Abstract
Lipin-1 deficiency in the mouse causes generalized lipodystrophy, characterized by impaired adipose tissue development and insulin resistance. Lipin-1 expression in differentiating preadipocytes is required for normal expression of adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma and CCAAT enhancer binding protein alpha, and for the synthesis of triacylglycerol. The requirement of lipin-1 for adipocyte differentiation can be explained, in part, by its activity as the sole adipocyte phosphatidic acid phosphatase-1 enzyme, which converts phosphatidate to diacylglycerol, the immediate precursor of triacylglycerol. Here we identify glucocorticoids as the stimulus for the induction of lipin-1 expression in differentiating adipocytes, and characterize a glucocorticoid response element (GRE) in the Lpin1 promoter. The Lpin1 GRE binds to the glucocorticoid receptor and leads to transcriptional activation in adipocytes and hepatocytes, as demonstrated by reporter gene transcription, electrophoretic mobility shift, and chromatin immunoprecipitation assays. This represents the first gene regulatory element identified to directly influence lipin-1 expression levels, and may modulate lipin-1 mRNA levels in adipose tissue and liver in conditions associated with increased local glucocorticoid concentrations in vivo, such as obesity and fasting.
Highlights
Lipin-1 deficiency in the mouse causes generalized lipodystrophy, characterized by impaired adipose tissue development and insulin resistance
In contrast to lipin-1, diacylglycerol acyltransferase 1 (DGAT1) was induced by MIX, whereas neither glycerol 3-phosphate acyltransferase (GPAT) nor acylglycerolphosphate acyltransferase 2 (AGPAT2) was increased after a 4 h treatment with any of the components (Fig. 1B)
Adipose tissue plays an important role in metabolic homeostasis, inasmuch as both too little and too much adipose tissue can promote insulin resistance and hyperlipidemia [33, 34]
Summary
Lipin-1 deficiency in the mouse causes generalized lipodystrophy, characterized by impaired adipose tissue development and insulin resistance. The Lpin GRE binds to the glucocorticoid receptor and leads to transcriptional activation in adipocytes and hepatocytes, as demonstrated by reporter gene transcription, electrophoretic mobility shift, and chromatin immunoprecipitation assays This represents the first gene regulatory element identified to directly influence lipin-1 expression levels, and may modulate lipin-1 mRNA levels in adipose tissue and liver in conditions associated with increased local glucocorticoid concentrations in vivo, such as obesity and fasting.—Zhang, P., L. Lipin-1 was originally identified as the defective gene product that causes lipodystrophy in the fatty liver dystrophy (fld) mouse [1] Lipodystrophy in these animals is characterized by a lack of normal adipose tissue throughout the body and insulin resistance [2]. The mechanism is not known, possible contributions may be effects of lipin-1 on glucose uptake and oxidative gene expression in adipose tissue, and enhanced triglyceride storage in adipose tissue as protection against
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