Laminin-α4 Is Uniquely Upregulated in Subcutaneous White Adipose Tissue in Murine and Human Models of Obesity

Abstract As research into the adipocyte microenvironment has advanced, it is becoming more widely accepted that the extracellular matrix (ECM) contributes to adipocyte dysfunction. The majority of current published work focuses on the role of collagens in metabolic disease while less emphasis has been placed on the contribution of laminins, an important component of the adipocyte basement membrane. Laminins are trimeric ECM proteins composed of α, β, and γ chains. The α chains contain sites which can interact with cell surface receptors and is considered the driver of tissue-specific expression and specialized signaling. Our group has shown that the laminin-α4 (LAMA4) chain, which is highly expressed in mature adipocytes, plays a role in adipocyte function and thermogenesis in mice (1). In this study we investigate the relationship between laminin α chain expression and obesity by assessing gene expression of LAMA1-5 in subcutaneous white adipose tissue (sWAT) from mice fed chow (RCD) and 45% high fat diet (HFD) for 8 weeks. Expression of LAMA2 and LAMA4 was significantly increased in the HFD sWAT compared to chow (6.1 fold, p=0.01 and 4.9 fold, p=0.001 respectively), however LAMA4 displayed a much stronger positive correlation with weight (R2=0.697) than did LAMA2 (R2=0.382). In order to validate the relevance of these findings in human models of obesity, we evaluated gene expression of LAMA2, LAMA4, and LAMA5 in sWAT biopsies from non-diabetic adult females with obesity (class II or higher). sWAT samples from obese subjects exhibited 4.5 fold higher LAMA4 expression (p=0.0089) than samples from non-obese control subjects, suggesting that the LAMA4 chain may play an important role in human obesity. Lastly we examined changes in sWAT LAMA4 expression following a period of weight loss in obese mice and in human subjects after bariatric surgery, and found that LAMA4 expression levels remain largely unchanged in both cases. In this study we demonstrate the relationship between LAMA4 expression and obesity and present findings that can be extended to human models of obesity. Reference: (1) Vaicik et al., Endocrinology. 2018 Jan;159(1):356–67.