Chemical gastric inhibitory polypeptide receptor antagonism protects against obesity, insulin resistance, glucose intolerance and associated disturbances in mice fed high-fat and cafeteria diets

Gault, Victor; McClean, Paula; Cassidy, Roslyn; Irwin, Nigel; Flatt, Peter R.

doi:10.1007/s00125-007-0710-4

Cited by 117 publications

(109 citation statements)

References 43 publications

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“…However, GIP is also believed to play a role in lipid metabolism and fat deposition [45]. Accordingly, GIP receptor antagonism can potentially protect against or even reverse many of the obesity-associated abnormalities of type 2 diabetes [46][47][48]. Similar to the conundrum regarding the clinical use of GIP receptor agonists or antagonists, both genetic knockout [49] and overexpression [50] of GIP has been shown to protect against obesity and development of diabetes.…”

Section: Resultsmentioning

confidence: 99%

An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

Hasib

Gault

et al. 2016

Diabetologia

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Aims/hypothesis Glucose-dependent insulinotropic polypeptide (GIP) and xenin, regulatory gut hormones secreted from enteroendocrine K cells, exert important effects on metabolism. In addition, xenin potentiates the biological actions of GIP. The present study assessed the actions and therapeutic utility of a (DAla 2 )GIP/xenin-8-Gln hybrid peptide, in comparison with the parent peptides (DAla 2 )GIP and xenin-8-Gln. Methods Following confirmation of enzymatic stability, insulin secretory activity of (DAla 2 )GIP/xenin-8-Gln was assessed in BRIN-BD11 beta cells. Acute and persistent glucose-lowering and insulin-releasing effects were then examined in vivo. Finally, the metabolic benefits of twice daily injection of (DAla 2 )GIP/xenin-8-Gln was determined in high-fat-fed mice.

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Section: Resultsmentioning

confidence: 99%

An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

Hasib

Gault

et al. 2016

Diabetologia

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“…7 Furthermore, this result was reproduced by daily treatment of normal mice fed with high-fat diets with a stable GIPR antagonist, (Pro 3 )GIP. 10 However, in differentiated 3T3-L1 cells, GIP has been reported to behave as a lipolytic hormone, as it was observed to stimulate glycerol release through the activation of adenylate cyclase. 14 Interestingly, the effect of GIP was inhibited by the coincubation of insulin, suggesting that the response of the adipocyte to GIP may depend upon the prevailing circulating insulin level.…”

Section: Discussionmentioning

confidence: 99%

“…7 A similar response was also observed when ob/ob mice were treated daily with a stable GIPR antagonist, (Pro 3 )GIP. 9 (Pro 3 )GIP has also been reported to protect against obesity, insulin resistance, glucose intolerance and associated metabolic disturbances in mice fed with high-fat diets, 10 and protect ob/ob mice from developing diabetes. 11 The GIPR belongs to the seven transmembrane helix family of G-protein-coupled receptors and is widely distributed in peripheral tissues and several regions in the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

Functional expression of glucose-dependent insulinotropic polypeptide receptors is coupled to differentiation in a human adipocyte model

et al. 2008

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Objective: To establish that human adipocytes express functional glucose-dependent insulinotropic peptide (GIP) receptors and in particular the regulation of GIP receptor (GIPR) expression in the context of the dynamic process of adipocyte differentiation. Design: A combination of semiquantitative real-time PCR and measurement of GIP-stimulated cAMP accumulation was used to establish the expression and functional coupling of GIPRs during in vitro differentiation of human Simpson-Golabi-Behmel syndrome (SGBS) preadipocytes. Results: Semiquantitative real-time PCR revealed that GIPR expression was substantially increased by day 4 of differentiation, reaching a maximum around 6-8 days (B200-fold increase above undifferentiated cells, n ¼ 2). We also analysed the expression of the adipocyte fatty acid binding protein (FABP4) to relate GIPR expression to a molecular differentiation marker of adipogenesis. FABP4 expression was barely detectable in undifferentiated cells. However, following exposure to adipogenic medium, FABP4 expression gradually increased, with a maximal expression level around 10 days (B1 600 000-fold increase above undifferentiated cells, n ¼ 2). Thus, the increases in GIPR mRNA during adipogenesis occur earlier than FABP4, suggesting that it might represent a gene expressed early in terminal differentiation and thus plays a role in fat droplet formation. A unit of 1 mM GIP failed to raise intracellular cAMP levels above basal levels in undifferentiated cells (n ¼ 3). In stark contrast, the 9-day differentiated cells produced a robust concentration-dependent increase in cAMP accumulation following stimulation with GIP, with an EC 50 value of 2.3 nM (n ¼ 3). The maximal response represented a 9-34-fold increase in cAMP accumulation above basal levels. Conclusions: This study demonstrates that GIPRs are expressed by human adipocytes, both GIPR mRNA and functional receptor expression being present in differentiated adipocytes but not in preadipocytes. Further investigation into the functional effects of GIP on differentiated SGBS cells could help towards understanding exactly how GIP regulates fat accumulation in human adipocytes.

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“…In addition, Nasteska et al 20 reported that chronic reduction of GIP improved obesity and insulin resistance in transgenic mice fed a high‐fat diet. Moreover, administration of GIP receptor antagonist, (Pro3) GIP, prevented the development of obesity and insulin resistance in diet‐induced obesity (DIO) mice and ob/ob mice 21, 22. However, this compound has also the effect of a partial or full agonist against GIP receptor 23.…”

Section: Introductionmentioning

confidence: 99%

Gastric inhibitory polypeptide receptor antagonist, SKL‐14959, suppressed body weight gain on diet‐induced obesity mice

Nakamura¹,

Tanimoto²,

Mizuno³

et al. 2018

Obesity Science & Practice

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SummaryObjectiveGastric inhibitory polypeptide plays a role in glucose and lipid metabolism and is associated with obesity and insulin resistance. The objective of this study is to confirm the anti‐obesity effects of the gastric inhibitory polypeptide receptor antagonist, SKL‐14959, on diet‐induced obesity mice.MethodDiet‐induced obesity mice at 20 weeks of age were administered with or without SKL‐14959 for 96 d. Body weight and food intake were monitored throughout the experiment. Mice were sacrificed, and physiological and biochemical markers were measured, and then histochemical and gene expression analyses were also performed. In further studies, mice were orally gavaged with [14C]‐oleic acid to investigate the excursion of digested lipids.ResultsSKL‐14959 significantly suppressed weight gain without affecting food intake, decreased triacylglycerol contents in the liver and the muscle and the intensity stained with oil‐red in the liver. It also improved plasma glutamic pyruvic transaminase and 3‐hydroxybutyrate levels in addition to notably down‐regulated relative gene expression of srebf1 and dgat1 in the liver despite not altering in the adipose tissue. Furthermore, SKL‐14959 showed remarkable inhibition of lipid uptake in the adipose tissue after the oil challenge.ConclusionSKL‐14959 inhibited lipids uptake and improved lipids metabolism, results in suppression of body‐weight gain.

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Chemical gastric inhibitory polypeptide receptor antagonism protects against obesity, insulin resistance, glucose intolerance and associated disturbances in mice fed high-fat and cafeteria diets

Cited by 117 publications

References 43 publications

An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

Functional expression of glucose-dependent insulinotropic polypeptide receptors is coupled to differentiation in a human adipocyte model

Gastric inhibitory polypeptide receptor antagonist, SKL‐14959, suppressed body weight gain on diet‐induced obesity mice

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