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.
Highlights
Of beige/brown adipocytes, when LAMA4 was absent[20,21]
Most collagen molecules identified were lower in SubQ adipose tissue from knockout mice (KO) mice, with both collagen 1A1 (CO1A1) and collagen 3A1 (CO3A1) showing significantly different levels (p < 0.0001 and p < 0.01 respectively, Fig. 2C)
PGC1A levels were lower in cells on the coated surfaces, with a significant decrease on CO1A1 compared to uncoated surfaces. These results demonstrate that culture of adipose tissue stem cells (ASC) on the ECM proteins present at higher levels in Wild type (WT) adipose tissue results in lower UCP1 expression
Summary
Of beige/brown adipocytes, when LAMA4 was absent[20,21]. While it is clear that the absence of LAMA4 results in increased expression of UCP1 in subcutaneous WAT (SubQ WAT) and BAT18, the mechanism driving this behavior is unknown. The disruption can influence ECM assembly resulting in changes to the structure and mechanical properties. These broad changes indicate that the UCP1 expression observed in the absence of LAMA4 may result from other changes secondary to the absence of LAMA4. The fate of adipose tissue stem cells (ASC) is influenced by both the chemical composition and mechanical properties of the ECM, and cell-ECM interactions primarily occurs through integrins[23]. The ECM composition of adipose tissue of LAMA4 knockout mice (KO) was examined in order to identify candidate ECM molecules and integrins potentially involved in regulating UCP1 expression. This work provides substantial support for integrin-matrix interactions as important modulators of the thermogenic capacity of adipose tissue
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