Endocrinol Metab.  2020 Jun;35(2):470-479. 10.3803/EnM.2020.35.2.470.

Serotonin Regulates De Novo Lipogenesis in Adipose Tissues through Serotonin Receptor 2A

• Shong KE
• Oh CM
• Namkung J
• Park S
• Kim H

• KMID: 2503277
• DOI: http://doi.org/10.3803/EnM.2020.35.2.470

Abstract

Background
Obesity is defined as excessive fat mass and is a major cause of many chronic diseases such as diabetes, cardiovascular disease, and cancer. Increasing energy expenditure and regulating adipose tissue metabolism are important targets for the treatment of obesity. Serotonin (5-hydroxytryptophan [5-HT]) is a monoamine metabolite of the essential amino acid tryptophan. Here, we demonstrated that 5-HT in mature adipocytes regulated energy expenditure and lipid metabolism.
Methods
Tryptophan hydroxylase 1 (TPH1) is the rate-limiting enzyme during 5-HT synthesis in non-neural peripheral tissues. We generated adipose tissue-specific Tph1 knockout (Tph1 FKO) mice and adipose tissue-specific serotonin receptor 2A KO (Htr2a FKO) mice and analyzed their phenotypes during high-fat diet (HFD) induced obesity.
Results
Tph1 FKO mice fed HFD exhibited reduced lipid accumulation, increased thermogenesis, and resistance to obesity. In addition, Htr2a FKO mice fed HFD showed reduced lipid accumulation in white adipose tissue and resistance to obesity.
Conclusion
These data suggest that the inhibition of serotonin signaling might be an effective strategy in obesity.

Keyword

Serotonin; Adipose tissue, white; Obesity; Lipogenesis

Figure

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  Fig. 1 Tryptophan hydroxylase 1 (Tph1) knockout (FKO) protects against high-fat diet (HFD)-induced obesity. (A) Volcano plot for mRNA expression of adipose tissue from the BXD strains. (B) Bodyweight curves in wild type (WT) and Tph1 FKO mice fed standard chow diet (SCD) or HFD for 12 weeks. Bodyweight of WT and Tph1 FKO mice were measured weekly from week 4 to week 20; n=5 in each group fed SCD, n=8 in each group fed HFD. (C). Body fat and lean body mass of mice after 12 weeks of HFD feeding. (D, E) Gross appearance and fat mass of visceral, inguinal and brown fat of 20-week-old WT and Tph1 FKO mice (left) fed on HFD. Adipose tissue weight (right); n=7 in each group. (F) Glucose tolerance tests. Blood glucose concentrations were measured at the indicated time points after fasted for 16 hours; n=10 in each group fed HFD. iWAT, inguinal white adipose tissue; eWAT, epidydimal white adipose tissue; BAT, brown adipose tissue. aP<0.05; bP<0.01 indicated significance.

• 

  Fig. 2 Tryptophan hydroxylase 1 (Tph1) knockout (FKO) increased energy expenditure. (A) Oxygen (O2) consumption (left), carbon dioxide (CO2) production (middle) and heat production (right) in wild type (WT) and Tph1 FKO mice fed on high-fat diet (HFD) for 12 weeks; n=8 in each group fed HFD. (B, C) In vivo luciferase assay of WT and Tph1 FKO mice. Tph1 FKO mice show increased uncoupled protein 1 (UCP1) activity. (D) Histological analysis of brown adipose tissue (BAT) at the indicated age. Adipose tissue sections were stained with H&E (scale bar, 100 μm). SCD, standard chow diet. aP<0.05; bP<0.01 indicated significance.

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  Fig. 3 Representative images of adipose tissues of tryptophan hydroxylase 1 (Tph1) knockout (FKO) mice. (A) Histological analysis of iWAT at the indicated age. Adipose tissue was stained with H&E. (B) Immunostaining of UCP1 in iWAT (scale bar, 100 μm). (C) Histological analysis of eWAT at the indicated age. Adipose tissue sections were stained with H&E (scale bar, 100 μm). (D) The adipocyte size was analyzed using ImageJ software (NIH). iWAT, inguinal white adipose tissue; UCP1, uncoupled protein 1; eWAT, epididymal white adipose tissue; SCD, standard chow diet; HFD, high-fat diet; WT, wild type. aP<0.05 indicated significance.

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  Fig. 4 Inhibition of adipose tissue-specific serotonin receptor 2A (HTR2A) signaling reduces lipid accumulation in white adipose tissue (WAT). (A) Representative images of immunofluorescence staining of differentiated 3T3-L1 adipocytes with BODIPY (green), anti-5-hydroxytryptophan (5-HT) antibody (red), and 4′,6-diamidino-2-phenylindole (DAPI; blue). White arrow indicates BODIPY and 5-HT co-positive cells. (B) Body weight curves in wild type (WT) and Htr2a FKO mice fed standard chow diet (SCD) or high-fat diet (HFD) for 12 weeks. (C) Histological analysis of epididymal white adipose (eWAT) in of WT and Htr2a FKO mice fed SCD or HFD. (D) The adipocyte sizes were analyzed using the ImageJ program. (E) mRNA expression level of fatty acid synthesis (Acaca, Fasn, Scd1), triglyceride synthesis (Dgat1, Dgat2, Gpam, Mogat1), and Plin1. Acaca, acetyl-coA carboxylase alpha; Fasn, fatty acid synthase; Scd1, stearoyl-CoA desaturase 1; Dgat1, diacylglycerol O-acyltransferase 1; Dgat2, diacylglycerol O-acyltransferase 2; Gpam, glycerol-3-phosphate acyltransferase, mitochondrial; Mogat1, monoacylglycerol O-acyltransferase 1; Plin1, perilipin 1. aP<0.05; bP<0.001 indicated significance.

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