Tissue inhibitor of metalloproteinase-3 knockout mice exhibit enhanced energy expenditure through thermogenesis

• Published in: PloS one 2014-04, Vol.9 (4), p.e94930-e94930
• Main Authors: Hanaoka, Yohsuke, Yasuda, Osamu, Soejima, Hirofumi, Miyata, Keishi, Yamamoto, Eiichiro, Izumiya, Yasuhiro, Maeda, Nobuyo, Ohishi, Mitsuru, Rakugi, Hiromi, Oike, Yuichi, Kim-Mitsuyama, Shokei, Ogawa, Hisao
• Format: Article
• Language: English
• Subjects: Adipocytes; Animals; Apoptosis; Biology and Life Sciences; Body temperature; Carbon dioxide; Cold Temperature; Deoxyribonucleic acid; Diabetes; Disorders; DNA; Energy expenditure; Energy metabolism; Energy Metabolism - genetics; Extracellular matrix; Food intake; Gastrocnemius muscle; Gene expression; Homeostasis; Hypertension; Inhibition; Insulin resistance; Locomotor activity; Male; Matrix metalloproteinase; Medicine; Metabolic disorders; Metabolic syndrome; Metabolism; Metalloproteinase; Mice; Mice, Knockout; Mitochondria; Mitochondria - metabolism; Muscle, Skeletal - metabolism; Muscles; Obesity; Oxygen; Oxygen consumption; Peroxisome proliferator-activated receptors; Phosphorylation; Physiological aspects; Proteins; Research and Analysis Methods; Rodents; Soleus muscle; Temperature; Temperature effects; Thermogenesis; Thermogenesis - genetics; Tissue inhibitor of metalloproteinase 3; Tissue Inhibitor of Metalloproteinase-3 - deficiency; Tissue Inhibitor of Metalloproteinase-3 - genetics; Tumor necrosis factor; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Vascular endothelial growth factor
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0094930

Tissue inhibitors of metalloproteinases (TIMPs) regulate matrix metalloproteinase activity and maintain extracellular matrix homeostasis. Although TIMP-3 has multiple functions (e.g., apoptosis, inhibition of VEGF binding to VEGF receptor, and inhibition of TNFα converting enzyme), its roles in thermogenesis and metabolism, which influence energy expenditure and can lead to the development of metabolic disorders when dysregulated, are poorly understood. This study aimed to determine whether TIMP-3 is implicated in metabolism by analyzing TIMP-3 knockout (KO) mice. TIMP-3 KO mice had higher body temperature, oxygen consumption, and carbon dioxide production than wild-type (WT) mice, although there were no differences in food intake and locomotor activity. These results suggest that metabolism is enhanced in TIMP-3 KO mice. Real-time PCR analysis showed that the expression of PPAR-δ, UCP-2, NRF-1 and NRF-2 in soleus muscle, and PGC-1α and UCP-2 in gastrocnemius muscle, was higher in TIMP-3 KO mice than in WT mice, suggesting that TIMP-3 deficiency may increase mitochondrial activity. When exposed to cold for 8 hours to induce thermogenesis, TIMP-3 KO mice had a higher body temperature than WT mice. In the treadmill test, oxygen consumption and carbon dioxide production were higher in TIMP-3 KO mice both before and after starting exercise, and the difference was more pronounced after starting exercise. Our findings suggest that TIMP-3 KO mice exhibit enhanced metabolism, as reflected by a higher body temperature than WT mice, possibly 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.