Mice with chronically increased circulating ghrelin develop age-related glucose intolerance

Reed, Jacquelyn A.; Benoit, Stephen C.; Pfluger, Paul T.; Tschöp, Matthias H.; D’Alessio, David A.; Seeley, Randy J.

doi:10.1152/ajpendo.00463.2007

Cited by 43 publications

(29 citation statements)

References 33 publications

(64 reference statements)

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“…Ghrelin administration to rodents dose-dependently increases fasting blood glucose, lowers insulin levels, and attenuates insulin responses during glucose tolerance testing (15,16). Similar ghrelin-mediated effects on blood glucose and/or insulin release have been demonstrated in isolated rodent islets and pancreata, in ghrelin-overexpressing mice, and in humans (3,6,15,16,47). Ghrelin also directly stimulates glucagon secretion from pancreatic ␣-cells (5).…”

Section: Discussionmentioning

confidence: 93%

Glucose-mediated control of ghrelin release from primary cultures of gastric mucosal cells

Sakata

Park

Walker

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

108

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-The peptide hormone ghrelin is released from a distinct group of gastrointestinal cells in response to caloric restriction, whereas its levels fall after eating. The mechanisms by which ghrelin secretion is regulated remain largely unknown. Here, we have used primary cultures of mouse gastric mucosal cells to investigate ghrelin secretion, with an emphasis on the role of glucose. Ghrelin secretion from these cells upon exposure to different D-glucose concentrations, the glucose antimetabolite 2-deoxy-D-glucose, and other potential secretagogues was assessed. The expression profile of proteins involved in glucose transport, metabolism, and utilization within highly enriched pools of mouse ghrelin cells and within cultured ghrelinoma cells was also determined. Ghrelin release negatively correlated with D-glucose concentration. Insulin blocked ghrelin release, but only in a low D-glucose environment. 2-Deoxy-D-glucose prevented the inhibitory effect of high D-glucose exposure on ghrelin release. mRNAs encoding several facilitative glucose transporters, hexokinases, the ATPsensitive potassium channel subunit Kir6.2, and sulfonylurea type 1 receptor were expressed highly within ghrelin cells, although neither tolbutamide nor diazoxide exerted direct effects on ghrelin secretion. These findings suggest that direct exposure of ghrelin cells to low ambient D-glucose stimulates ghrelin release, whereas high D-glucose and glucose metabolism within ghrelin cells block ghrelin release. Also, low D-glucose sensitizes ghrelin cells to insulin. Various glucose transporters, channels, and enzymes that mediate glucose responsiveness in other cell types may contribute to the ghrelin cell machinery involved in regulating ghrelin secretion under these different glucose environments, although their exact roles in ghrelin release remain uncertain. secretion THE PEPTIDE HORMONE GHRELIN is the endogenous ligand of the growth hormone secretagogue receptor (GHSR) and is named for its ability to stimulate growth hormone release (32, 59). Ghrelin also regulates gastrointestinal motility, chronic stressinduced mood-related behaviors, and alcohol-seeking behaviors, among many other actions (1,13,15,18,31,32,34,37). Perhaps best studied are ghrelin's actions in signaling and responding to states of energy insufficiency. Regarding its role in signaling energy-insufficient states, ghrelin levels are known to rise prior to set meals, following food deprivation, and after weight loss linked to exercise, cachexia, and anorexia nervosa (9,10,33,39,42,45,55,57,60). Several lines of evidence suggest that the rise in plasma ghrelin upon caloric restriction is likely related, at least in part, to binding of norepinephrine released from the sympathetic nervous system to ␤ 1 -adrenergic receptors embedded in the plasma membranes of ghrelin cells (14,28,41,63). Regarding ghrelin's role in responding to energy-insufficient states, infusions of ghrelin or GHSR agonists increase body weight via proorexigenic actions and/or decreases in energy expenditure (1...

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Section: Discussionmentioning

confidence: 93%

Glucose-mediated control of ghrelin release from primary cultures of gastric mucosal cells

Sakata

Park

Walker

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

108

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“…Acetic acid was added to each solution to adjust the final concentration to 1 M before tissue homogenization. We determine the tissue ghrelin concentration in supernatants obtained after centrifugation by radioimmunoassay (RIA) using anti-ghrelin [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] (C-RIA) and anti-ghrelin [1][2][3][4][5][6][7][8][9][10][11] (N-RIA) antisera, as described previously (12,15).…”

Section: Measurement Of Plasma and Tissue Ghrelin Concentrationsmentioning

confidence: 99%

“…Although several studies have demonstrated contradictory results (1,5,11,18,24), data from genetically engineered mice are consistent with this concept. Chronic elevation of plasma ghrelin levels suppresses insulin secretion, inducing glucose intolerance in transgenic mice (2,13,21), whereas ablation of ghrelin improves glucose tolerance by enhancing insulin secretion in diet-induced obesity (7) or ob/ob mouse models (23).…”

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confidence: 99%

Transgenic overexpression of intraislet ghrelin does not affect insulin secretion or glucose metabolism in vivo

