Islet‐activating protein discriminates the antilipolytic mechanism of insulin from that of other antilipolytic compounds

Kather, H; Aktor, Klaus; Schulz, G; Jakobs, Karl H.

doi:10.1016/0014-5793(83)80749-2

Cited by 28 publications

(13 citation statements)

References 15 publications

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“…Taken together, these findings demonstrate that the adverse side effect of cutaneous flushing associated with the administration of nicotinic acid is mediated by β-arrestin1. In contrast, the effects on serum FFAs are mediated by β-arrestinindependent -G i /G o protein dependent -mechanisms, which have previously been shown to be pertussis toxin sensitive (26).…”

Section: Resultsmentioning

confidence: 87%

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β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice

Walters¹,

Shukla²,

Kovacs³

et al. 2009

J. Clin. Invest.

207

174

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Nicotinic acid is one of the most effective agents for both lowering triglycerides and raising HDL. However, the side effect of cutaneous flushing severely limits patient compliance. As nicotinic acid stimulates the GPCR GPR109A and G i /G o proteins, here we dissected the roles of G proteins and the adaptor proteins, β-arrestins, in nicotinic acid-induced signaling and physiological responses. In a human cell line-based signaling assay, nicotinic acid stimulation led to pertussis toxin-sensitive lowering of cAMP, recruitment of β-arrestins to the cell membrane, an activating conformational change in β-arrestin, and β-arrestin-dependent signaling to ERK MAPK. In addition, we found that nicotinic acid promoted the binding of β-arrestin1 to activated cytosolic phospholipase A 2 as well as β-arrestin1-dependent activation of cytosolic phospholipase A 2 and release of arachidonate, the precursor of prostaglandin D 2 and the vasodilator responsible for the flushing response. Moreover, β-arrestin1-null mice displayed reduced cutaneous flushing in response to nicotinic acid, although the improvement in serum free fatty acid levels was similar to that observed in wild-type mice. These data suggest that the adverse side effect of cutaneous flushing is mediated by β-arrestin1, but lowering of serum free fatty acid levels is not. Furthermore, G protein-biased ligands that activate GPR109A in a β-arrestin-independent fashion may represent an improved therapeutic option for the treatment of dyslipidemia.

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Section: Resultsmentioning

confidence: 87%

“…Both of these responses require GPR109A, and the decrease in FFAs has also been shown to require G i /G o proteins (26). This nicotinic acid-induced decrease in serum FFAs has been used as a surrogate for its lipidlowering effects.…”

Section: Resultsmentioning

confidence: 99%

β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice

Walters¹,

Shukla²,

Kovacs³

et al. 2009

J. Clin. Invest.

207

174

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“…Vascular Tone and Reactivity. Through its actions on GPR109A, nicotinic acid has been shown to decrease serum free fatty acids by activating G i /G o signaling and to increase cutaneous blood flow/flushing in humans and in mice by stimulating cytosolic phospholipase A 2 , leading to the production and secretion of prostaglandin D 2 (Kather et al, 1983;Pike, 2005). Comparison of the responses of wild-type C57BL/6, arrestin2-null, and arrestin3-null mice to nicotinic acid demonstrates that neither arrestin2 nor arrestin3 is required for nicotinic acid-induced changes in free fatty acid levels.…”

Section: Vascular Smooth Muscle Hypertrophy and Hyperplasiamentioning

confidence: 99%

Beyond Desensitization: Physiological Relevance of Arrestin-Dependent Signaling

2010

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“…Fat-cell DNA was 11.1 + 1.4 and 8.4 + 0.9 jug/ml of incubation-flask contents in the euthyroid and hypothyroid states respectively. All incubations contained adenosine deaminase (1 unit/ml (Kather et al, 1983), and it is therefore noteworthy that insulin differs from the other inhibitory agonists (Fig. 5d) in that 1.8 nM-insulin increased the EC50 for glucagon 5-fold without altering the maximum response.…”

Section: Vol 238 387 Preparation and Incubation Of Adipocytesmentioning

confidence: 99%

Sensitivity of adipocyte lipolysis to stimulatory and inhibitory agonists in hypothyroidism and starvation

Saggerson¹

1986

Biochemical Journal

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1. The responsiveness of lipolysis to the stimulatory agonists noradrenaline, corticotropin and glucagon and to the inhibitory agonists N6-phenylisopropyladenosine, prostaglandin E1 and nicotinic acid was investigated with rat white adipocytes incubated with a high concentration of adenosine deaminase (1 unit/ml). 2. The cells were obtained from fed or 48 h-starved euthyroid animals or from fed or starved animals rendered hypothyroid by 4 weeks of treatment with low-iodine diet and propylthiouracil. 3. Hypothyroidism increased sensitivity to and efficacy of all three inhibitory agonists in their opposition of noradrenaline-stimulated lipolysis. Starvation decreased sensitivity to all three inhibitory agonists when opposing basal lipolysis. 4. Hypothyroidism decreased sensitivity to noradrenaline, glucagon and corticotropin by 37-, 4-and 4-fold respectively and decreased the maximum response to these agonists by approx. 50%, 50% and 75% respectively. Starvation reversed decreases in maximum response to these agonists in hypothyroidism. 5. Starvation in the euthyroid state increased sensitivity to glucagon and noradrenaline, but did not alter sensitivity to corticotropin. 6. Cells from hypothyroid rats were relatively insensitive to Bordetella pertussis toxin, which substantially increased basal lipolysis in the euthyroid state. INTRODUCTIONLipolysis in adipose tissue can be stimulated by the catecholamines, corticotropin and glucagon. Conversely, other agonists, e.g. adenosine, E-series prostaglandins and nicotinic acid, act through specific receptors to inhibit lipolysis. The activity of hormone-sensitive lipase is dependent on protein phosphorylation, which is the resultant of the activities of cyclic AMP-dependent protein kinase and phosphoprotein phosphatase(s). In turn, the cellular content of cyclic AMP is dependent on the relative activities of adenylate cyclase and cyclic nucleotide phosphodiesterase. Receptors for the inhibitory agonists are coupled to adenylate cyclase by a guanine nucleotide-binding protein (N1) distinct from that (N.) which couples receptors for stimulatory agonists to the enzyme (Rodbell, 1980;Murayama & Ui, 1983;Olansky et al., 1983;Moreno et al., 1983;Bokoch et al., 1984;Codina et al., 1984). In hypothyroidism adenylate cyclase, the increase in cyclic AMP, and lipolysis all show diminished responsiveness to the stimulatory agonists (Goodman & Bray, 1966;Armstrong et al., 1974;Correze et al., 1974;Malbon et al., 1978;Ohisalo & Stouffer, 1979;Goswami & Rosenberg, 1980). Conversely, the inhibitory effect of adenosine mediated by the A1 (Van Calker et al., 1979) or Ri (Londos et al., 1980) adenosine receptor is increased in hypothyroidism (Ohisalo & Stouffer, 1979;Malbon & Graziano, 1983;Chohan et al., 1984;Malbon et al., 1985). This enhanced responsiveness is most easily measured in the presence of adenosine deaminase by using the non-metabolized analogue PIA and appears to reflect an increase in the abundance of Ni in the adipocyte plasma membrane (Malbon et al., 1985) without any in...

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Islet‐activating protein discriminates the antilipolytic mechanism of insulin from that of other antilipolytic compounds

Cited by 28 publications

References 15 publications

β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice

β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice

Beyond Desensitization: Physiological Relevance of Arrestin-Dependent Signaling

Sensitivity of adipocyte lipolysis to stimulatory and inhibitory agonists in hypothyroidism and starvation

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