Objective

Hyperleptinemia per se is sufficient to promote leptin resistance in the obese state. Leptin sensitivity can be restored by reducing circulating leptin levels within a physiologically healthy range and is a viable antiobesity and antidiabetic strategy. However, a previous study suggests that partial leptin deficiency favors diet-induced obesity and related metabolic disorders in mice, arguing that a lower leptin level may indeed promote diet-induced obesity and its associated metabolic disorders. Here, we aim to elucidate what the impact of partial leptin deficiency is on fat mass and insulin sensitivity.

Methods

We used two different mouse models of partial leptin deficiency: an adipocyte-specific congenital heterozygous leptin knockout mouse line (LepHZ) and the well-established whole body heterozygous leptin knockout mouse (OBHZ). The metabolic studies of OBHZ and LepHZ mice were performed both on normal carbohydrate-rich chow diet and on a high-fat diet (HFD). Male and female mice were included in the study to account for sex-specific differences. Body weight, food intake, glucose tolerance, and insulin tolerance were tested. Histology of adipose tissue and liver tissue allowed insights into adipose tissue inflammation and hepatic triglyceride content. Immunohistochemistry was paired with RT-PCR analysis for expression levels of inflammatory markers.

Results

Both OBHZ and LepHZ mice displayed reduced circulating leptin levels on the chow diet and HFD. On chow diet, male OBHZ and LepHZ mice showed elevated fat mass and body weight, while their glucose tolerance and insulin sensitivity remained unchanged. However, the inability in partially leptin-deficient mice to fully induce circulating leptin during the development of diet-induced obesity results in reduced food intake and leaner mice with lower body weight compared to their littermate controls. Importantly, a strong reduction of adipose tissue inflammation is observed along with improvements in insulin sensitivity and enhanced glucose tolerance. Additionally, partial leptin deficiency protects the mice from fatty liver and liver fibrosis. Chronically HFD-fed OBHZ and LepHZ mice remain more sensitive to exogenous leptin injection, as reflected by their reduced food intake upon an acute leptin treatment.

Conclusion

In response to HFD feeding, the inability to upregulate leptin levels due to partial leptin deficiency protects mice from diet-induced obesity and metabolic dysregulation. Thus, in an obesogenic environment, maintaining lower leptin levels is highly beneficial for both obesity and diabetes management. Chronic leptin reduction represents a viable preventive strategy whose efficacy awaits clinical testing.

中文翻译：

---

瘦素的部分缺乏会赋予小鼠对饮食诱发的肥胖的抵抗力。

目的

高瘦素血症本身足以促进肥胖状态下的瘦素抵抗。瘦素敏感性可通过在生理健康范围内降低循环中的瘦素水平来恢复，并且是可行的抗肥胖和抗糖尿病策略。然而，一项先前的研究表明，瘦素的部分缺乏有利于饮食引起的肥胖症和小鼠相关的代谢紊乱，认为较低的瘦素水平确实可能促进饮食引起的肥胖症及其相关的代谢紊乱。在这里，我们旨在阐明部分瘦素缺乏对脂肪量和胰岛素敏感性的影响。

方法

我们使用了两种不同的部分瘦素缺乏症小鼠模型：脂肪细胞特异性先天性杂合瘦素敲除小鼠品系（LepHZ）和成熟的全身杂合瘦素敲除小鼠（OBHZ）。OBHZ和LepHZ小鼠的代谢研究均采用富含碳水化合物的普通食物和高脂饮食（HFD）进行。研究中包括雄性和雌性小鼠，以解释性别特异性差异。测试了体重，食物摄入量，葡萄糖耐量和胰岛素耐量。脂肪组织和肝组织的组织学使人们能够深入了解脂肪组织炎症和肝甘油三酯含量。免疫组织化学与RT-PCR分析相结合，用于检测炎症标志物的表达水平。

结果

OBHZ和LepHZ小鼠在日常饮食和HFD上均表现出降低的循环瘦素水平。在日常饮食中，雄性OBHZ和LepHZ小鼠脂肪含量和体重增加，而其葡萄糖耐量和胰岛素敏感性保持不变。但是，部分瘦素缺乏的小鼠不能在饮食诱导的肥胖发生过程中完全诱导循环瘦素，这导致食物摄入减少，而体重较轻的小鼠则更瘦。重要的是，观察到脂肪组织炎症的强烈减少以及胰岛素敏感性的改善和葡萄糖耐量的提高。此外，部分瘦素缺乏可保护小鼠免于脂肪肝和肝纤维化。长期由HFD喂养的OBHZ和LepHZ小鼠对外源瘦素注射更加敏感，

结论

响应HFD喂养，由于部分瘦素缺乏而无法上调瘦素水平，可以保护小鼠免于饮食引起的肥胖和代谢异常。因此，在致肥胖的环境中，保持较低的瘦素水平对肥胖和糖尿病治疗都非常有益。慢性瘦素减少是一种可行的预防策略，其疗效有待临床测试。