Dataset Information

Deletion of matrix metalloproteinase-12 improves energy metabolism and brown adipose tissue function in mice prone to develop cardiometabolic disease

ABSTRACT: Matrix metalloproteinase-12 (MMP12) is a proinflammatory protein secreted by macrophages. We have previously demonstrated that the genetic deletion of MMP12 in a cardiometabolic mouse model (low-density lipoprotein receptor-deficient (LdlrKO) mice fed a high-fat, sucrose- and cholesterol-enriched diet) ameliorated obesity-induced low-grade inflammation, white adipose tissue dysfunction, and atherosclerosis. Here, we hypothesized that the deletion of MMP12 might also positively affect whole-body energy metabolism and/or brown adipose tissue (BAT) function. Ldlr/Mmp12 double knockout (DKO) mice housed at room temperature (22°C) showed increased energy expenditure and decreased BAT size and triglyceride (TG) content. Untargeted proteomic analyses revealed the upregulation of several 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. As we detected MMP12 expression in the mitochondrial fraction of BAT, its absence in DKO BAT was consistent with reduced oxygen consumption, compactness, and sphericity of the mitochondria. Following an acute cold exposure, DKO mice had decreased BAT weights and 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.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brown Adipose Tissue

SUBMITTER: Monika Svecla

LAB HEAD: Dagmar Kratky

PROVIDER: PXD063623 | Pride | 2026-01-19

REPOSITORIES: Pride

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Deletion of MMP12 improves energy metabolism and brown adipose tissue function in mice prone to cardiometabolic disease.

Amor Melina M Diaz Malena M Fuerlinger Alexander A Svecla Monika M Bianco Valentina V Schooltink Laszlo L Dobrijević Anja A Schwarz Birgit B Akhmetshina Alena A Vujić Nemanja N Korbelius Melanie M Hirtl Martin M Buerger Martin M Pirchheim Anita A Rainer Silvia S Schauer Silvia S Beretta Giangiacomo G Goessler Walter W Kolb Dagmar D Hoefler Gerald G Hackl Hubert H Madreiter-Sokolowski Corina C Abdellatif Mahmoud M Norata Giuseppe Danilo GD Kratky Dagmar D

Journal of lipid research 20251126 1

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 hypo ...[more]

PMID: 41308745

Similar Datasets

Project description:Thoracic perivascular adipose tissue (PVAT) is a unique adipose depot that likely influences vascular function and susceptibility to pathogenesis in obesity and metabolic syndrome. Surprisingly, PVAT has been reported to share characteristics of both brown and white adipose, but a detailed direct comparison to interscapular brown adipose tissue (BAT) has not been performed. Here we show by full genome DNA microarray analysis that global gene expression profiles of PVAT are virtually identical to BAT, with equally high expression of Ucp-1, Cidea and other genes known to be uniquely or very highly expressed in BAT. PVAT and BAT also displayed nearly identical phenotypes upon immunohistochemical analysis, and electron microscopy confirmed that PVAT contained multilocular lipid droplets and abundant mitochondria. Compared to white adipose tissue (WAT), PVAT and BAT from C57BL/6 mice fed a high fat diet for 13 weeks had markedly lower expression of immune cell-enriched mRNAs, suggesting resistance to obesity-induced inflammation. Indeed, staining of BAT and PVAT for macrophage markers (F4/80, CD68) in obese mice showed virtually no macrophage infiltration, and FACS analysis of BAT confirmed the presence of very few CD11b+/CD11c+ macrophages in BAT (1.0%) in comparison to WAT (31%). In summary, murine PVAT from the thoracic aorta is virtually identical to interscapular BAT, is resistant to diet-induced macrophage infiltration, and thus may play an important role in protecting the vascular bed from thermal and inflammatory stress. 8-week-old male C57BL6/J mice were fed a normal (ND) or high fat diet (HFD) (Research Diets 12451, 45 kcal% fat) for 13 weeks. Mice were then euthanized and four different adipose depots were harvested for RNA analysis: perivascular fat from the lesser curvature of the aortic arch (PVAT), interscapular brown adipose (BAT), inguinal adipose tissue (SAT), and epididymal adipose tissue (VAT). 250 ng total RNA pooled from two mice was used for cDNA synthesis; 3 biological replicates per tissue and diet were performed for a total of 24 hybridizations.

			Action	DRS
	BAT_DKO1.mzML	Mzml
	BAT_DKO1.mzTab	Mztab
	BAT_DKO1.raw	Raw
	BAT_DKO2.mzML	Mzml
	BAT_DKO2.mzTab	Mztab