The leptin receptor (Lepr) pathway is important for food intake regulation, energy expenditure and body weight. Mutations in leptin and the Lepr have been shown to cause early-onset severe obesity in mice and humans. In studies with C57BL/6NCrl mice, we found a mouse with extreme obesity. To identify a putative spontaneous new form of monogenic obesity, we performed backcross studies with this mouse followed by a quantitative trait locus (QTL) analysis and sequencing of the selected chromosomal QTL region. We thereby identified a novel Lepr mutation (C57BL/6N-Lepr^{L536Hfs∗6-1NKB}), which is located at chromosome 4, exon 11 within the CRH2-leptin binding site. Compared to C57BL/6N mice, Lepr^L536Hfs∗6 develop early onset obesity and their body weight exceeds that of Lepr^db/db mice at an age of 30 weeks. Similar to Lepr^db/db mice, the Lepr^L536Hfs∗6 model is characterized by hyperphagia, obesity, lower energy expenditure and activity, hyperglycemia, and hyperinsulinemia compared to C57BL/6N mice. Crossing Lepr^db/wt with Lepr^{L536Hfs∗6/wt} mice results in compound heterozygous Lepr^{L536Hfs∗6/db} mice, which develop even higher body weight and fat mass than both homozygous Lepr^db/db and Lepr^L536Hfs∗6 mice. Our study suggests that the phenotype of monogenic Lepr deficient mice depends on the molecular localization of the Lepr mutation. Compound heterozygous Lepr deficiency affecting functionally different regions of the Lepr causes more severe obesity than the parental homozygous mutations.

中文翻译：

---

一种新的复合杂合瘦素受体突变导致比 Leprdb/db 小鼠更严重的肥胖。

瘦素受体 (Lepr) 通路对食物摄入调节、能量消耗和体重很重要。瘦素和麻风病的突变已被证明会导致小鼠和人类早发性严重肥胖。在对 C57BL/6NCrl 小鼠的研究中，我们发现了一只极度肥胖的小鼠。为了鉴定推定的自发新形式的单基因肥胖，我们用这只小鼠进行了回交研究，然后对选定的染色体 QTL 区域进行数量性状基因座 (QTL) 分析和测序。因此，我们鉴定了一个新的 Lepr 突变（C57BL/6N-Lepr ^{L536Hfs*6-1NKB}），它位于 CRH2-瘦素结合位点内的第 4 号染色体、第 11 外显子。与 C57BL/6N 小鼠相比，Lepr ^L536Hfs∗6出现早发性肥胖，体重超过 Lepr ^db/db30 周龄的小鼠。与 Lepr ^db/db小鼠相似，与 C57BL/6N 小鼠相比，Lepr ^L536Hfs*6模型的特点是食欲过盛、肥胖、能量消耗和活动降低、高血糖和高胰岛素血症。将Lepr ^db/wt与 Lepr ^L536Hfs*6/wt小鼠杂交产生复合杂合 Lepr ^L536Hfs*6/db小鼠，其体重和脂肪量甚至高于纯合 Lepr ^db/db和 Lepr ^L536Hfs*6老鼠。我们的研究表明，单基因 Lepr 缺陷小鼠的表型取决于 Lepr 突变的分子定位。影响 Lepr 功能不同区域的复合杂合 Lepr 缺陷导致比亲本纯合突变更严重的肥胖。