Cleavage of the leptin receptor by matrix metalloproteinase-2 promotes leptin resistance and obesity in mice
| Autor: | Mazor, Rafi, Friedmann-Morvinski, Dinorah, Alsaigh, Tom, Kleifeld, Oded, Kistler, Erik B, Rousso-Noori, Liat, Huang, Cheng, Li, Joyce B, Verma, Inder M, Schmid-Schönbein, Geert W |
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| Rok vydání: | 2018 |
| Předmět: |
Leptin
Male Knockout Hypothalamus Wistar Inbred C57BL Weight Gain Cardiovascular Medical and Health Sciences Oral and gastrointestinal Mice Receptors Animals 2.1 Biological and endogenous factors Obesity Aetiology Metabolic and endocrine Nutrition Cancer Prevention NF-kappa B Neurosciences Brain Biological Sciences Rats Diet Enzyme Activation Stroke High-Fat Matrix Metalloproteinase 2 Signal Transduction |
| Zdroj: | Science translational medicine, vol 10, iss 455 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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