胃饥饿素与糖脂代谢、能量平衡及肥胖的关系
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摘要
胃饥饿素(Ghrelin)是胃底黏膜分泌的一种脑肠肽,为生长激素促泌剂受体的内源性配体。Ghrelin不但能促进生长激素分泌,对机体糖脂代谢及能量平衡也有重要影响,与机体食欲、肥胖等关系密切。深入研究Ghrelin在机体糖脂代谢及能量平衡中的作用及机制,有助于为糖尿病、肥胖等代谢疾病提供新的思路和治疗靶点。
Ghrelin is a brain-gut peptide secreted by the gastric mucosa and is an endogenous ligand for the growth hormone secretagogue receptor(GHSR). Recent studies have found that Ghrelin can not only promote the secretion of growth hormone,but affect glucose-lipid metabolism and energy balance. Ghrelin is closely related to appetite and obesity. Further research on the role of Ghrelin in metabolism and energy balance may help to provide new therapeutic targets for diabetes,obesity and other metabolic diseases.
Ghrelin is a brain-gut peptide secreted by the gastric mucosa and is an endogenous ligand for the growth hormone secretagogue receptor(GHSR). Recent studies have found that Ghrelin can not only promote the secretion of growth hormone,but affect glucose-lipid metabolism and energy balance. Ghrelin is closely related to appetite and obesity. Further research on the role of Ghrelin in metabolism and energy balance may help to provide new therapeutic targets for diabetes,obesity and other metabolic diseases.
引文
[1]Kojima M,Hosoda H,Date Y,et al.Ghrelin is a growth-hormone-releasing acylated peptide from stomach.Nature,1999,402:656-660.
[2]Soares JB,Leite-Moreira AF.Ghrelin,des-acyl ghrelin and obestatin:Three pieces of the same puzzle.Peptides,2008,29:1255-1270.
[3]Delhanty PJ,Huisman M,Julien M,et al.The acylated(AG)to unacylated(UAG)ghrelin ratio in esterase inhibitor-treated blood is higher than previously described.Clin Endocrino(l Oxf),2015,82:142-146.
[4]Gauna C,Delhanty PJD,Hofland LJ,et al.Ghrelin stimulates,whereas des-octanoyl Ghrelin inhibits,glucose output by primary hepatocytes.J Clin Endocrinol Metab,2005,90:1055-1060.
[5]Mihalache L,Gherasim A,Ni..O,et al.Effects of ghrelin in energy balance and body weight homeostasis.Hormones(Athens),2016,15:186-196.
[6]Garin MC,Burns CM,Kaul S,et al.The human experience with Ghrelin administration.J Clin Endocrinol Metab,2013,98:1826-1837.
[7]Churm R,Davies JS,Stephens JW,et al.Ghrelin function in human obesity and type 2 diabetes:a concise review.Obes Rev,2016,18:140-148.
[8]Castada TR,Tong J,Datta R,et al.Ghrelin in the regulation of body weight and metabolism.Front Neuroendocrinol,2010,31:44-60.
[9]Lindqvist A,Shcherbina L,Fischer AT,et al.Ghrelin is a regulator of Glucagon-like peptide 1 secretion and transcription in mice.Front Endocrinol(Lausanne),2017,8:135.
[10]Soengas JL.Contribution of glucose-and fatty acid sensing systems to the regulation of food intake in fish:a review.Gen Comp Endocrinol,2014,205:36-48.
[11]Delhanty PJD,Neggers SJ,van der Lely AJ.Should we consider des-acyl ghrelin as a separate hormone and if so,what does it do?.Front Horm Res,2014,42:163-174.
[12]Zigman JM,Bouret SG,Andrews ZB.Obesity impairs the action of the neuroendocrine Ghrelin system.Trends Endocrinol Metab,2016,27:54-63.
[13]Oya M,Kitaguchi T,Harada K,et al.Low glucose-induced ghrelin secretion is mediated by an ATP-sensitive potassium channel.J Endocrinol,2015,226:25-34.
[14]Mani BK,Uchida A,Lee Y,et al.Hypoglycemic effect of combined Ghrelin and Glucagon receptor blockade.Diabetes,2017,66:1847-1857.
