Laminin-α4 Negatively Regulates Adipocyte Beiging Through the Suppression of AMPKα in Male Mice

Laminin-alpha 4 (LAMA4) is an extracellular matrix protein implicated in the regulation of adipocyte differentiation and function. Prior research describes a role for LAMA4 in modulating adipocyte thermogenesis and uncoupling protein-1 (UCP1) expression in white adipose; however, the mechanisms involved are poorly understood. Here, we describe that Lama4 knockout mice (Lama4-/-) exhibit heightened mitochondrial biogenesis and peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) expression in subcutaneous white adipose tissue (sWAT). Furthermore, the acute silencing of LAMA4 with small interfering RNA in primary murine adipocytes was sufficient to upregulate the expression of thermogenic markers UCP1 and PR domain containing 16 (PRDM16). Silencing also resulted in an upregulation of PGC1-alpha and adenosine 5'-monophosphate-activated protein kinase (AMPK)-alpha expression. Subsequently, we show that integrin-linked kinase (ILK) is downregulated in the sWAT of Lama4-/- mice, and its silencing in adipocytes similarly resulted in elevated expression of UCP1 and AMPK alpha. Last, we demonstrate that treatment of human induced pluripotent stem cell-derived thermogenic adipocytes with LAMA4 (LN411) inhibited the expression of thermogenic markers and AMPK alpha. Overall, our results indicate that LAMA4 negatively regulates a thermogenic phenotype and pathways involving mitochondrial biogenesis in adipocytes through the suppression of AMPK alpha.

Automated summary

This study found that LAMA4 negatively regulates thermogenic phenotype and pathways involving mitochondrial biogenesis in adipocytes through the suppression of AMPK alpha.