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Cleavage of the Leptin Receptor by Matrix metalloproteinase-2 Promotes Leptin Resistance and Obesity in Mice

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

Sci Transl Med. 2018 Aug 22;10(455):eaah6324.

PMID: 30135249

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4248699	Matrix Metalloproteinase-2 from mouse			Price

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