L-PGDS-produced PGD(2) 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 PGD(2) 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 PGD(2) 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 PGD(2) produced by L-PGDS in premature adipocytes is involved in the regulation of body weight gain and insulin resistance under nutrient-dense conditions.