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

## TL;DR

Deleting the MMP12 gene in mice improves energy metabolism and brown fat function, reducing inflammation and cholesterol levels.

## Contribution

This study shows that MMP12 deletion improves brown adipose tissue function and energy expenditure in a cardiometabolic mouse model.

## Key findings

- MMP12 deletion increases energy expenditure and reduces brown adipose tissue triglyceride content.
- Loss of MMP12 reduces macrophage infiltration and inflammation in brown adipose tissue.
- Cold exposure enhances the beneficial effects of MMP12 deletion on lipid metabolism and thermogenesis.

## 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 the abundance of proteins and pathways associated with inflammation was 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 mitochondrial dysfunction in BAT.

•MMP12 deletion is linked to inflammation-related pathways in brown adipose tissue.•Reduced macrophages in the brown adipose tissue of Mmp12-deficient mice.•Improved energy expenditure in cardiometabolic Mmp12-deficient mice.•MMP12 is expressed in the mitochondrial fraction of brown adipose tissue.•Cold exposure exacerbates the effects of MMP12 deficiency in brown adipose tissue.

MMP12 deletion is linked to inflammation-related pathways in brown adipose tissue.

Reduced macrophages in the brown adipose tissue of Mmp12-deficient mice.

Improved energy expenditure in cardiometabolic Mmp12-deficient mice.

MMP12 is expressed in the mitochondrial fraction of brown adipose tissue.

Cold exposure exacerbates the effects of MMP12 deficiency in brown adipose tissue.