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In previous genome-wide association studies (GWAS), genetic loci associated with obesity and impaired fat distribution (FD) have been identified. In the present study, we elucidated the role of the <i>PEMT</i> gene, including the waist–hip-ratio-associated single nucleotide polymorphism rs4646404, and its influence on obesity-related metabolic traits. DNA from 2926 metabolically well-characterized subjects was used for genotyping. <i>PEMT</i> expression was analyzed in paired visceral (vis) and subcutaneous (sc) adipose tissue (AT) from a subset of 574 individuals. Additionally, <i>PEMT</i> expression was examined in vis, sc AT and liver tissue in a separate cohort of 64 patients with morbid obesity and liver disease. An in vitro <i>Pemt</i> knockdown was conducted in murine epididymal and inguinal adipocytes. Our findings highlight tissue-specific variations in <i>PEMT</i> mRNA expression across the three studied tissues. Specifically, vis <i>PEMT</i> mRNA levels correlated significantly with T2D and were implicated in the progression of non-alcoholic steatohepatitis (NASH), in contrast to liver tissue, where no significant associations were found. Moreover, sc <i>PEMT</i> expression showed significant correlations with several anthropometric- and metabolic-related parameters. The rs4646404 was associated with vis AT <i>PEMT</i> expression and also with diabetes-related traits. Our in vitro experiments supported the influence of <i>PEMT</i> on adipogenesis, emphasizing its role in AT biology. In summary, our data suggest that <i>PEMT</i> plays a role in regulating FD and has implications in metabolic diseases.