Anneli Lauhio1,2, Esa Färkkilä1,2,3, Kirsi H Pietiläinen2,4,5,6, Pirjo Åström7,8, Alina Winkelmann9, Taina Tervahartiala9, Emma Pirilä7,8, Aila Rissanen4,10, Jaakko Kaprio5,11,12, Timo A Sorsa3,9,13, Tuula Salo7,8,14,15. 1. Department of Infectious Diseases, Helsinki University Central Hospital, Helsinki, Finland. 2. Clinicum, University of Helsinki, Helsinki, Finland. 3. Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland. 4. Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland. 5. FIMM, Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. 6. Endocrinology, Abdominal Center, Helsinki University Central Hospital, Helsinki, Finland. 7. Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland. 8. Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland. 9. Department of Periodontology, Institute of Dentistry, University of Helsinki, Helsinki, Finland. 10. Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland. 11. Department of Public Health, University of Helsinki, Helsinki, Finland. 12. Department of Health, National Institute for Health and Welfare, Helsinki, Finland. 13. Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden. 14. Department of Oral Pathology, Institute of Dentistry, University of Helsinki, Helsinki, Finland. 15. Helsinki University Central Hospital, Helsinki, Finland.
Abstract
BACKGROUND: Obesity has been recognized as a state of subclinical inflammation resulting in a loss of insulin receptors and decreased insulin sensitivity. We here studied in vivo the role of circulating matrix metalloproteinase-8 (MMP-8) among young healthy twin adults. Also, in vitro analysis of the cleavage of human insulin receptor (INSR) by MMP-8 was investigated as well its inhibition by doxycycline and other MMP-8 inhibitor, Ilomastat/GM6001, which are broad-spectrum MMP inhibitors. MATERIALS AND METHODS: We analysed serum MMP-8 levels by a time-resolved immunofluorometric assay in obese (n = 34), overweight (n = 76) and normal weight (n = 130) twin individuals. The effect of MMP-8 on INSR and the effects of synthetic MMP-8 inhibitors, doxycycline and Ilomastat/GM6001, were studied by SDS-PAGE. RESULTS: We found that in obese individuals relative to normal weight individuals, the serum MMP-8 levels and MMP-8/TIMP-1 ratio were significantly increased (P = 0·0031 and P = 0·031, respectively). Among normal weight and obese individuals, also smoking significantly increases serum MMP-8 and MMP-8/TIMP-1 ratio. In vitro, we found that INSR was degraded by MMP-8 and this was inhibited by doxycycline and Ilomastat/GM6001. CONCLUSIONS: Obesity associated with elevated circulating MMP-8 found among young adults may contribute to progression of insulin resistance by cleaving INSR. This INSR cleavage by MMP-8 can be inhibited by synthetic MMP-8 inhibitors such as doxycycline. In addition to obesity, also smoking independently explained increased MMP-8 levels. Our results suggest that MMP-8 is an essential mediator in systemic subclinical inflammatory response in obesity, and a potential drug target.
BACKGROUND:Obesity has been recognized as a state of subclinical inflammation resulting in a loss of insulin receptors and decreased insulin sensitivity. We here studied in vivo the role of circulating matrix metalloproteinase-8 (MMP-8) among young healthy twin adults. Also, in vitro analysis of the cleavage of humaninsulin receptor (INSR) by MMP-8 was investigated as well its inhibition by doxycycline and other MMP-8 inhibitor, Ilomastat/GM6001, which are broad-spectrum MMP inhibitors. MATERIALS AND METHODS: We analysed serum MMP-8 levels by a time-resolved immunofluorometric assay in obese (n = 34), overweight (n = 76) and normal weight (n = 130) twin individuals. The effect of MMP-8 on INSR and the effects of synthetic MMP-8 inhibitors, doxycycline and Ilomastat/GM6001, were studied by SDS-PAGE. RESULTS: We found that in obese individuals relative to normal weight individuals, the serum MMP-8 levels and MMP-8/TIMP-1 ratio were significantly increased (P = 0·0031 and P = 0·031, respectively). Among normal weight and obese individuals, also smoking significantly increases serum MMP-8 and MMP-8/TIMP-1 ratio. In vitro, we found that INSR was degraded by MMP-8 and this was inhibited by doxycycline and Ilomastat/GM6001. CONCLUSIONS:Obesity associated with elevated circulating MMP-8 found among young adults may contribute to progression of insulin resistance by cleaving INSR. This INSR cleavage by MMP-8 can be inhibited by synthetic MMP-8 inhibitors such as doxycycline. In addition to obesity, also smoking independently explained increased MMP-8 levels. Our results suggest that MMP-8 is an essential mediator in systemic subclinical inflammatory response in obesity, and a potential drug target.
Authors: Steven Tun; Caleb James Spainhower; Cameron Lee Cottrill; Hari Vishal Lakhani; Sneha S Pillai; Anum Dilip; Hibba Chaudhry; Joseph I Shapiro; Komal Sodhi Journal: Front Pharmacol Date: 2020-08-13 Impact factor: 5.810
Authors: Ismo T Räisänen; Kehinde A Umeizudike; Pirjo Pärnänen; Pia Heikkilä; Taina Tervahartiala; Solomon O Nwhator; Andreas Grigoriadis; Dimitra Sakellari; Timo Sorsa Journal: Med Hypotheses Date: 2020-09-16 Impact factor: 1.538
Authors: J Mazuchová; E Halašová; J Mazuch; M Šarlinová; V Valentová; M Franeková; Š Zelník; K Krkošková; K Javorka; M Péč; M Grendár Journal: Physiol Res Date: 2020-12-31 Impact factor: 1.881