During the past several decades, the prevalence of obesity and related metabolic diseases has reached epidemic scale across the world. While obesity alone heavily impacts the healthcare system, it also increases the risk for developing co-occurring health conditions including heart disease, stroke, and certain forms of cancer. Moreover, those of lower socioeconomic status and from minority racial and ethnic populations are disproportionately burdened by these diseases. There is a clear and imminent need for non-invasive therapies to effectively treat obesity. Recently, the field of adipocyte thermogenesis has gained increasing momentum towards the development of such therapies. However, the complexity of thermogenic regulation in adipocytes has made it difficult to isolate drug targets that are successful in vivo and in clinical stages. Through increasing our knowledge of thermogenic regulators in adipose tissue, we can build a more comprehensive picture of the drivers of phenotypic shifts in adipocytes to identify more appropriate targets for drug discovery pipelines. One such potential regulator of adipocyte behavior and thermogenesis is the extracellular matrix protein laminin-α4 (LAMA4). The work presented in this dissertation illuminates the role of laminin-α4 in human obesity and in suppressing adipocyte beiging and contributes novel findings to the field of adipocyte thermogenesis and metabolic research. Chapter 1 provides background on metabolic diseases, adipose tissue, thermogenesis, and the extracellular matrix, including an introduction to laminin proteins and an overview of their current applications in biomedicine and tissue engineering. Chapter 2 details the findings of a comparative study of LAMA4 expression patterns in white adipose tissue in humans and mice with obesity and following weight loss. This investigation uncovered a parallel upregulation of LAMA4 expression on both the mRNA and protein levels in the subcutaneous white adipose tissue of mice and human subjects with obesity. However, LAMA4 expression remained unchanged following short-term weight loss in both models. Chapter 3 of this dissertation describes a mechanistic investigation into the regulation of adipocyte thermogenesis by LAMA4 in human and murine models. In vivo, the absence of LAMA4 in mice led to elevated mitochondrial marker and peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) expression. Murine beige adipocytes transfected with siRNA targeting LAMA4 exhibited enhanced uncoupling protein 1 (UCP1) and AMP-activated protein kinase α (AMPKα) expression. When thermogenic adipocytes derived from human induced pluripotent stem cells were treated with recombinant human laminin-411 during differentiation, UCP1 and AMPKα expression were suppressed, suggesting that LAMA4 negatively regulates adipocyte thermogenesis via the AMPK-PGC-1α pathway. The observed extracellular-to-intracellular signaling transduction may be mediated through integrins and integrin linked kinase (ILK), as silencing of ILK in murine adipocytes mirrored the results of the LAMA4 silencing experiments. Overall, the results of this dissertation describe a regulatory function of LAMA4 in maintaining a white adipocyte phenotype through the inhibition of adipocyte beiging. Additionally, this work validates the relevance of these findings in human adipocyte models and obesity, laying the foundation for future examination into the therapeutic benefit of targeting LAMA4 in humans.