Ponse of preadipocytes from COX-2+/mice to adiponectin was negligible. Poor viability of homozygous COX-2mice precluded

Ponse of preadipocytes from COX-2+/mice to adiponectin was negligible. Poor viability of homozygous COX-2mice precluded their use in our experiments, and adiponectin unresponsiveness in the heterozygotes suggests a substantial gene dose effect. Furthermore, a COX-2 inhibitory compound blocked the inhibition of fat cell formation in cultures of cloned preadipocytes. COX-2 is induced in response to proinflammatory cytokines or hormones, and is usually a ratelimiting enzyme within the biosynthesis of PGs. It mediates the conversion of arachidonic acid into PGH2, which can be subsequently converted to various types of PGs by specific synthases (38). PGs appear to contribute to fat cell formation in complex ways. By way of example, PGE2 and prostacyclin (PGI2), the two main PGs synthesized by fat cells (10, 40), appear to haveMay 2002 Volume 109 Numberopposing actions on adipogenesis. PGE2 was shown to negatively regulate fat cell improvement by lowering cAMP production (37). Conversely, PGI2 is proposed as an adipogenic agonist (41). Our data CaMK III drug confirm the inhibitory effect of PGE2 on marrow fat cell differentiation, and additional suggest a vital contribution to the inhibitory influence adiponectin has on adipogenesis. Other PGs that influence fat cell development incorporate PGJ2, a vital ligand for the adipogenic transcription issue PPAR-. This PG promotes adipocyte differentiation (4, 5). In contrast, PGF2 inhibits the adipogenic differentiation of 3T3-L1 cells (42). Again, PGs with opposing actions are synthesized from PGH2, a COX-2 solution. In our hands, the 3T3-L1 line generated fat cells in standard culture medium where insulin was the only inducing agent, and this differentiation was minimally impacted by addition of either adiponectin or PGE2 (data not shown). Comparison of 3T3-L1 cells to adiponectinsensitive preadipocytes should be informative about inducible genes and could reveal functional heterogeneity amongst fat cells in typical tissues. Two other adipocyte merchandise, agouti and angiotensin II (AGT II), are identified to contribute to obesity (43, 44). Agouti induces fatty acid and triglyceride synthesis in cultured adipocytes within a calcium influx ependent manner (45). AGT II Bombesin Receptor Biological Activity expression is nutritionally regulated, rising with high-fat diet program and fatty acids concomitant with fat mass (46). Adiponectin expression is also affected by diet, but the direction is contrary to that of AGT II (25). AGT II promotes adipocyte differentiation by stimulating release of PGI2 from mature adipocytes (41). Hence, PG synthesis seems to play an indispensable part in paracrine actions of adipocyte items on fat cell differentiation. There are really interesting parallels and functional relationships involving adiponectin and TNF-. The three-dimensional structure on the C-terminal globular domain of adiponectin is strikingly equivalent to that of TNF- (19). Both molecules are secreted from fat cells, and each straight inhibit fat cell improvement. However, their physiological levels and actions might be rather diverse. Plasma levels of adiponectin decrease in obese men and women, whilst concentrations of TNF- are reported to increase and may well contribute to insulin resistance and diabetes (8). In contrast, two current reports suggest that adiponectin may possibly be useful for therapy of variety II diabetes (25, 26). Adiponectin inhibits TNF- production in macrophages (29), even though TNF- suppresses adiponectin expression in adipocytes (20). TNF- stimulates NF-B signaling in aortic endothelia.