Butyrate increases intracellular calcium levels and enhances growth hormone release from rat anterior pituitary cells via the G-protein-coupled receptors GPR41 and 43
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Butyrate is a short-chain fatty acid (SCFA) closely related to the ketone body ß-hydroxybutyrate (BHB), which is considered to be the major energy substrate during prolonged exercise or starvation. During fasting, serum growth hormone (GH) rises concomitantly with the accumulation of BHB and butyrate. Interactions between GH, ketone bodies and SCFA during the metabolic adaptation to fasting have been poorly investigated to date. In this study, we examined the effect of butyrate, an endogenous agonist for the two G-protein-coupled receptors (GPCR), GPR41 and 43, on non-stimulated and GH-releasing hormone (GHRH)-stimulated hGH secretion. Furthermore, we investigated the potential role of GPR41 and 43 on the generation of butyrate-induced intracellular Ca2+ signal and its ultimate impact on hGH secretion. To study this, wt-hGH was transfected into a rat pituitary tumour cell line stably expressing the human GHRH receptor. Treatment with butyrate promoted hGH synthesis and improved basal and GHRH-induced hGH-secretion. By acting through GPR41 and 43, butyrate enhanced intracellular free cytosolic Ca2+. Gene-specific silencing of these receptors led to a partial inhibition of the butyrate-induced intracellular Ca2+ rise resulting in a decrease of hGH secretion. This study suggests that butyrate is a metabolic intermediary, which contributes to the secretion and, therefore, to the metabolic actions of GH during fasting.
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Butyrate enhances growth hormone secretion in pituitary cells via GPR41/43 activation and intracellular accumulation of Ca2+.
“Moreover, Miletta and colleagues found that butyrate enhances growth hormone (GH) secretion in pituitary cells via GPR41/43 activation and intracellular accumulation of Ca2+ (131).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [131]
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References 46 · Cited by 51
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- [1]Norrelund H (2005) The metabolic role of growth hormone in humans with particular reference to fasting. Growth Horm IGF Res 15: 95– 122. 15809014
- [4]Copeland KC, Nair KS (1994) Acute growth hormone effects on amino acid and lipid metabolism. J Clin Endocrinol Metab 78: 1040– 1047. 8175957
- [5]Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, et al (2013) Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339: 211– 214. 23223453 PMC3735349
- [6]Cahill GF Jr (2006) Fuel metabolism in starvation. Annu Rev Nutr 26: 1– 22. 16848698
- [7]Le Poul E, Loison C, Struyf S, Springael JY, Lannoy V, et al (2003) Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem 278: 25481– 25489. 12711604
- [8]Juul A, Jorgensen JOL (2000) Growth Hormone in Adults: Physiological and Clinical Aspects: Cambridge University Press. 498 p.
- [9]Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, et al (2003) The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 278: 11312– 11319. 12496283
- [10]Wang A, Gu Z, Heid B, Akers RM, Jiang H (2009) Identification and characterization of the bovine G protein-coupled receptor GPR41 and GPR43 genes. J Dairy Sci 92: 2696– 2705. 19448003
- [11]Nilsson NE, Kotarsky K, Owman C, Olde B (2003) Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem Biophys Res Commun 303: 1047– 1052. 12684041
- [12]Ishiwata H, Katoh K, Chen C, Yonezawa T, Sasaki Y, et al (2005) Suppressing actions of butyrate on growth hormone (GH) secretion induced by GH-releasing hormone in rat anterior pituitary cells. Gen Comp Endocrinol 143: 222– 230. 15927184
- [13]Bancroft FC (1973) Intracellular location of newly synthesized growth hormone. Exp Cell Res 79: 275– 278. 4205699
- [14]Petkovic V, Godi M, Lochmatter D, Eble A, Fluck CE, et al (2010) Growth hormone (GH)-releasing hormone increases the expression of the dominant-negative GH isoform in cases of isolated GH deficiency due to GH splice-site mutations. Endocrinology 151: 2650– 2658. 20351314
- [15]Besson A, Salemi S, Deladoey J, Vuissoz JM, Eble A, et al (2005) Short stature caused by a biologically inactive mutant growth hormone (GH-C53S). J Clin Endocrinol Metab 90: 2493– 2499. 15713716
- [16]Fluck CE, Martens JW, Conte FA, Miller WL (2002) Clinical, genetic, and functional characterization of adrenocorticotropin receptor mutations using a novel receptor assay. J Clin Endocrinol Metab 87: 4318– 4323. 12213892
- [17]Everitt B, Rabe-Hesketh S (2001) Analyzing Medical Data Using S-PLUS: Springer. 486 p.
