[show abstract][hide abstract] ABSTRACT: The neuropeptide Y (NPY)/peptide YY (PYY) system has been implicated in the physiology of obesity for several decades. More recently ignited enormous interest in PYY3-36, an endogenous Y2-receptor agonist, as a promising anti-obesity compound. Despite this interest, there have been remarkably few subsequent reports reproducing or extending the initial findings, while at the same time studies finding no anti-obesity effects have surfaced. Out of 41 different rodent studies conducted (in 16 independent labs worldwide), 33 (83%) were unable to reproduce the reported effects and obtained no change or sometimes increased food intake, despite use of the same experimental conditions (i.e. adaptation protocols, routes of drug administration and doses, rodent strains, diets, drug vendors, light cycles, room temperatures). Among studies by authors in the original study, procedural caveats are reported under which positive effects may be obtained. Currently, data speak against a sustained decrease in food intake, body fat, or body weight gain following PYY3-36 administration and make the previously suggested role of the hypothalamic melanocortin system unlikely as is the existence of PYY deficiency in human obesity. We review the studies that are in the public domain which support or challenge PYY3-36 as a potential anti-obesity target.
[show abstract][hide abstract] ABSTRACT: This study compared the potency of a somatostatin receptor (sstr)2-sstr5 analog, BIM-23244, of an sstr2-dopamine D2 receptor (sstr2-DAD2) molecule, BIM-23A387 and of new somatostatin-dopamine chimeric molecules with differing, enhanced affinities for sstr2, sstr5 and DAD2, BIM-23A758, BIM-23A760 and BIM-23A761, to suppress GH and prolactin (PRL) from 18 human GH adenomas that are partially responsive to octreotide or lanreotide.
The sstr2, sstr5 and DAD2 mRNA levels were determined by RT-PCR. The effect of drugs was tested in cell cultures at various concentrations.
In all tumors, the sstr2, sstr5 and DAD2 mRNA levels were coexpressed (mean levels+/-s.e.m. 0.4+/-0.1, 5.3+/-1.9 and 2.0+/-0.4 copy/copy beta-glucuronidase). In 13 tumors, the maximal suppression of GH secretion produced by BIM-23A387 (30+/-3%) and BIM-23244 (28+/-3%) was greater than that produced by octreotide (23+/-3%). In six out of 13 tumors, BIM-23A758, BIM-23A760 and BIM- 23A761 produced greater maximal suppression of GH secretion than octreotide (33+/-5, 38+/-2 and 41+/-2 vs 24+/-2%). Their EC(50) values were 10, 2 and 4 pmol/l. BIM-23A761 was more effective than BIM-23A387 in GH suppression (41+/-2 vs 32+/-4%). The new chimeric molecules produced maximal PRL suppression greater than octreotide (62+/-8 to 74+/-5 vs 46+/-11%).
Novel dopamine-somatostatin chimeric molecules with differing, enhanced activity at sstr2, sstr5 and DAD2, consistently produced significatly greater suppression of GH and PRL than either octreotide or single-receptor-interacting ligands in tumors from patients classified as only partially responsive to octreotide therapy. The higher efficacy of the chimeric compounds was, at least partially, linked to their high affinity for sstr2 (IC50 1-10 pmol/l). The other mechanisms by which such molecules produce an enhanced inhibition of GH remain to be elucidated.
European Journal of Endocrinology 08/2005; 153(1):135-41. · 3.14 Impact Factor
[show abstract][hide abstract] ABSTRACT: We report the comparative efficacy of a somatostatin receptor 1 and 5 subtypes (SSTR2 and SSTR5), and dopamine D2 (DAD2) compound, BIM-23A760, in suppressing GH secretion, in cell culture from human GH-secreting tumors, from patients partially responsive to long-term treatments with octreotide or lanreotide. In 18 tumors tested, the SSTR2, SSTR5, and DAD2 mRNAs were coexpressed. The SSTR2-selective analog, BIM-23197, the SSTR5-selective analog, BIM-23268, and the dopamine (DA) analog, BIM-53097, produced a mean maximal suppression of GH secretion (24 +/- 3, 20 +/- 3, and 20 +/- 3%, respectively) that was similar to that obtained with octreotide (23 +/- 3%). Nevertheless, based on individual responses, 60% of the tumors were mostly sensitive to the SSTR2 analog while 19 and 21% of the tumors were mainly responsive to the SSTR5 analog and to the DA analog, respectively. Among a series of new chimeric compounds that bind the SSTR2, SSTR5, and DAD2 receptors with variable affinities, BIM-23A760 produced greater maximal suppression of GH secretion than octreotide (38 +/- 2 vs 24 +/- 2%; p<0.03). The EC50 for BIM-23A760 was 2 pmol/l. In the presence of sulpride, the dose response inhibition of GH secretion by the trihybrid molecule, BIM-23A760, was partially reversed. The trihybrid produced also a maximal suppression of PRL greater than octreotide (74 +/- 5 vs 46 +/- 11%). When SSTRs pan inhibitors such as BIM-23A779 (binding affinity for SSTR1, SSTR2, SSTR3, SSTR5, respectively: 2.5, 0.3, 0.6, 0.6 nmol/l) or SOM230 were tested for their suppressive effects on GH secretion, they were less potent than the previous dopastatin hybrid molecule. After a brief exposure to a SSTR2-selective analog, BIM-23197, or to a DA analog, BIM-53097, the maximal GH suppression was achieved during 12 h. Under exposure to BIM-23A760, in the same conditions, maximal suppression of GH secretion lasted for 24 h. Such a longer biological effect, yet not explained, probably participates in the higher efficacy of BIM-23A760. The higher efficacy of BIM-23A760 is, at least partially, linked to its high affinity for the SSTR2 receptor subtype (IC50: 3 pmol/l). As compared to the dopastatin compound, the lower efficacy of the universal somatostatin ligands in the inhibition of GH secretion of GH-secreting tumors argues for the use of drugs targeted, according to specific receptors expression and functionality which may vary among the various classes of tumors.
[show abstract][hide abstract] ABSTRACT: Batterham et al. report that the gut peptide hormone PYY3-36 decreases food intake and body-weight gain in rodents, a discovery that has been heralded as potentially offering a new therapy for obesity. However, we have been unable to replicate their results. Although the reasons for this discrepancy remain undetermined, an effective anti-obesity drug ultimately must produce its effects across a range of situations. The fact that the findings of Batterham et al. cannot easily be replicated calls into question the potential value of an anti-obesity approach that is based on administration of PYY3-36.
Nature 08/2004; 430(6996):1 p following 165; discussion 2 p following 165. · 38.60 Impact Factor