Alternatively spliced lipin isoforms exhibit distinct expression pattern, subcellular localization, and role in adipogenesis

We recently identified mutations in the Lpin1 (lipin) gene to be responsible for lipodystrophy in the fatty liver dystrophy (fld) mouse strain. Previous studies revealed that lipin plays a critical role in adipogenesis, explaining the adipose-deficient phenotype of the fld mouse. In the current study, we demonstrate that alternative mRNA splicing generates two lipin isoforms, lipin-α and lipin-β, which are differentially expressed during adipocyte differentiation. Lipin-α expression peaks at day 2 of 3T3-L1 cell differentiation, after which its levels gradually decrease. In contrast, lipin-β expression is transiently elevated at 10 h, followed by a drop to background levels at 20 h and a gradual increase between days 2 and 6 of differentiation. The two lipin isoforms also exhibit differences in subcellular localization. Lipin-α is predominantly nuclear, whereas lipin-β is primarily located in the cytoplasm of 3T3-L1 adipocytes, suggesting distinct cellular functions. Using primary mouse embryonic fibroblasts expressing either lipin-α or lipin-β, we demonstrate functional differences between the two isoforms. Whereas lipin-α is required for adipocyte differentiation, the predominant effect of lipin-β expression is the induction of lipogenic genes. In vivo, overexpression of lipin-β specifically in mature adipocytes leads to elevated expression of lipogenic genes and adipocyte hypertrophy, confirming a role of lipin-β in the regulation of lipogenesis. In conclusion, our data suggest that the two lipin isoforms have distinct, but complementary, functions in adipogenesis, with lipin-α playing a primary role in differentiation and lipin-β being predominantly involved in lipogenesis.