G. Baumann,et al.  Characteristics of the somatotropic axis in insulin dependent diabetes mellitus. , 1995, Archives of medical research.

[106]  L. Suva,et al.  The Somatotrope as a Metabolic Sensor: Deletion of Leptin Receptors Causes Obesity Endocrinology. First Published Ahead of Print Materials and Methods Production of Deletion Mutant Mice Detection of Growth and Pubertal Changes Pituitary Cell Dispersion and Leptin Stimulation Immunolabeling Protocols , 2022 .