Adipocyte-Specific Laminin Alpha 4 Deletion Preserves Adipose Tissue Health despite Increasing Adiposity

Abstract

Laminins are heterotrimeric glycoproteins with structural and functional roles in basement membranes. The predominant laminin alpha chain found in adipocyte basement membranes is laminin α4 (LAMA4). Global LAMA4 deletion in mice leads to reduced adiposity and increased energy expenditure, but also results in vascular defects that complicate the interpretation of metabolic data. Here, we describe the generation and initial phenotypic analysis of an adipocyte-specific LAMA4 knockout mouse (Lama4AKO). We first performed an in-silico analysis to determine the degree to which laminin α4 was expressed in human and murine adipocytes. Next, male Lama4AKO and control mice were fed chow or high-fat diets and glucose tolerance was assessed along with serum insulin and leptin levels. Adipocyte area was measured in both epididymal and inguinal white adipose tissue (eWAT and iWAT, respectively), and eWAT was used for RNA-sequencing. We found that laminin α4 was highly expressed in human and murine adipocytes. Further, chow-fed Lama4AKO mice are like control mice in terms of body weight, body composition, and glucose tolerance, although they have larger eWAT adipocytes and lower insulin levels. High-fat-fed Lama4AKO mice are fatter and more glucose tolerant when compared to control mice. Transcriptionally, the eWAT of high-fat fed Lama4AKO mice resembles that of chow-fed control mice. We conclude from these findings that adipocyte-specific LAMA4 deletion is protective in an obesogenic environment, even though overall adiposity is increased.

Laminin α4 Expression in Human Adipose Tissue Depots and Its Association with Obesity and Obesity Related Traits

“…Several studies have shown that LAMA4 knock-out in mice resulted in healthier phenotypes and metabolisms [13,18,20]. Contrasting these results, we did not find associations of low LAMA4 expression with metabolically healthy obesity.…”

“…We were unable to confirm this finding in our cohort (Figure 1D), possibly due to our cohort's structure comprising of individuals predominantly with obesity and a low number of individuals with normal or overweight. Nevertheless, our findings support previous reports [18,20,21] which associated LAMA4 expression with obesity and increased fat mass.…”

“…However, it is unclear whether these effects are due to LAMA4-loss induced expression change of laminin α5 [13,19]. Transcriptome analysis revealed that adipocyte-specific deletion of LAMA4 seems to preserve the transcription patterns of healthy adipose tissue in DIO mice despite weight gain [20]. A more recent study reported an overall upregulation of LAMA4 in SC white AT in both high-fat-diet (HFD)-fed mice and a human cohort of ten women with obesity, but without diabetes, compared to three healthy, lean women at the gene expression level [21].…”