Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 10, Issue 455, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aah6324
Keywords
-
Categories
Funding
- American Heart Association Postdoctoral Fellowship [10POST4150064]
- NIH [HL10881, GM85052]
- Career Development Award (CDA2) from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development [1IK2BX001277-01A1]
- Foundation for Anesthesia Education and Research
- American Society of Critical Care Anesthesiologists
- NCI [P30 CA014195-40, R01 AI048034-15]
- Leona M. and Harry B. Helmsley Charitable Trust
- Berger Foundation
Ask authors/readers for more resources
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 wildtype 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available