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

Author:

Goddi Anna1ORCID,Carmona Alanis2,Park Soo-Young2,Dalgin Gokhan2,Gonzalez Porras Maria A3,Brey Eric M3,Cohen Ronald N12ORCID

Affiliation:

1. Committee on Molecular Metabolism and Nutrition, The University of Chicago , Chicago, Illinois 60637 , USA

2. Section of Endocrinology, Diabetes, and Metabolism, The University of Chicago , Chicago, Illinois 60637 , USA

3. Department of Biomedical Engineering and Chemical Engineering, The University of Texas at San Antonio , San Antonio, Texas 78249 , USA

Abstract

Abstract Laminin-α4 (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 γ 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-α and adenosine 5′-monophosphate–activated protein kinase (AMPK)-α 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 AMPKα. Last, we demonstrate that treatment of human induced pluripotent stem cell–derived thermogenic adipocytes with LAMA4 (LN411) inhibited the expression of thermogenic markers and AMPKα. Overall, our results indicate that LAMA4 negatively regulates a thermogenic phenotype and pathways involving mitochondrial biogenesis in adipocytes through the suppression of AMPKα.

Funder

University of Chicago

National Institutes of Health

National Institute of Diabetes and Digestive and Kidney Diseases

Publisher

The Endocrine Society

Subject

Endocrinology

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