Food and Behaviour Research

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

Mazor R, Friedmann-Morvinski D, Alsaigh T, Kleifeld O, Kistler EB, Rousso-Noori L, Huang C, Li JB, Verma IM, Schmid-Schönbein GW (2018) Sci Transl Med.  2018 Aug;10(455).  pii: eaah6324. doi: 10.1126/scitranslmed.aah6324. 

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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.