[15]Adriaenssens AE,Svendsen B,Lam BYH,et al.Transcriptomic profiling of pancreatic alpha,beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets.Diabetologia,2016,59:2156-2165.
[16]Teuffel P,Wang L,Prinz P,et al.Treatment with the ghrelin-O-acyltransferase(GOAT)inhibitor GO-CoA-Tat reduces food intake by reducing meal frequency in rats.J Physiol Pharmacol,2015,66:493-503.
[17]Pradhan G,Wu CS,Han Lee J,et al.Obestatin stimulates glucose-induced insulin secretion through ghrelin receptor GHS-Rscientific reports,Nature Publishing Group,2017,7:967.
[18]Gagnon J,Anini Y.Insulin and norepinephrine regulate Ghrelin secretion from a rat primary stomach cell culture.Endocrinol,2012,153:3646-3656.
[19]Chabot F,Caron A,Laplante M,et al.Interrelationships between ghrelin,insulin and glucose homeostasis:Physiological relevance.World J Diabetes,2014,5:328-341.
[20]Li Z,Xu G,Qin Y,et al.Ghrelin promotes hepatic lipogenesis by activation of mTOR-PPARγsignaling pathway.Proc Natl Acad Sci USA,2014,111:13163-13168.
[21]Zhang SR,Fan XM.Ghrelin-ghrelin O-acyltransferase system in the pathogenesis of nonalcoholic fatty liver disease.World J Gastroenterol,2015,21:3214-3222.
[22]Davies JS,Kotokorpi P,Eccles SR,et al.Ghrelin induces abdominal obesity via GHS-R-dependent lipid retention.Mol Endocrinol,2009,23:914-924.
[23]Rodríguez A,Gómez-Ambrosi J,Catalán V,et al.Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes.Int J Obes(Lond),2009,33:541-552.
[24]Hosoda H,Kojima M,Mizushima T,et al.Structural divergence of human ghrelin.Identification of multiple ghrelin-derived molecules produced by post-translational processing.J Biol Chem,2003,278:64-70.
[25]Stevanovic D,Trajkovic V,Müller-Lühlhoff S,et al.Ghrelininduced food intake and adiposity depend on central mTORC1/S6K1 signaling.Mol Cell Endocrinol,2013,381:280-290.
[26]Alen F,Crespo I,Ramírez-López MT,et al.Ghrelin-induced orexigenic effect in rats depends on the metabolic status and is counteracted by peripheral CB1 receptor antagonism.PLoS One,2013,8:e60918.
[27]Pradhan G,Samson SL,Sun Y.Ghrelin:Much more than a hunger hormone.Curr Opin Clin Nutr Metab Care,2013,16:619-624.
[28]Carey AL,Kingwell BA.Brown adipose tissue in humans:therapeutic potential to combat obesity.Pharmacol Ther,2013,140:26-33.
[29]Lin L,Saha PK,Ma X,et al.Ablation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues.Aging Cell,2011,10:996-1010.
[30]Papandreou D,Karavolias C,Arvaniti F,et al.Fasting Ghrelin levels are decreased in obese subjects and are significantly related with insulin resistance and body mass index.Open Access Maced J Med Sci,2017,5:699-702.
[31]Briggs DI,Enriori PJ,Lemus MB,et al.Diet-induced obesity causes Ghrelin resistance in arcuate NPY/AgRP neurons.Endocrinol,2010,151:4745-4755.
[32]Delhanty PJD,Neggers SJ,van der Lely AJ.Ghrelin:the differences between acyl-and des-acyl ghrelin.Eur J Endocrinol,2012,167:601-608.
[33]Huang L,Tong Y,Zhang F,et al.Increased acyl ghrelin but decreased total ghrelin and unacyl ghrelin in Chinese Han people with impaired fasting glucose combined with impaired glucose tolerance.Peptides,2014,60:86-94.
[34]St-Pierre DH,Karelis AD,Coderre L,et al.Association of acylated and nonacylated ghrelin with insulin sensitivity in overweight and obese postmenopausal women.J Clin Endocrinol Metab,2007,92:264-269.
