Hashimoto K, Nagao Y, Ida K, Takeda M, Murakami N, Kato K, Mizota M
Department of Pharmacology, Fuji Central Research Laboratory, Mochida Pharmaceutical Co., Ltd., Tokyo, Japan.
Biochem Pharmacol. 1996 Nov 22;52(10):1529-35. doi: 10.1016/s0006-2952(96)00552-7.
The effects of BRL35135A ((R*,R*)-(+/-)-methyl-4-[2-[2-hydroxy-2 -(3-chlorophenyl)ethylamino]propyl]-phenoxyacetate hydrobromide), a beta 3-adrenoceptor agonist, on visceral and subcutaneous fat weight and metabolic disorders were studied in genetically obese C57BL/KsJ db/db mice and Zucker fa/fa rats. In db/db mice, four weeks of oral administration of BRL35135A (0.5 and 5 mg/kg/day) decreased body weight gain and reduced white fat weight. The rates of reduction of white fat weight were in the order mesenteric fat > retroperitoneal fat > subcutaneous fat. In fa/fa rats, daily administration of BRL35135A (0.05 mg/kg/day)) for 6 weeks reduced the visceral white fat weight/total energy intake ratio, particularly for mesenteric fat, without any clear effect on body weight gain. This tendency of the compound to exert effects on visceral fat was consistent with the findings that the effect of BRL37344 ((R*,R*)-(+/-) -methyl-4-[2-[2-hydroxy-2-(3-chlorophenyl)ethylamino]propyl]-phenoxyacet ic acid), an active metabolite of BRL35135A, on the lipolytic activity of isolated adipocytes and the tissue concentration of [14C]BRL37344 in male Wistar rats were each greater in visceral fat than in subcutaneous fat. Moreover, BRL35135A at 0.05 mg/kg/day elevated serum insulin levels and improved hyperglycemia in db/db mice without reducing body weight gain, whereas at doses of 0.5 and 5 mg/kg/day it ameliorated hyperglycemia and hyperlipidemia, and tended to decrease serum insulin levels. In fa/fa rats, BRL35135A (0.005 mg/kg/day) was also effective in improving hyperinsulinemia, glucose intolerance, and hypertriglyceridemia without any effect on body weight gain or fat distribution. These findings suggest that the improvement of metabolic disorders by BRL35135A may be due to improvement in insulin resistance as well as reduction of visceral fat weight.
研究了β3 -肾上腺素能受体激动剂BRL35135A（（R*，R*）-（±）-甲基-4-[2-[2-羟基-2-（3-氯苯基）乙基氨基]丙基]-苯氧基乙酸氢溴酸盐）对遗传性肥胖的C57BL/KsJ db/db小鼠和Zucker fa/fa大鼠内脏及皮下脂肪重量和代谢紊乱的影响。在db/db小鼠中，口服BRL35135A（0.5和5毫克/千克/天）四周可减少体重增加并降低白色脂肪重量。白色脂肪重量的减少率顺序为肠系膜脂肪＞腹膜后脂肪＞皮下脂肪。在fa/fa大鼠中，每天给予BRL35135A（0.05毫克/千克/天）持续6周可降低内脏白色脂肪重量/总能量摄入比，特别是肠系膜脂肪，对体重增加无明显影响。该化合物对内脏脂肪产生作用的这种趋势与以下发现一致：BRL35135A的活性代谢物BRL37344（（R*，R*）-（±）-甲基-4-[2-[2-羟基-2-（3-氯苯基）乙基氨基]丙基]-苯氧基乙酸）对雄性Wistar大鼠分离脂肪细胞的脂解活性以及[14C]BRL37344在内脏脂肪中的组织浓度均高于皮下脂肪。此外，0.05毫克/千克/天的BRL35135A可提高db/db小鼠的血清胰岛素水平并改善高血糖症，且不降低体重增加，而在0.5和5毫克/千克/天的剂量下，它可改善高血糖症和高脂血症，并倾向于降低血清胰岛素水平。在fa/fa大鼠中，BRL35135A（0.005毫克/千克/天）在不影响体重增加或脂肪分布的情况下，对改善高胰岛素血症、葡萄糖耐量异常和高甘油三酯血症也有效。这些发现表明，BRL35135A对代谢紊乱的改善可能归因于胰岛素抵抗的改善以及内脏脂肪重量的减少。
