Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Amor, M; Diaz, M; Fuerlinger, A; Svecla, M; Bianco, V; Schooltink, L; Dobrijević, A; Schwarz, B; Akhmetshina, A; Vujić, N; Korbelius, M; Hirtl, M; Buerger, M; Pirchheim, A; Rainer, S; Schauer, S; Beretta, G; Goessler, W; Kolb, D; Hoefler, G; Hackl, H; Madreiter-Sokolowski, C; Abdellatif, M; Norata, GD; Kratky, D.
Deletion of MMP12 improves energy metabolism and brown adipose tissue function in mice prone to cardiometabolic disease.
J Lipid Res. 2025; 100951
Doi: 10.1016/j.jlr.2025.100951
PubMed
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- Führende Autor*innen der Med Uni Graz
- Amor Melina
- Kratky Dagmar
- Co-Autor*innen der Med Uni Graz
- Abdellatif Mahmoud
- Akhmetshina Alena
- Bianco Valentina
- Bürger Martin
- Diaz Malena
- Fürlinger Alexander
- Hirtl Martin
- Höfler Gerald
- Kolb Dagmar
- Korbelius Melanie
- Madreiter-Sokolowski Corina
- Pirchheim Anita
- Rainer Silvia
- Schauer Silvia
- Schooltink Laszlo
- Schwarz Birgit
- Vujic Nemanja
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- Abstract:
- Matrix metalloproteinase-12 (MMP12) is a proinflammatory macrophage-secreted protein with immunomodulatory functions that affects neutrophil infiltration, cytokine release, macrophage recruitment, and proliferation. We have previously demonstrated that the genetic deletion of MMP12 in a cardiometabolic mouse model ameliorates obesity-induced low-grade inflammation, white adipose tissue dysfunction, and atherosclerosis. Based on the various beneficial metabolic effects of MMP-12 deletion, we hypothesized that loss of MMP-12 also positively affects whole-body energy metabolism and/or brown adipose tissue (BAT) function in a cardiometabolic mouse model. To investigate the effects of MMP12 deletion on whole-body energy metabolism and/or BAT function, we used low-density lipoprotein receptor (Ldlr)/Mmp12 double knockout (DKO) fed a high-fat, sucrose- and cholesterol-enriched diet. DKO mice housed at 22°C showed increased energy expenditure and decreased BAT size and triglyceride (TG) content. Untargeted proteomic analyses revealed the upregulation of proteins and pathways related to mitochondrial function, glucose metabolism, and fatty acid oxidation in the BAT of DKO mice, whereas abundance of proteins and pathways associated with inflammation were reduced. In addition, DKO mice exhibited reduced macrophage infiltration in BAT with the infiltrating macrophages showing lower expression of lipid-associated marker genes. Loss of MMP12 was associated with reduced compactness and sphericity of the mitochondria in the BAT. Following an acute cold exposure, DKO mice had decreased circulating lipid concentrations, especially very low-density lipoprotein-TG and LDL-cholesterol, and increased expression of thermogenic genes. We conclude that MMP12 may play a detrimental role in whole-body energy homeostasis and thermogenesis, as it triggers macrophage infiltration, inflammation, and mitochondria dysfunction in BAT.