Abstract
Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is responsible for the production of PGD2 in adipocytes and is selectively induced by a high-fat diet (HFD) in adipose tissue. In this study, we investigated the effects of HFD on obesity and insulin resistance in two distinct types of adipose-specific L-PGDS gene knockout (KO) mice: fatty acid binding protein 4 (fabp4, aP2)-Cre/L-PGDSflox/flox and adiponectin (AdipoQ)-Cre/L-PGDSflox/flox mice. The L-PGDS gene was deleted in adipocytes in the premature stage of the former strain and after maturation of the latter strain. The L-PGDS expression and PGD2 production levels decreased in white adipose tissue (WAT) under HFD conditions only in the aP2-Cre/L-PGDSflox/flox mice, but were unchanged in the AdipoQ-Cre/L-PGDSflox/flox mice. When fed an HFD, aP2-Cre/L-PGDSflox/flox mice significantly reduced body weight gain, adipocyte size, and serum cholesterol and triglyceride levels. In WAT of the HFD-fed aP2-Cre/L-PGDSflox/flox mice, the expression levels of the adipogenic, lipogenic, and M1 macrophage marker genes were decreased, whereas those of the lipolytic and M2 macrophage marker genes were enhanced or unchanged. Insulin sensitivity was improved in the HFD-fed aP2-Cre/L-PGDSflox/flox mice. These results indicate that PGD2 produced by L-PGDS in premature adipocytes is involved in the regulation of body weight gain and insulin resistance under nutrient-dense conditions.
Highlights
Obesity is a critical health problem worldwide and is reaching pandemic levels[1]
We examined the expression of the lipocalin-type PGD synthase (PGDS) (L-PGDS) gene and two adipogenic marker genes, aP2 (Fabp4) and adiponectin (AdipoQ) during adipogenesis of mouse adipocyte 3T3-L1 cells (Fig. 1b)
The expression of the AdipoQ gene was very low at 2 days in premature adipocytes and was induced at 4 days in the mature stage of adipogenesis, indicating that the AdipoQ gene was selectively expressed in mature adipocytes and that its expression came later than those of the L-PGDS and aP2 genes
Summary
Obesity is a critical health problem worldwide and is reaching pandemic levels[1]. CCAAT/enhancer-binding proteins (C/EBPs), peroxisome proliferator-activated receptor (PPAR) γ, and sterol regulatory element-binding protein-1c (SREBP-1c) are critical in the regulation of adipogenesis[6,7,8]. These transcription factors regulate gene expression for various adipogenic proteins, which are involved in the regulation of adipogenesis[6,7,8]. Synthase-1 in adipocytes[15] and represses adipogenesis through the EP4 receptors[16] by increasing the synthesis of anti-adipogenic PGE2 and PGF2α in mouse embryonic fibroblasts (MEFs)[17] and mouse adipocytic 3T3-L1 cells[18]. PGD2 exerts its physiological effects through two G protein-coupled receptors, the PGD2 receptors (DP), DP1 receptors and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), DP2 receptors[27]
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