The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse

Steneberg, Pär; Rubins, Nir; Bartoov-Shifman, Reut; Walker, Michael D.; Edlund, Helena

doi:10.1016/j.cmet.2005.03.007

Cited by 373 publications

(408 citation statements)

References 61 publications

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“…There is a firm consensus that GPR40 is expressed in β-cells and this has been confirmed at the mRNA level in a range of species including mouse [23], rat [24] and man [25].…”

Section: Expression Of Gpr40mentioning

confidence: 90%

“…In particular, it is known that prolonged elevation of circulating fatty acids leads to a decline in insulin secretion and, ultimately, to loss of β-cell viability but there are conflicting views as to the role played by GPR40 in these processes. Initial data were provided by Steneberg and colleagues [64] who generated GPR40 knock-out (KO) mice and observed that, when maintained on a high fat diet, these animals failed to develop the characteristic metabolic abnormalities seen in wild type animals. Specifically, the GPR40 KO animals had lower fasting insulin, greater insulin Page 9 of 34 A c c e p t e d M a n u s c r i p t sensitivity and improved glucose tolerance than the animals with normal levels of GPR40 expression.…”

Section: Role Of Gpr40 In Lipotoxicitymentioning

confidence: 99%

“…However, after the initial flush of excitement spawned by the early findings of Steneberg et al [66], the field has become more circumspect since a number of workers have now developed GPR40 KO mice but none has shown the dramatic improvement in phenotype during high fat feeding, reported initially. For example, Kebede et al [67] observed that deletion of GPR40 did not prevent any of the detrimental metabolic effects of a high fat diet in C57BL/6 mice.…”

Section: Role Of Gpr40 In Lipotoxicitymentioning

confidence: 99%

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G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell

Morgan¹,

Dhayal²

2009

Biochemical Pharmacology

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It is increasingly clear that some of the effects of both free and derivatised long chain fatty acids in pancreatic beta-cells are mediated by a group of G-protein coupled receptors. Some of these display close structural homology while others are more divergent. This Commentary reviews the expression and functional roles of three such molecules, GPR40, GPR119 and GPR120. GPR40 is the best characterised of this group and appears to mediate the acute stimulatory effects of long chain fatty acids on insulin secretion. GPR40 has also been proposed as a potential mediator of fatty acid toxicity but this is more controversial. GPR119 is also involved in stimulation of insulin secretion and responds primarily to ethanolamine derivatives of long chain fatty acids and also to some lysophospholipids rather than to free fatty acids. It may represent a useful target for the development of new insulin secretagogues aimed to enhance insulin release in patients with type 2 diabetes. GPR120 is the most enigmatic of the lipid responsive cell-surface receptors and its function remains to be established. It has been proposed to play a cytoprotective role in certain other cell types but it is unclear whether it fulfils a similar function in beta-cells.

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“…There is a firm consensus that GPR40 is expressed in β-cells and this has been confirmed at the mRNA level in a range of species including mouse [23], rat [24] and man [25].…”

Section: Expression Of Gpr40mentioning

confidence: 90%

Section: Role Of Gpr40 In Lipotoxicitymentioning

confidence: 99%

Section: Role Of Gpr40 In Lipotoxicitymentioning

confidence: 99%

See 1 more Smart Citation

G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell

Morgan¹,

Dhayal²

2009

Biochemical Pharmacology

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“…These events may very well be driven by the increased flux of NEFA that arises in the mice as a consequence of HF feeding. The fact that beta cells express G-protein-coupled receptors that utilise NEFA as ligands, the GPR 40 family [27][28][29], raises the possibility that receptor-mediated events triggered by lipids account, at least partially, for the mitochondrial adaptation. Whereas the physiological role of the GPR 40 receptors is still unresolved, our present findings point to an interesting area of beta cell physiology that could be examined with GPR 40 receptors in mind.…”

