Abstract 12888: Tissue Inhibitor of Metalloproteinase-3 Knockout Mice Exhibit Enhanced Energy Expenditure through Thermogenesis
Objective: Tissue inhibitors of metalloproteinases (TIMPs) regulate matrix metalloproteinase activity and maintain extracellular matrix homeostasis. TIMP-3 is unique among TIMPs in that it is bound to the extracellular matrix. Although TIMP-3 has multiple functions (e.g., inducing apoptosis, inhibiting VEGF binding to VEGF receptor, and inhibiting TNFα converting enzyme), its roles in thermogenesis and body metabolism, which influence energy expenditure and can lead to metabolic disorders when dysregulated, are poorly understood. This study aimed to determine whether TIMP-3 is implicated in body metabolism.
Methods: The effects of TIMP-3 deficiency on body weight, food intake, activity, respiratory metabolism, and body temperature were evaluated using wild type (WT) and TIMP-3 knockout mice housed in metabolic chambers. Real-time polymerase chain reaction (PCR) was used to compare metabolic gene expression between WT and TIMP-3 KO mice. Mice were placed in a room at 4°C for cold-exposure experiments and body temperature was measured using a rectal probe attached to a digital thermometer.
Results: TIMP-3 KO mice had a higher body temperature compared to WT mice. While food intake and activity did not differ between WT and TIMP-3 KO mice, oxygen consumption and carbon dioxide elimination were higher in TIMP-3 KO mice. These results suggest that metabolism is enhanced in TIMP-3 KO mice. Expression of PPARδ, a regulator of mitochondrial energy metabolism, was higher in TIMP-3 KO mice than in WT mice. Expression of UCP2, NRF1, and NRF2, markers of mitochondrial biogenesis and metabolism, was also higher in TIMP-3 KO mice than in WT mice. These results suggested that TIMP-3 deficiency increases mitochondrial activity and enhances thermogenesis. When exposed to cold for 8 hours to induce thermogenesis, a principal factor of energy expenditure, TIMP-3 KO mice had a higher body temperature than WT mice.
Conclusion: TIMP-3 KO mice have enhanced metabolism, as reflected in a higher body temperature than WT mice, due to increased mitochondrial activity. Given that TIMP-3 deficiency increases energy expenditure, TIMP-3 may present a novel therapeutic target for preventing metabolic disorders.
- © 2013 by American Heart Association, Inc.