L-PGDS-produced PGD₂ in premature, but not in mature, adipocytes increases obesity and insulin resistance.

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-PGDS ^flox/flox and adiponectin (AdipoQ)-Cre/L-PGDS ^flox/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-PGDS ^flox/flox mice, but were unchanged in the AdipoQ-Cre/L-PGDS ^flox/flox mice. When fed an HFD, aP2-Cre/L-PGDS ^flox/flox mice significantly reduced body weight gain, adipocyte size, and serum cholesterol and triglyceride levels. In WAT of the HFD-fed aP2-Cre/L-PGDS ^flox/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-PGDS ^flox/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.

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