Section: Discussionmentioning

confidence: 99%

Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet

et al. 2006

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Aim/hypothesis Hyperinsulinaemia maintains euglycaemia in insulin-resistant states. The precise cellular mechanisms by which the beta cells adapt are still unresolved. A peripherally derived cue, such as increased circulating fatty acids, may instruct the beta cell to initiate an adaptive programme to maintain glucose homeostasis. When this fails, type 2 diabetes ensues. Because mitochondria play a key role in beta cell pathophysiology, we tested the hypothesis that mitochondrial metabolism is critical for beta cell adaptation to insulin resistance. Methods C57BL/6J mice were given high-fat (HF) diet for 12 weeks. We then analysed islet hormone secretion, metabolism in vivo and in vitro, and beta cell morphology.Results HF diet resulted in insulin resistance and glucose intolerance but not frank diabetes. Basal insulin secretion was elevated in isolated islets from HF mice with almost no additional response provoked by high glucose. In contrast, a strong secretory response was seen when islets from HF mice were stimulated with fuels that require mitochondrial metabolism, such as glutamate, glutamine, alpha-ketoisocaproic acid and succinate. Moreover, while glucose oxidation was impaired in islets from HF mice, oxidation of glutamine and palmitate was enhanced. Ultrastructural analysis of islets in HF mice revealed an accumulation of lipid droplets in beta cells and a twofold increase in mitochondrial area. Conclusions/interpretation We propose that beta cells exposed to increased lipid flux in insulin resistance respond by increasing mitochondrial volume. This expansion is associated with enhanced mitochondrial metabolism as a means of beta cell compensation.

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“…Hyperinsulinaemia compensates for insulin resistance to maintain normoglycaemia. However, hyperinsulinaemia per se deteriorates insulin resistance [6] and is thought to trigger the progression of the metabolic syndrome [7,8]. The mechanisms linking obesity and insulin resistance to hyperinsulinaemia and beta cell hyperplasia are incompletely understood [3].…”

mentioning

confidence: 99%

Regulation of insulin secretion, glucokinase gene transcription and beta cell proliferation by adipocyte-derived Wnt signalling molecules

et al. 2007

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Aims/hypothesis Adipocytes secrete signalling molecules that elicit responses from target cells, including pancreatic beta cells. Wnt signalling molecules have recently been identified as novel adipocyte-derived factors. They also regulate insulin secretion in pancreatic beta cells and the cell cycle. The aim of this study was to investigate the effect of adipocyte-derived Wnt signalling molecules on insulin secretion and beta cell proliferation. Methods Human adipocytes were isolated to generate fat cell-conditioned medium (FCCM). Ins-1 cells were stimulated with FCCM and transiently transfected with reporter genes. Proliferation assays using [ 3 H]thymidine incorporation were carried out in Ins-1 cells and primary islet cells. Insulin secretion from primary islets was assessed by radioimmunoassay. Gene expression in primary islets was assessed by Taqman PCR. Results Treatment with human FCCM increased the transcription of a T cell-specific transcription factor reporter gene (TOPFLASH) in Ins-1 cells (241%, p<0.05). FCCM induced the proliferation of Ins-1 cells (1.8 fold, p<0.05) and primary mouse islet cells (1.6 fold, p<0.05). Antagonizing Wnt signalling with secreted Frizzled-related protein 1 (FRP-1) inhibited the proliferative effect induced by Wnt3a and FCCM on Ins-1 cells by 49 and 41%, respectively. In addition, FCCM led to a twofold (p<0.05) induction of cyclin D1 promoter activity in Ins-1 cells. Furthermore, FCCM stimulated insulin secretion (204% of controls, p>0.05) in primary mouse islets, and this stimulation was inhibited by sFRP-1. At a molecular level, canonical Wnt signalling induced glucokinase gene transcription in a peroxisome proliferator-activated receptor γ-dependent fashion, thereby defining the glucokinase gene as a novel Wnt target gene. Conclusions/interpretation Taken together, these data show that adipocyte-derived Wnt signalling molecules induce beta cell proliferation and insulin secretion in vitro, suggesting a novel mechanism linking obesity to hyperinsulinaemia.

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The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse

Cited by 373 publications

References 61 publications

G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell

G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell

Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet

Regulation of insulin secretion, glucokinase gene transcription and beta cell proliferation by adipocyte-derived Wnt signalling molecules

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