Bando

Iwakura

Ariyasu

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Whereas ghrelin is produced primarily in the stomach, a small amount of it is produced in pancreatic islets. Although exogenous administration of ghrelin suppresses insulin secretion in vitro or in vivo, the role of intraislet ghrelin in the regulation of insulin secretion in vivo remains unclear. To understand the physiological role of intraislet ghrelin in insulin secretion and glucose metabolism, we developed a transgenic (Tg) mouse model, rat insulin II promoter ghrelin-internal ribosomal entry site-ghrelin O-acyl transferase (RIP-GG) Tg mice, in which mouse ghrelin cDNA and ghrelin O-acyltransferase are overexpressed under the control of the rat insulin II promoter. Although pancreatic desacyl ghrelin levels were elevated in RIP-GG Tg mice, pancreatic ghrelin levels were not altered in animals on a standard diet. However, when Tg mice were fed a medium-chain triglyceride-rich diet (MCTD), pancreatic ghrelin levels were elevated to ϳ16 times that seen in control animals. It seems likely that the gastric ghrelin cells possess specific machinery to provide the octanoyl acid necessary for ghrelin acylation but that this machinery is absent from pancreatic ␤-cells. Despite the overexpression of ghrelin, plasma ghrelin levels in the portal veins of RIP-GG Tg mice were unchanged from control levels. Glucose tolerance, insulin secretion, and islet architecture in RIP-GG Tg mice were not significantly different even when the mice were fed a MCTD. These results indicate that intraislet ghrelin does not play a major role in the regulation of insulin secretion in vivo.pancreas; ghrelin D-acyltransferase GHRELIN IS A 28-AMINO ACID PEPTIDE HORMONE, with a unique modification of acylation at the third serine residue, first described by Kojima et al. (17) in 1999. The acyl modification of ghrelin is mediated by the recently discovered enzyme ghrelin O-acyl transferase (29), and the modification is essential for ghrelin binding to its cognate receptor (12). Ghrelin is produced primarily in the stomach, but small amounts of ghrelin are also produced in pancreatic islets (1,5,8,10,12,26,27). Controversy remains about which type of islet cell produces ghrelin (5,20,26,27). Date et al. (5) reported that ghrelin is present in ␣-cells in humans and rats, whereas Volante et al. (26) reported that ghrelin is produced by ␤-cells in humans. In contrast, Wierup and colleagues (27, 28) and Prado et al. (20) reported that ghrelin-expressing cells comprise a new islet cell type distinct from ␣-, ␤-, and ␦-cells and PP cells in human, rat, and mouse islets.Exogenous ghrelin suppresses insulin secretion from pancreatic ␤-cells in vitro (4, 9, 22) or in vivo (3,22,25). Although several studies have demonstrated contradictory results (1,5,11,18,24), data from genetically engineered mice are consistent with this concept. Chronic elevation of plasma ghrelin levels suppresses insulin secretion, inducing glucose intolerance in transgenic mice (2, 13, 21), whereas ablation of ghrelin improves glucose tolerance by enhancing insulin secretion in...

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“…These findings therefore suggest that ghrelin signaling contributes minimally to glucose homeostasis, at least during prolonged exposure to low-fat diet conditions. In contrast, transgenic mice with neuron-specific (and to a much lesser extent liver-specific) overexpression of ghrelin developed glucose intolerance at 32 weeks of age despite having lower body weights (96).…”

Section: Ghrelin and Pyy: Current Evidence From Mouse Mutagenesismentioning

confidence: 93%

“…Besides, Sun et al (114) crossed leptin deficient (ob/ob) mice with mice deficient in ghrelin to study the interaction of ghrelin and leptin signaling. Moreover, two recent studies described 1) a specific impairment of GHSR activation in the hypothalamus of rats (109) and 2) transgenic overexpression of ghrelin driven by the neuron-specific enolase promotor in mice (96). Such modulation of ghrelin function in the hypothalamus, a well-known central regulator of energy homeostasis, provides useful knowledge to dissect central versus peripheral actions of ghrelin.…”

Section: Ghrelin and Pyy: Current Evidence From Mouse Mutagenesismentioning

confidence: 99%

Ghrelin and PYY in the regulation of energy balance and metabolism: lessons from mouse mutants

Kirchner

Tong

Tschöp

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Effective control of body weight and energy homeostasis requires stringent regulation of caloric intake and energy expenditure. Gut-brain interactions comprise a central axis for the control of energy homeostasis by integrating the intake of nutrients with an effective utilization of ingested calories either by storage or by expenditure as cellular fuel. Ghrelin, a stomach-derived peptide, is the only known circulating orexigenic hormone. It is acylated with a medium-chain fatty acid by the enzyme ghrelin O-acetyltransferase (GOAT) and displays a broad range of activity, from central control of food intake to peripheral functions such as gastric emptying and insulin secretion. PYY, a peptide produced by L cells of the small intestine and rectum, has been shown to inhibit gut motility and is proposed to stimulate a powerful central satiety response. In recent years, pharmacological studies in animals and clinical studies in humans have contributed to our knowledge of principal ghrelin and PYY actions. However, valuable findings from studies using ghrelin-deficient mice, ghrelin receptor [growth hormone secretagogue receptor-1a (GHSR1a)]-deficient mice, double-knockout mice (for ghrelin and GHSR), and GOAT-deficient or -overexpressor mice, as well as mice deficient for PYY or neuropeptide Y receptors have allowed better definition of the actual physiological functions of ghrelin and PYY. This review summarizes findings from mutant mouse studies with emphasis on respective gene knockout and transgenic animals and describes how these studies contribute to the current understanding of how endogenous ghrelin and PYY as two major representatives of endocrine gut-brain communications may regulate energy and glucose homeostasis.

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Mice with chronically increased circulating ghrelin develop age-related glucose intolerance

Cited by 43 publications

References 33 publications

Glucose-mediated control of ghrelin release from primary cultures of gastric mucosal cells

Glucose-mediated control of ghrelin release from primary cultures of gastric mucosal cells

Transgenic overexpression of intraislet ghrelin does not affect insulin secretion or glucose metabolism in vivo

Ghrelin and PYY in the regulation of energy balance and metabolism: lessons from mouse mutants

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