- [18]Yang SK, Wang K, Parkington H, Chen C (2008) Involvement of tetrodotoxin-resistant Na+ current and protein kinase C in the action of growth hormone (GH)-releasing hormone on primary cultured somatotropes from GH-green fluorescent protein transgenic mice. Endocrinology 149: 4726– 4735. 18535104
- [19]Chang JP, Habibi HR, Yu Y, Moussavi M, Grey CL, et al (2012) Calcium and other signalling pathways in neuroendocrine regulation of somatotroph functions. Cell Calcium 51: 240– 252. 22137240
- [20]Chen C, Xu R, Clarke IJ, Ruan M, Loneragan K, et al (2000) Diverse intracellular signalling systems used by growth hormone-releasing hormone in regulating voltage-gated Ca2+ or K channels in pituitary somatotropes. Immunol Cell Biol 78: 356– 368. 10947860
- [21]Yang SK, Steyn F, Chen C (2012) Influence of membrane ion channel in pituitary somatotrophs by hypothalamic regulators. Cell Calcium 51: 231– 239. 22243899
- [22]Nakamura K, Kamouchi M, Arimura K, Nishimura A, Kuroda J, et al (2012) Extracellular acidification activates cAMP responsive element binding protein via Na+/H+ exchanger isoform 1-mediated Ca(2)(+) oscillation in central nervous system pericytes. Arterioscler Thromb Vasc Biol 32: 2670– 2677. 22922957
- [23]Stanley F, Samuels HH (1984) n-Butyrate effects thyroid hormone stimulation of prolactin production and mRNA levels in GH1 cells. J Biol Chem 259: 9768– 9775. 6086648
- [24]Yen PM, Tashjian AH Jr (1981) Short chain fatty acids increase prolactin and growth hormone production and alter cell morphology in the GH3 strain of rat pituitary cells. Endocrinology 109: 17– 22. 7238401
- [25]Dannies PS, Gautvik KM, Tashjian AH Jr (1976) A possible role of cyclic AMP in mediating the effects of thyrotropin-releasing hormone on prolactin release and on prolactin and growth hormone synthesis in pituitary cells in culture. Endocrinology 98: 1147– 1159. 177274
- [26]Miller AA, Kurschel E, Osieka R, Schmidt CG (1987) Clinical pharmacology of sodium butyrate in patients with acute leukemia. Eur J Cancer Clin Oncol 23: 1283– 1287. 3678322
- [27]Chen ZX, Breitman TR (1994) Tributyrin: a prodrug of butyric acid for potential clinical application in differentiation therapy. Cancer Res 54: 3494– 3499. 8012972
- [28]Vescovi PP, Coiro V (2001) Different control of GH secretion by gamma-amino- and gamma-hydroxy-butyric acid in 4-year abstinent alcoholics. Drug Alcohol Depend 61: 217– 221. 11164685
- [29]Volpi R, Chiodera P, Caffarra P, Scaglioni A, Malvezzi L, et al (2000) Muscarinic cholinergic mediation of the GH response to gamma-hydroxybutyric acid: neuroendocrine evidence in normal and parkinsonian subjects. Psychoneuroendocrinology 25: 179– 185. 10674281
- [30]Quabbe HJ, Trompke M, Luyckx AS (1983) Influence of ketone body infusion on plasma growth hormone and glucagon in man. J Clin Endocrinol Metab 57: 613– 618. 6348066
- [31]Yudkoff M, Daikhin Y, Nissim I, Horyn O, Lazarow A, et al (2005) Response of brain amino acid metabolism to ketosis. Neurochem Int 47: 119– 128. 15888376
- [32]Lussier BT, French MB, Moore BC, Kraicer J (1991) Free intracellular Ca2+ concentration ([Ca2+]i) and growth hormone release from purified rat somatotrophs. I. GH-releasing factor-induced Ca2+ influx raises [Ca2+]i. Endocrinology 128: 570– 582. 1846113
- [33]Lussier BT, French MB, Moor BC, Kraicer J (1991) Free intracellular Ca2+ concentration and growth hormone (GH) release from purified rat somatotrophs. III. Mechanism of action of GH-releasing factor and somatostatin. Endocrinology 128: 592– 603. 1670926