[35]Barazzoni R,Gortan CG,Semolic A,et al.Plasma total and unacylated ghrelin predict 5-year changes in insulin resistance.Clin Nutr,2016,35:1168-1173.
[36]Rotkvic V,Altabas V.Anti-ghrelin antibodies in appetite suppression:recent advances in obesity pharmacotherapy.Immunotargets Ther,2015:123-128.
[37]McGovern KR,Darling JE,Hougland JL.Progress in small molecule and biologic therapeutics targeting Ghrelin signaling.Mini Rev Med Chem,2016,16:465-480.
[38]Kouno T,Akiyama N,Ito T,et al.Ghrelin O-acyltransferase knockout mice show resistance to obesity when fed high-sucrose diet.J Endocrinol,2016,228:115-125.
[2]Soares JB,Leite-Moreira AF.Ghrelin,des-acyl ghrelin and obestatin:Three pieces of the same puzzle.Peptides,2008,29:1255-1270.
[3]Delhanty PJ,Huisman M,Julien M,et al.The acylated(AG)to unacylated(UAG)ghrelin ratio in esterase inhibitor-treated blood is higher than previously described.Clin Endocrino(l Oxf),2015,82:142-146.
[4]Gauna C,Delhanty PJD,Hofland LJ,et al.Ghrelin stimulates,whereas des-octanoyl Ghrelin inhibits,glucose output by primary hepatocytes.J Clin Endocrinol Metab,2005,90:1055-1060.
[5]Mihalache L,Gherasim A,Ni..O,et al.Effects of ghrelin in energy balance and body weight homeostasis.Hormones(Athens),2016,15:186-196.
[6]Garin MC,Burns CM,Kaul S,et al.The human experience with Ghrelin administration.J Clin Endocrinol Metab,2013,98:1826-1837.
[7]Churm R,Davies JS,Stephens JW,et al.Ghrelin function in human obesity and type 2 diabetes:a concise review.Obes Rev,2016,18:140-148.
[8]Castada TR,Tong J,Datta R,et al.Ghrelin in the regulation of body weight and metabolism.Front Neuroendocrinol,2010,31:44-60.
[9]Lindqvist A,Shcherbina L,Fischer AT,et al.Ghrelin is a regulator of Glucagon-like peptide 1 secretion and transcription in mice.Front Endocrinol(Lausanne),2017,8:135.
[10]Soengas JL.Contribution of glucose-and fatty acid sensing systems to the regulation of food intake in fish:a review.Gen Comp Endocrinol,2014,205:36-48.
[11]Delhanty PJD,Neggers SJ,van der Lely AJ.Should we consider des-acyl ghrelin as a separate hormone and if so,what does it do?.Front Horm Res,2014,42:163-174.
[12]Zigman JM,Bouret SG,Andrews ZB.Obesity impairs the action of the neuroendocrine Ghrelin system.Trends Endocrinol Metab,2016,27:54-63.
[13]Oya M,Kitaguchi T,Harada K,et al.Low glucose-induced ghrelin secretion is mediated by an ATP-sensitive potassium channel.J Endocrinol,2015,226:25-34.
[14]Mani BK,Uchida A,Lee Y,et al.Hypoglycemic effect of combined Ghrelin and Glucagon receptor blockade.Diabetes,2017,66:1847-1857.
[15]Adriaenssens AE,Svendsen B,Lam BYH,et al.Transcriptomic profiling of pancreatic alpha,beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets.Diabetologia,2016,59:2156-2165.
[16]Teuffel P,Wang L,Prinz P,et al.Treatment with the ghrelin-O-acyltransferase(GOAT)inhibitor GO-CoA-Tat reduces food intake by reducing meal frequency in rats.J Physiol Pharmacol,2015,66:493-503.
[17]Pradhan G,Wu CS,Han Lee J,et al.Obestatin stimulates glucose-induced insulin secretion through ghrelin receptor GHS-Rscientific reports,Nature Publishing Group,2017,7:967.
