Abstract 3594: Serotonin in Adipose Tissue Acts as an Autocrine Factor Required for Adipocyte Differentiation and Lipolysis

The differentiation of preadiopocytes (preAdps) into mature adipocytes (Adps) is closely associated with the expression of adipocyte (Adp)-specific gene products that are deeply involved in insulin resistance; therefore, it is critical to identify genes required for Adp differentiation. We used retrovirus insertion-mediated random mutagenesis to generate 3T3-L1 preAdp cells which lose their ability to differentiate into mature Adps. Using this approach, we discovered that tryptophan hydroxylase-1 (TPH1), a rate-limiting enzyme for the biosynthesis of serotonin (Ser), was required for Adp differentiation. While differentiation was clearly reduced in a mutant 3T3-L1 cell line that lacked expression of the normal TPH1 gene, reconstitution of the TPH1 gene in this cell line restored its differentiation potential. The administration of Ser enhanced differentiation in 3T3-L1 cells and in cells of the stromal vascular fraction from adult mice. On the other hand, differentiation was inhibited by 5-hydroxy tryptophan type 2A (5HT2A) receptor antagonists as well as the Ser synthesis inhibitor. Differentiation into mature Adp was significantly impaired in preAdps prepared from TPH1−/− mice compared to those from wild-type mice. We observed no differences in the histology of adipose tissue between TPH1−/−and wild-type mice at the basal state; however, after obesity was induced by a high-fat diet, increases in body weight and mesenteric fat weight were more prominent in TPH1−/− mice than in wild-type mice. In obese groups, we observed extremely large (140μm∼) Adps without any small Adps in TPH1−/− mice, in contrast to usually hypertrophied (μ80∼m) Adps and small Adps in wild-type mice. Interestingly, Ser treatment of mature cultured Adps enhanced lipolysis, which was blocked by the 5HT7 receptor antagonist but not by the 5HT2A receptor antagonist. Oral administration of 5HT2A receptor antagonist in high fat diet-induced obese mice reduced mesenteric fat weight and the number of small adipocytes; however, it did not increase the number of extremely large adipocytes as seen in TPH1−/−mice. Thus, Ser in adipose tissue acts as an autocrine factor required for Adp differentiation and lipolysis. Distinct receptor subtypes appear to mediate these two processes.