Abstract
Obesity affects nearly one billion globally and can lead to life-threatening sequelae. Consequently, there is an urgent need for novel therapeutics. We have previously shown that laminin, alpha 4 (Lama4) knockout in mice leads to resistance to adipose tissue accumulation; however, the relationship between LAMA4 and obesity in humans has not been established. In this study we measured laminin-α chain and collagen mRNA expression in the subcutaneous white adipose tissue (sWAT) of mice placed on chow (RCD) or 45% high fat diet (HFD) for 8 weeks, and also in HFD mice then placed on a “weight loss” regimen (8 weeks HFD followed by 6 weeks RCD). To assess extracellular matrix (ECM) components in humans with obesity, laminin subunit alpha mRNA and protein expression was measured in sWAT biopsies of female control subjects (BMI<30) or subjects with obesity undergoing bariatric surgery at the University of Chicago Medical Center (BMI>35) both before and three months after surgery. Lama4 was significantly higher in sWAT of HFD compared to RCD mice at both the RNA and protein level (p<0.001, p<0.05 respectively). sWAT from human subjects with obesity also showed significantly higher LAMA4 mRNA (p<0.01) and LAMA4 protein expression (p<0.05) than controls. Interestingly, even though LAMA4 expression was increased in both humans and murine models of obesity, no significant difference in Lama4 or LAMA4 expression was detected following short-term weight loss in either mouse or human samples, respectively. From these results we propose a significant association between obesity and elevated LAMA4 expression in humans, as well as in mouse models of obesity. Further studies should clarify the mechanisms underlying this association to target LAMA4 effectively as a potential therapy for obesity.
Highlights
Obesity is an epidemic affecting 13% of people worldwide and contributing to more than $2 trillion in global economic impact [1, 2]
Preliminary dietary studies showed that female mice placed on high fat diet (HFD) did not gain significant weight during the dietary study timeline and were not a good model to study the association of Lama4 and obesity (Supplemental Figure 1)
At 16 weeks of age we assessed the mRNA expression of laminina chains in adipose depots by quantitative real-time PCR
Summary
Obesity is an epidemic affecting 13% of people worldwide and contributing to more than $2 trillion in global economic impact [1, 2]. Obesity can lead to the development of serious health conditions including cancer, hypertension, heart disease, and type 2 diabetes [3,4,5]. A clear necessity arises for the development of adipose targeted therapies to ameliorate metabolic dysfunction and reduce overall adiposity. Much has been learned about adipocyte biology, in particular the intracellular signaling pathways and transcription factors that mediate its function. Less attention has been paid to the adipose microenvironment, with the exception of significant focus on macrophage infiltration that occurs in the setting of obesity. Recent work suggests that the extracellular matrix (ECM) itself considerably affects adipocyte biology
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