[18]Gagnon J,Anini Y.Insulin and norepinephrine regulate Ghrelin secretion from a rat primary stomach cell culture.Endocrinol,2012,153:3646-3656.
[19]Chabot F,Caron A,Laplante M,et al.Interrelationships between ghrelin,insulin and glucose homeostasis:Physiological relevance.World J Diabetes,2014,5:328-341.
[20]Li Z,Xu G,Qin Y,et al.Ghrelin promotes hepatic lipogenesis by activation of mTOR-PPARγsignaling pathway.Proc Natl Acad Sci USA,2014,111:13163-13168.
[21]Zhang SR,Fan XM.Ghrelin-ghrelin O-acyltransferase system in the pathogenesis of nonalcoholic fatty liver disease.World J Gastroenterol,2015,21:3214-3222.
[22]Davies JS,Kotokorpi P,Eccles SR,et al.Ghrelin induces abdominal obesity via GHS-R-dependent lipid retention.Mol Endocrinol,2009,23:914-924.
[23]Rodríguez A,Gómez-Ambrosi J,Catalán V,et al.Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes.Int J Obes(Lond),2009,33:541-552.
[24]Hosoda H,Kojima M,Mizushima T,et al.Structural divergence of human ghrelin.Identification of multiple ghrelin-derived molecules produced by post-translational processing.J Biol Chem,2003,278:64-70.
[25]Stevanovic D,Trajkovic V,Müller-Lühlhoff S,et al.Ghrelininduced food intake and adiposity depend on central mTORC1/S6K1 signaling.Mol Cell Endocrinol,2013,381:280-290.
[26]Alen F,Crespo I,Ramírez-López MT,et al.Ghrelin-induced orexigenic effect in rats depends on the metabolic status and is counteracted by peripheral CB1 receptor antagonism.PLoS One,2013,8:e60918.
[27]Pradhan G,Samson SL,Sun Y.Ghrelin:Much more than a hunger hormone.Curr Opin Clin Nutr Metab Care,2013,16:619-624.
[28]Carey AL,Kingwell BA.Brown adipose tissue in humans:therapeutic potential to combat obesity.Pharmacol Ther,2013,140:26-33.
[29]Lin L,Saha PK,Ma X,et al.Ablation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues.Aging Cell,2011,10:996-1010.
[30]Papandreou D,Karavolias C,Arvaniti F,et al.Fasting Ghrelin levels are decreased in obese subjects and are significantly related with insulin resistance and body mass index.Open Access Maced J Med Sci,2017,5:699-702.
[31]Briggs DI,Enriori PJ,Lemus MB,et al.Diet-induced obesity causes Ghrelin resistance in arcuate NPY/AgRP neurons.Endocrinol,2010,151:4745-4755.
[32]Delhanty PJD,Neggers SJ,van der Lely AJ.Ghrelin:the differences between acyl-and des-acyl ghrelin.Eur J Endocrinol,2012,167:601-608.
[33]Huang L,Tong Y,Zhang F,et al.Increased acyl ghrelin but decreased total ghrelin and unacyl ghrelin in Chinese Han people with impaired fasting glucose combined with impaired glucose tolerance.Peptides,2014,60:86-94.
[34]St-Pierre DH,Karelis AD,Coderre L,et al.Association of acylated and nonacylated ghrelin with insulin sensitivity in overweight and obese postmenopausal women.J Clin Endocrinol Metab,2007,92:264-269.
[35]Barazzoni R,Gortan CG,Semolic A,et al.Plasma total and unacylated ghrelin predict 5-year changes in insulin resistance.Clin Nutr,2016,35:1168-1173.
[36]Rotkvic V,Altabas V.Anti-ghrelin antibodies in appetite suppression:recent advances in obesity pharmacotherapy.Immunotargets Ther,2015:123-128.
[37]McGovern KR,Darling JE,Hougland JL.Progress in small molecule and biologic therapeutics targeting Ghrelin signaling.Mini Rev Med Chem,2016,16:465-480.
[38]Kouno T,Akiyama N,Ito T,et al.Ghrelin O-acyltransferase knockout mice show resistance to obesity when fed high-sucrose diet.J Endocrinol,2016,228:115-125.