The mechanismus of leptin resistance in obesity and its improvement.

为了了解瘦素抵抗在肥胖中的作用机制，我们检测了肥胖小鼠肥胖模型中ob基因受体(Ob-Rb、Ob-Ra)和UCP家族(UCP-1、UCP-2和UCP-3)的表达。我们还研究了致热肾上腺素能β3激动剂BRL37344对基因表达的影响。雌性ICR小鼠出生后第9天隔日皮下注射MSG(2 mg/g)。在13周龄时，一些小鼠给予BRL37344(0.1 mg/kg)，连续2周。RT-PCR检测下丘脑和脂肪组织(棕色：蝙蝠和白色：WAT)和骨骼肌中ob基因受体的mRNA丰度。OB-Rb(长形)功能活跃，主要存在于下丘脑，但在脂肪组织(BAT、WAT)和骨骼肌中也有少量存在。MSG肥胖小鼠下丘脑OB-Rb表达明显减少，可能存在瘦素抵抗。被认为缺乏信号的OB-Ra(缩写形式)在下丘脑和外周组织(BAT、WAT和骨骼肌)中都有表达。但下丘脑OB-Ra的表达不受味精肥胖的影响。BRL37344处理的味精小鼠BAT中UCP-1mRNA的表达增加，表明对肾上腺素能β3激动剂的反应仍然存在。BRL37344对BAT、WAT和骨骼肌等多种组织中UCP-2的表达无明显影响。UCP-3在骨骼肌中含量最高，在骨骼肌和蝙蝠中表达增加，在WAT中新诱导表达。因此，提示味精诱导肥胖小鼠的瘦素抵抗可能与下丘脑ob基因受体，尤其是ob-Rb受体下调有关。

To understand the mechanismus of leptin resistance in obesity, we examined the expression of ob gene receptors (OB-Rb, OB-Ra) and UCP family (UCP-1, UCP-2 and UCP-3) in the obese mice induced by monosodium-L-glutamate (MSG). We also assessed the effect of thermogenic adrenergic β3 agonist, BRL37344, on the gene expressions. Female ICR mice were subcutaneously injected with MSG (2 mg/g) every other day during the first 9 days of birth. At the age of 13-week-old, some mice received BRL37344 (0.1 mg/kg) for 2 weeks. Abundance for mRNA for ob gene receptors in hypothalamus and UCP family in adipose tissue (brown:BAT and white:WAT) and skeletal muscle was determined by RT-PCR. OB-Rb (long form) which is fanctionally active, predominates in the hypothalamus, but is also present at low levels in adipose tissue (BAT, WAT) and skeletal muscle. The expression of OB-Rb in hypothalamus was markedly reduced in MSG obese mice which may have leptin resistance. The expression of OB-Ra (short form), considered to lack signaling was observed both in hypothalamus and in peripheral tissues (BAT, WAT and skeletal muscle). However, the expression of OB-Ra in hypothalamus was not altered by MSG obesity. The expression of UCP-1 mRNA in BAT was increased in BRL37344-treated MSG mice, showing remain the response to adrenergic β3 agonist. The expression of UCP-2, which distributes in many tissues including BAT, WAT and skeletal muscle, was not affected by BRL37344 treatment. The expression of UCP-3, which is most abundant in skeletal muscle, increased in skeletal muscle and BAT, and was newly induced in WAT. Thus, it is suggested that leptin resistance in obese mice induced by MSG might be associated with down-regulation of hypothalamic ob gene receptor, especially OB -Rb.