Research ArticleObesity

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

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Science Translational Medicine  22 Aug 2018:
Vol. 10, Issue 455, eaah6324
DOI: 10.1126/scitranslmed.aah6324

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Restoring leptin’s effects in obesity

Obesity is the most common metabolic disease in the developed world. Although obese individuals have increased plasma concentrations of the anorexigenic hormone leptin, they are refractory to its anorexigenic effect. Mazor et al. showed that, in rodents, obesity induced matrix metalloproteinase–2 (Mmp-2) activation in the hypothalamus. In turn, Mmp-2 activation reduced leptin-mediated signaling by promoting leptin receptor degradation. Mmp-2 deletion in the hypothalamus increased leptin receptor expression and reduced fat accumulation in mice fed a high-fat diet. The results suggest that targeting Mmp-2 might be an effective strategy for treating obesity by restoring the anorexigenic effects of leptin.

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.

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