Integrins and extracellular matrix proteins modulate adipocyte thermogenic capacity

Abstract

Obesity and the metabolic disease epidemic has led to an increase in morbidity and mortality. A rise in adipose thermogenic capacity via activation of brown or beige fat is a potential treatment for metabolic diseases. However, an understanding of how local factors control adipocyte fate is limited. Mice with a null mutation in the laminin α4 (LAMA4) gene (KO) exhibit resistance to obesity and enhanced expression of thermogenic fat markers in white adipose tissue (WAT). In this study, changes in WAT extracellular matrix composition in the absence of LAMA4 were evaluated using liquid chromatography/tandem mass spectrometry. KO-mice showed lower levels of collagen 1A1 and 3A1, and integrins α7 (ITA7) and β1 (ITB1). ITA7-ITB1 and collagen 1A1-3A1 protein levels were lower in brown adipose tissue compared to WAT in wild-type mice. Immunohistochemical staining confirmed lower levels and different spatial distribution of ITA7 in KO-WAT. In culture studies, ITA7 and LAMA4 levels decreased following a 12-day differentiation of adipose-derived stem cells into beige fat, and knock-down of ITA7 during differentiation increased beiging. These results demonstrate that extracellular matrix interactions regulate adipocyte thermogenic capacity and that ITA7 plays a role in beige adipose formation. A better understanding of the mechanisms underlying these interactions can be used to improve systemic energy metabolism and glucose homeostasis.

cytoNet: Spatiotemporal network analysis of cell communities

“…These characterizations are consistent with the observation that adipose in knockout mice is more similar to beige adipose tissue. Overall, these observations align with findings that the absence of laminin α4 leads to changes in stromal cell distribution in pericapillary niches within adipose tissue [ 59 ]. The resulting data can be used to guide studies into understanding the mechanisms underlying the effect of laminin α4 on adipose tissue function.…”

Semaphorin 4B is an ADAM17-cleaved inhibitor of adipocyte thermogenesis

“…However, evidence for semaphorin-mediated promotion of adipose tissue fibrosis is limited to a single study on Sema3C [121], while the impact of pro-fibrotic genes in adipocyte thermogenesis is still poorly understood [122,123]. Speculatively, cleaved Sema4B could act on pre-adipocytes or mature adipocytes to promote fibrosis, to trigger a range of negative impacts on adipocyte physiology like on adipose tissue plasticity and insulin resistance [121] or thermogenesis [124].…”

Adipose Tissue Development Relies on Coordinated Extracellular Matrix Remodeling, Angiogenesis, and Adipogenesis

“…There have also been recent experiments exploring potential extracellular components that regulate thermogenic capacity and the conversion of white adipose tissue towards beige adipose tissue. It has been shown that ASCs induced towards a beige lineage when on top of Collagen 1A1, Collagen 3A1, and Laminin A4 had lower levels of Uncoupling Protein 1 (UCP-1) (a critical component for the regulation of brown/beige adipose tissue) compared to those differentiated on uncoated dishes [ 121 ]. In the absence of the Laminin A4 gene, thermogenic markers were upregulated in white adipose tissue, suggesting that the ECM’s composition plays a role in maintaining white adipocytes [ 121 , 122 , 123 , 124 ].…”