- [34]Sun S, Li W, Zhang H, Zha L, Xue Y, et al (2012) Requirement for store-operated calcium entry in sodium butyrate-induced apoptosis in human colon cancer cells. Biosci Rep 32: 83– 90. 21699495
- [35]Kimura I, Ozawa K, Inoue D, Imamura T, Kimura K, et al (2013) The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun 4: 1829. 23652017 PMC3674247
- [36]Lussier BT, Wood DA, French MB, Moor BC, Kraicer J (1991) Free intracellular Ca2+ concentration ([Ca2+]i) and growth hormone release from purified rat somatotrophs. II. Somatostatin lowers [Ca2+]i by inhibiting Ca2+ influx. Endocrinology 128: 583– 591. 1670925
- [37]Xiong Y, Miyamoto N, Shibata K, Valasek MA, Motoike T, et al (2004) Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proc Natl Acad Sci U S A 101: 1045– 1050. 14722361 PMC327148
- [38]Carro E, Senaris R, Considine RV, Casanueva FF, Dieguez C (1997) Regulation of in vivo growth hormone secretion by leptin. Endocrinology 138: 2203– 2206. 9112421
- [39]Tannenbaum GS, Gurd W, Lapointe M (1998) Leptin is a potent stimulator of spontaneous pulsatile growth hormone (GH) secretion and the GH response to GH-releasing hormone. Endocrinology 139: 3871– 3875. 9724042
- [40]Nohr MK, Pedersen MH, Gille A, Egerod KL, Engelstoft MS, et al (2013) GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes. Endocrinology 154: 3552– 3564. 23885020
- [41]Cummings BP, Bettaieb A, Graham JL, Stanhope KL, Dill R, et al (2011) Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats. Proc Natl Acad Sci U S A 108: 14670– 14675. 21873226 PMC3167517
- [42]Fulop M, Murthy V, Michilli A, Nalamati J, Qian Q, et al (1999) Serum beta-hydroxybutyrate measurement in patients with uncontrolled diabetes mellitus. Arch Intern Med 159: 381– 384. 10030312
- [43]Gilbert DL, Pyzik PL, Freeman JM (2000) The ketogenic diet: seizure control correlates better with serum beta-hydroxybutyrate than with urine ketones. J Child Neurol 15: 787– 790. 11198492
- [45]Ho KY, Veldhuis JD, Johnson ML, Furlanetto R, Evans WS, et al (1988) Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man. J Clin Invest 81: 968– 975. 3127426 PMC329619
- Authors
- Miletta, M. C., Petkovic, V., Eblé, A., Ammann, R. A., Flück, C. E., & Mullis, P.-E.
- Affiliations
- University Children’s Hospital Bern (CH)
- University of Bern (CH)
- Corresponding author
- Mullis, Primus-E.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-10-13
- Volume
- 9
- Issue
- 10
- Pages
- e107388
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4195582
- OpenAlex
- W2107519520
- Cited by
- 51
- References
- 46
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 8 · 2020: 6 · 2019: 4 · 2018: 3 · 2017: 3 · 2015: 3
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- BORIS (University Library Bern) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Open Access CRIS of the University of Bern
- Funders
- National Science Foundation
- Inselspital, Universitätsspital Bern
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (320000, 121998)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- butyrate, short-chain fatty acids, growth hormone secretion, anterior pituitary cells, GPR41, GPR43, G protein-coupled receptors, intracellular calcium, growth hormone-releasing hormone, fasting, ketone bodies, beta-hydroxybutyrate, metabolic adaptation
- MeSH terms
- Animals, Calcium, Cell Line, Pituitary Gland, Anterior, Growth Hormone, Growth Hormone-Releasing Hormone, Butyric Acid, Gene Silencing, RNA, Small Interfering, Receptors, G-Protein-Coupled, Rats
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