Interaction of MMP-3 and sex hormones in the control of energy balance.

Abstract

Matrix metalloproteinase-3 (MMP-3) is an endopeptidase important for regulating cell-to-cell interactions and remodeling the extracellular matrix, including the development of adipose tissue. We hypothesized that MMP-3 is also active in the central nervous system, specifically acting to cleave synedecan-3 and thereby regulate AgRP signaling. Because previous studies have shown sex difference in syndecan-3-mediated regulation of food intake, we also tested the hypothesis that CNS MMP-3 might mediate the sex-differences underlying syndecan-3 regulation of energy balance. We first observed that MMP-3 deficient mice are hyperphagic and gain significantly more weight on high-fat diet compared to wild-type controls. Second, MMP-3 null mice exhibit a delayed and prolonged orexigenic response to ICV NPY and AgRP, compared to wild-type controls. These findings are consistent with our hypothesis that MMP-3 regulates cleavage of cell-surface syndecan-3. To test the role of sex hormones in mice lacking MMP-3, we assessed food intake following ovariectomy (OVX). WT-ovariectomized mice exhibit hyperphagia and increased food intake and body weight compared to sham-controls. A separate cohort of MMP-3 null or WT female mice was randomized to receive OVX or sham surgery, after which we recorded daily food intake and body weights. While MMP-3 null and WT OVX mice exhibited similar amounts of hyperphagia, MMP-3 KO mice gained more weight than WT controls. Collectively, these data suggest an important role for MMP-3 in the regulation of food intake and the mediation of sex-hormones on energy balance, consistent with a potential role to regulate cleavage of hypothalamic syndecans.