Cleavage of the leptin receptor by matrix metalloproteinase-2 promotes leptin resistance and obesity in mice

Rafi Mazor, Dinorah Friedmann-Morvinski, Tom Alsaigh, Oded Kleifeld, Erik B. Kistler, Liat Rousso-Noori, Cheng Huang, Joyce B. Li, Inder M. Verma, Geert W. Schmid-Schönbein

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42 Citations (Scopus)


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 Mmp-2 in the hypothalamus of wild-type mice prevented leptin receptor cleavage and reduced fat accumulation. In contrast, lentiviral delivery of Mmp-2 in the hypothalamus of Mmp-2−/− 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.

Original languageEnglish
Article numbereaah6324
Number of pages11
JournalScience Translational Medicine
Issue number455
Publication statusPublished - 22 Aug 2018

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