Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Sci Transl Med. 2018 Aug 22;10(455). doi: 10.1126/scitranslmed.aah6324.
Obesity and related morbidities pose a major health threat. Obesity is associated with increased blood concentrations of the anorexigenic hormone leptin; however, obese individuals are resistant to its anorexigenic effects. We examined the phenomenon of reduced leptin signaling in a high-fat diet-induced obesity model in mice. Obesity promoted matrix metalloproteinase-2 (Mmp-2) activation in the hypothalamus, which cleaved the leptin receptor's extracellular domain and impaired leptin-mediated signaling. Deletion of Mmp-2 restored leptin receptor expression and reduced circulating leptin concentrations in obese mice. Lentiviral delivery of short hairpin RNA to silence in the hypothalamus of wild-type mice prevented leptin receptor cleavage and reduced fat accumulation. In contrast, lentiviral delivery of in the hypothalamus of mice promoted leptin receptor cleavage and higher body weight. In a genetic mouse model of obesity, transduction of cleavage-resistant leptin receptor in the hypothalamus reduced the rate of weight gain compared to uninfected mice or mice infected with the wild-type receptor. Immunofluorescence analysis showed that astrocytes and agouti-related peptide neurons were responsible for Mmp-2 secretion in mice fed a high-fat diet. These results suggest a mechanism for leptin resistance through activation of Mmp-2 and subsequent cleavage of the extracellular domain of the leptin receptor.
肥胖症及其相关的病态是一个主要的健康威胁。肥胖症与厌食激素瘦素的血液浓度升高有关；然而，肥胖者对其厌食作用有抵抗力。我们在高脂肪饮食诱导的肥胖症小鼠模型中研究了瘦素信号转导降低的现象。肥胖症促进了基质金属蛋白酶-2（Mmp-2）在下丘脑的激活，该酶切割了瘦素受体的细胞外结构域并损害了瘦素介导的信号转导。Mmp-2 的缺失恢复了肥胖小鼠瘦素受体的表达并降低了循环瘦素浓度。在野生型小鼠的下丘脑中，通过慢病毒传递短发夹 RNA 沉默该基因可防止瘦素受体的切割并减少脂肪堆积。相反，在 Mmp-2 敲除小鼠的下丘脑中，慢病毒传递的 Mmp-2 可促进瘦素受体的切割和体重增加。在肥胖症的遗传小鼠模型中，与未感染或感染野生型受体的小鼠相比，将抗切割的瘦素受体转导到下丘脑可降低体重增加的速度。免疫荧光分析表明，在高脂肪饮食喂养的小鼠中，星形胶质细胞和 agouti 相关肽神经元负责 Mmp-2 的分泌。这些结果表明，通过激活 Mmp-2 并随后切割瘦素受体的细胞外结构域，可能会导致瘦素抵抗。
