Regulation of systemic energy homeostasis by serotonin in adipose tissues

Drareg

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Not sure if this was posted on here yet, it’s interesting that 5ht is so active in adipose tissue.
Maybe topical application of a 5HT3 antagonist on adipose tissue may be helpful for people struggling in this area?

Inhibition of 5-HT synthesis increased thermogenesis​

In peripheral tissues, 5-HT is mainly produced and secreted by enterochromaffin cells in the gut and actively taken up by platelets, which store most of the body 5-HT2,16. However, gut-derived 5-HT is not associated with diet-induced obesity17, suggesting more localized effects of 5-HT in regulating energy homeostasis. It has been known that 5-HT is present in WAT and BAT, and it promotes adipogenesis in 3T3-L1 preadipocytes15,18,19. Thus, we tested 5-HT production in adipose tissues. Indeed, all the genes involved in 5-HT metabolism, except for Tph2, were expressed in adipose tissues (Supplementary Fig. 2a). Interestingly, the HFD feeding increased the Tph1 messenger RNA level in epididymal WAT (eWAT) and inguinal WAT (iWAT), and increased tissue 5-HT levels accordingly (Fig. 2a,b). These data suggested the potential role of adipocyte-derived 5-HT in the development of diet-induced obesity. Therefore, we investigated metabolic changes in adipose tissue.

To examine the mechanism of increased energy expenditure by PCPA treatment, we measured the metabolic activity of mouse organ by assessing 18fluorodeoxyglucose uptake, using positron emission tomography (PET)-computed tomography20. We found that the inhibition of 5-HT synthesis by PCPA significantly increased glucose uptake into BAT (Fig. 2c). Histological analysis also revealed that PCPA-treated mice showed decreased lipid droplet size and increased multilocular adipocytes in BAT (Fig. 2d). PCPA treatment increased the mRNA expression of thermogenic genes in BAT and the highest increase was observed in the Dio2 mRNA level (Fig. 2e and Supplementary Fig. 2b). In addition, the number and size of the mitochondria and the density of the cristae were increased in the BAT of PCPA-treated mice (Supplementary Fig. 2c). These data suggested that inhibition of 5-HT synthesis increased the thermogenic activity of BAT.

To exclude the possibility that anti-obesity effects of PCPA might be related to the inhibition of 5-HT synthesis in the brain, we have tested peripheral Tph inhibitior, LP-533401, which cannot cross the blood–brain barrier14. Mice treated with LP-533401 showed reduced weight gain and improved glucose tolerance compared with control mice under an HFD (Fig. 4a,b). The BAT of LP-533401-treated mice displayed similar histological changes to those observed in PCPA-treated mice after an HFD feeding (Fig. 4c). The BAT of LP-533401-treated mice also showed increased thermogenic gene expressions (Fig. 4d). Taken together, our data suggested that the inhibition of peripheral Tph1 increased energy expenditure by increasing thermogenic activity of BAT and iWAT.

Most peripheral 5-HT is produced in enterochromaffin cells in the gut and stored in platelets. However, gut-specific Tph1 KO mice did not show resistance to diet-induced obesity17, which led us to focus on adipose tissue-derived 5-HT. In the present study, we demonstrated that adipocytes can produce 5-HT separately from the gut and HFD increases Tph1 mRNA expression and tissue 5-HT levels in adipose tissues. Mice with inducible Tph1 KO in adipose tissues were resistant to HFD-induced weight gain and their glycemic control
was improved.


In the present study, we provide evidence for a complex model, explaining the regulation of energy metabolism in different adipose tissues (Fig. 10f). In the over-fed state, 5-HT level increased in WAT, leading to the augmentation of lipogenesis via Htr2a. 5-HT also suppressed thermogenesis in the BAT via Htr3. When 5-HT signalling was inhibited, lipogenesis decreased in the eWAT and thermogenesis increased in both iWAT and BAT. The β3AR signalling stimulated by an HFD coupled with uninhibited thermogenesis by the blocking of Htr3 signalling resulted in enhanced energy expenditure in BAT. Thus, the inhibition of 5-HT production in adipose tissues may represent a novel strategy for anti-obesity treatment.
 

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