We evaluated the pharmacological characteristics of (R)-2-(2-aminothiazol-4-yl)-4Ј-{2-[(2-hydroxy-2-phenylethyl)amino]-ethyl} acetanilide (YM178). YM178 increased cyclic AMP accumulation in Chinese hamster ovary (CHO) cells expressing human ␤ 3 -adrenoceptor (AR). The half-maximal effective concentration (EC 50 ) value was 22.4 nM. EC 50 values of YM178 for human ␤ 1 -and ␤ 2 -ARs were 10,000 nM or more, respectively. The ratio of intrinsic activities of YM178 versus maximal response induced by isoproterenol (nonselective ␤-AR agonist) was 0.8 for human ␤ 3 -ARs, 0.1 for human ␤ 1 -ARs, and 0.1 for human ␤ 2 -ARs. The relaxant effects of YM178 were evaluated in rats and humans bladder strips precontracted with carbachol (CCh) and compared with those of isoproterenol and 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (CGP-12177A) (␤ 3 -AR agonist). EC 50 values of YM178 and isoproterenol in rat bladder strips precontracted with 10 Ϫ6 M CCh were 5.1 and 1.4 M, respectively, whereas those in human bladder strips precontracted with 10 Ϫ7 M CCh were 0.78 and 0.28 M, respectively. In in vivo study, YM178 at a dose of 3 mg/kg i.v. decreased the frequency of rhythmic bladder contraction induced by intravesical filling with saline without suppressing its amplitude in anesthetized rats. These findings suggest the suitability of YM178 as a therapeutic drug for the treatment of symptoms of overactive bladder such as urinary frequency, urgency, and urge incontinence.

The mitochondrial uncoupling protein (UCP) is usually expressed only in brown adipose tissue (BAT) and a key molecule for metabolic thermogenesis. The effects of a highly selective ␤ 3-adrenergic agonist, CL316,243 (CL), on UCP expression in skeletal muscle and adipose tissues were examined in mice. Daily injection of CL (0.1 mg/kg, sc) to obese yellow KK mice for two weeks caused a significant reduction of body weight, associated with a marked decrease of white fat pad weight and hypertrophy of the interscapular BAT with a sixfold increase in UCP content. Clear signals of UCP protein and mRNA were detected by Western and Northern blot analyses in inguinal, mesenteric and retroperitoneal white fat pads, and also in gastrocnemius and quadriceps muscles, whereas no signal in saline-treated mice. The presence of UCP mRNA in muscle tissues was also confirmed by reverse transcription-PCR analysis. Weaker UCP signals were also detected in control C57BL mice treated with CL, but only in inguinal and retroperitoneal fat pads. Immunohistochemical examinations revealed that UCP stains in the white fat pads were localized on multilocular cells quite similar to typical brown adipocyte, and those in the muscle tissues on myocytes. The mitochondrial localization of UCP in myocytes was confirmed by immunoelectron microscopy. In addition to UCP protein, UCP mRNA was also detected in myocytes by in situ hybridization analysis. Thus, chronic stimulation of the ␤ 3-adrenergic receptor induces ectopic expression of UCP in adipose tissues conventionally considered as white fat and even in skeletal muscle, which probably contributes to the potent anti-obesity effect of the ␤ 3-adrenergic agonist. ( J. Clin. Invest. 1996. 97:2898-2904.) Key words: brown adipose tissue • immunohistochemistry • obesity • yellow KK mice

Aims/IntroductionIn the present dose–response study, we evaluated the efficacy and safety of ipragliflozin (ASP1941), a novel and selective inhibitor of sodium‐dependent glucose cotransporter 2, in Japanese patients with type 2 diabetes mellitus.Materials and MethodsA total of 361 patients from 39 Japanese centers were randomized to receive either once‐daily oral ipragliflozin (12.5, 25, 50 or 100 mg) or a placebo for 12 weeks.ResultsAll ipragliflozin‐treated groups had clinically significant, dose‐dependent decreases in glycated hemoglobin (HbA1c) and fasting plasma glucose levels compared with placebo‐treated groups. The adjusted mean difference in HbA1c change from baseline to the end of treatment between the placebo and 12.5, 25, 50, and 100 mg ipragliflozin groups were −0.61%, −0.97%, −1.29%, and −1.31%, respectively (P < 0.001). Reductions in HbA1c levels were similar between obese and non‐obese patients, and were larger in patients with baseline HbA1c ≥8.4% than in those with HbA1c <8.4%. Furthermore, bodyweight significantly (P < 0.001) and dose‐dependently decreased among ipragliflozin‐treated groups compared with the placebo group. The incidence of adverse events was similar across all groups. However, mild increases in hematocrit and blood urea nitrogen were found in ipragliflozin treated groups.ConclusionsOnce‐daily administration of ipragliflozin was dose‐dependently effective in glycemic control without major adverse effects. Ipragliflozin was equally effective between obese and non‐obese patients, and led to weight loss in both groups. Ipragliflozin was safe and well‐tolerated in Japanese patients with type 2 diabetes mellitus. This trial was registered with ClinicalTrials.gov (no. NCT00621868).

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Uncoupling protein 3 (UCP3), expressed abundantly in the skeletal muscle, is one of the carrier proteins dissipating the transmitochondrial electrochemical gradient as heat, and thereby has been implicated in the regulation of energy metabolism. We have investigated UCP3 mRNA expression in the widely used L6 myocyte cell line by Northern blot analysis. UCP3 mRNA was not detected in L6 myoblasts, but appeared after their differentiation to myotubes. The UCP3 mRNA level was increased when L6 myotubes were treated with increasing concentrations of triiodothyronine (T3), oleic acid, K K-bromopalmitate and carbacyclin, a non-selective ligand of peroxisome proliferator-activated receptors (PPARs), whereas it was not influenced when treated with selective ligands of PPARK K (WY 14 643) and PPARQ Q (troglitazone). A ligand of retinoid X receptor (RXR), 9-cis retinoic acid, was also effective by itself and in combination with carbacyclin in stimulating UCP3 mRNA expression. The mRNA analysis of individual PPAR isoforms revealed that L6 cell expressed a significant level of PPARN N but undetectable levels of PPARK K and PPARQ Q. These results suggest that UCP3 expression in myocytes is differentiation-dependent and regulated by the T3 receptor, RXR and PPARN N.z 1999 Federation of European Biochemical Societies.