Resistin Is a Key Mediator of Glucose-dependent Insulinotropic Polypeptide (GIP) Stimulation of Lipoprotein Lipase (LPL) Activity in Adipocytes

Kim, Sujin; Nian, Cuilan; McIntosh, Christopher H.S.

doi:10.1074/jbc.m704896200

Cited by 107 publications

(76 citation statements)

References 56 publications

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“…8 Further investigation of the slow time of onset of this response led to the conclusion that the activation of lipoprotein lipase stimulated by GIP was indirect and involved GIP-mediated secretion of the adipokine resistin. 35 This study demonstrates, using SGBS cells in culture, that the GIPR is expressed by human adipocytes, both GIPR mRNA and functional receptor expression being present in differentiated adipocytes but not in preadipocytes. The finding of differentiation-dependent regulation of the GIPR, with expression levels rising as the differentiating preadipocyte begins to accumulate lipid droplets, is in keeping with the previous proposal regarding the enteroadipocyte axis and that circulating levels of GIP directly links overnutrition to obesity.…”

Section: Discussionmentioning

confidence: 56%

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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Section: Discussionmentioning

confidence: 56%

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

et al. 2008

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“…Four weeks after the induction of MI by coronary ligation, the infarcted rat hearts were isolated and subjected to no treatment (vehicle), sitagliptin (5 μM), GIP (100 nM), GLP-1 (100 nM), or the combination of sitagliptin and GIP. The doses of sitagliptin, GIP and GLP-1 have been shown to be effective in modulating biological activities [25,26]. Noncirculating modified Tyrode's solution was used to perfuse each heart, containing glucose 5.5 mM, NaCl 117.0 mM, NaHCO 3 23.0 mM, KCl 4.6 mM, NaH 2 PO 4 0.8 mM, MgCl 2 1.0 mM and CaCl 2 2.0 mM, equilibrated at 37 • C with a 95 % O 2 and 5 % CO 2 gas mixture.…”

Section: Experiments 2 (Ex Vivo)mentioning

confidence: 99%

“…Noncirculating modified Tyrode's solution was used to perfuse each heart, containing glucose 5.5 mM, NaCl 117.0 mM, NaHCO 3 23.0 mM, KCl 4.6 mM, NaH 2 PO 4 0.8 mM, MgCl 2 1.0 mM and CaCl 2 2.0 mM, equilibrated at 37 • C with a 95 % O 2 and 5 % CO 2 gas mixture. Given that resistin secretion was evident within 1 h following GIP treatment [26], the drugs were infused for 60 min. All of the hearts (n = 5 each group) were used for western blot analysis for resistin protein at the remote zone (>2 mm outside the infarct).…”

Section: Experiments 2 (Ex Vivo)mentioning

confidence: 99%

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Sitagliptin decreases ventricular arrhythmias by attenuated glucose-dependent insulinotropic polypeptide (GIP)-dependent resistin signalling in infarcted rats

2016

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SynopsisMyocardial infarction (MI) was associated with insulin resistance, in which resistin acts as a critical mediator. We aimed to determine whether sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, can attenuate arrhythmias by regulating resistin-dependent nerve growth factor (NGF) expression in postinfarcted rats. Normoglycaemic male Wistar rats after ligating coronary artery were randomized to either vehicle or sitagliptin for 4 weeks starting 24 h after operation. Post-infarction was associated with increased myocardial noradrenaline [norepinephrine (NE)] levels and sympathetic hyperinnervation. Compared with vehicle, sympathetic innervation was blunted after administering sitagliptin, as assessed by immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and western blotting and real-time quantitative RT-PCR of NGF. Arrhythmic scores in the sitagliptintreated infarcted rats were significantly lower than those in vehicle. Furthermore, sitagliptin was associated with reduced resistin expression and increased Akt activity. Ex vivo studies showed that glucose-dependent insulinotropic polypeptide (GIP) infusion, but not glucagon-like peptide-1 (GLP-1), produced similar reduction in resistin levels to sitagliptin in postinfarcted rats. Furthermore, the attenuated effects of sitagliptin on NGF levels can be reversed by wortmannin (a phosphatidylinositol 3-kinase antagonist) and exogenous resistin infusion. Sitagliptin protects ventricular arrhythmias by attenuating sympathetic innervation in the non-diabetic infarcted rats. Sitagliptin attenuated resistin expression via the GIP-dependent pathway, which inhibited sympathetic innervation through a signalling pathway involving phosphatidylinositol 3-kinase (PI3K) and Akt protein.

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“…Receptors for glucagon and physiologic incretins (e.g., GIP) are present on adipocytes in animals, but it is not clear if they are also present on human adipocytes; these receptors may play a role in fat metabolism, with GIP promoting lipolysis (51)(52)(53)(54)(55)(56). These receptors are downregulated in certain animal models of T2D.…”

Section: Incretins In Physiologic Perspectivementioning

confidence: 99%

Exploiting the antidiabetic properties of incretins to treat type 2 diabetes mellitus: glucagon-like peptide 1 receptor agonists or insulin for patients with inadequate glycemic control?

Gaal¹,

Gutkin²,

Nauck³

2008

European Journal of Endocrinology

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Type 2 diabetes mellitus is associated with progressive decreases in pancreatic b-cell function. Most patients thus require increasingly intensive treatment, including oral combination therapies followed by insulin. Fear of hypoglycemia is a potential barrier to treatment adherence and glycemic control, while weight gain can exacerbate hyperglycemia or insulin resistance. Administration of insulin can roughly mimic physiologic insulin secretion but does not address underlying pathophysiology. Glucagon-like peptide 1 (GLP-1) is an incretin hormone released by the gut in response to meal intake that helps to maintain glucose homeostasis through coordinated effects on islet a-and b-cells, inhibiting glucagon output, and stimulating insulin secretion in a glucose-dependent manner. Biological effects of GLP-1 include slowing gastric emptying and decreasing appetite. Incretin mimetics (GLP-1 receptor agonists with more suitable pharmacokinetic properties versus GLP-1) significantly lower hemoglobin A1c, body weight, and postprandial glucose excursions in humans and significantly improve b-cell function in vivo (animal data). These novel incretin-based therapies offer the potential to reduce body weight or prevent weight gain, although the durability of these effects and their potential long-term benefits need to be studied further. This article reviews recent clinical trials comparing therapy with the incretin mimetic exenatide to insulin in patients with oral treatment failure, identifies factors consistent with the use of each treatment, and delineates areas for future research.European Journal of Endocrinology 158 773-784

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Resistin Is a Key Mediator of Glucose-dependent Insulinotropic Polypeptide (GIP) Stimulation of Lipoprotein Lipase (LPL) Activity in Adipocytes

Cited by 107 publications

References 56 publications

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

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

Sitagliptin decreases ventricular arrhythmias by attenuated glucose-dependent insulinotropic polypeptide (GIP)-dependent resistin signalling in infarcted rats

Exploiting the antidiabetic properties of incretins to treat type 2 diabetes mellitus: glucagon-like peptide 1 receptor agonists or insulin for patients with inadequate glycemic control?

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