Regulation of adipose tissue remodeling by peripheral serotonin

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1 Regulation of adipose tissue remodeling by peripheral serotonin Sangkyu Park Catholic Kwandong University College of Medicine Department of Biochemistry

2 Serotonin (5-HT) is a signaling molecule Hemostasis Vasoconstriction GI motility Anxiety Depression Food intake Sleep Nat Rev Neurosci. 23 2

3 Serotonin is synthesized from Tryptophan Tryptophan Tryptophan Hydroxylase 5-HTP (Tph) AADC 5-HT (serotonin) 3

4 Two separated pools of serotonin Peripheral serotonin Neuronal serotonin Tryptophan 5-HTP AADC Tph1 5-HT (serotonin) BBB Tryptophan Tph2 5-HTP AADC 5-HT (serotonin) 4

5 Serotonin receptors 5

6 Central serotonin is an anorectic neurotransmitter Tecott LH, Cell Metabolism, 27 6

7 Depletion of brain serotonin induces hyperphagia and body weight gain Tryptophan Tph 5-HTP PCPA (p-chloro phenylalanine) AADC 5-HT (serotonin) Breisch ST et al, Science,

8 Extracellular 5-HT levels were increased in the ventral hippocampus of SERT KO rats Homberg et al. Neuroscience, 27 8

9 SERT KO mice show obese phenotypes Murphy DL, Nat Rev Neurosci, 28 Chen X et al. PLOS One 7, 212 9

10 Genetic evidences for serotonin in obesity Association of Variations in TPH1 and HTR2B with Gestational Weight Gain and Measures of Obesity. Kwak SH et al. Obesity, 212 Association of variations in HTR2A with the different effects on BMI in men and women. Li P et al. Intl J Obesity, 213 Association of polymorphisms in HTR2A with increased energy and fat intake in French children. Herberth et al. Am J Clin Nutr, 25 Plasma serotonin is increased in diabetic patients. Pietraszek MH et al. Thrombosis Research,

11 High Fat Diet () increases serum 5-HT levels 11 Kim HJ et al. J Proteome Res, 211

12 Body weight (g) Glucose (mg/dl) Minor differences in body mass and adiposity in standard chow diet (SCD) mice SCD SCD+PCPA SCD SCD+PCPA Time (min) Age (wks) Oh et al. Nat Commun,

13 Body weight (g) Tph inhibition by PCPA protects from -induced obesity PCPA Age (wks) Breisch ST et al, Science,

14 Glucose (mg/dl) Glucose (mg/dl) PCPA increases glucose disposal in fed mice 5 GTT 15 ITT PCPA PCPA Time (min) Time (min) 14

15 Physical activity (1 5 cm/day) VO 2 (ml/h/kg) Heat (kcal/h/kg) Food intake (g/day) PCPA increases energy expenditure in mice , 4, 25 2 Vehicle PCPA 15 Vehicle PCPA 3, 2, , 5 5 Light Dark Light Dark Vehicle PCPA 15

16 Adipocyte size (um 2 ) Serotonin depletion decreases adipocyte cell size in ewat ewat 4, 3, 2, +Vehicle +PCPA 1, Vehicle PCPA +PCPA ewat: epidydimal (visceral) WAT 16

17 Relative expression PCPA decreases lipogenic gene expressions in ewat 1.5 Fasn 1.5 Gpam 1.5 Lpin1 1.5 Dgat1 1.5 Dgat SCD SCD+PCPA +PCPA. SCD SCD+PCPA +PCPA. SCD SCD+PCPA +PCPA. SCD SCD+PCPA +PCPA. SCD SCD+PCPA +PCPA 17

18 SCD SCD PCPA induces decreased cell size and increased Ucp1 expression in iwat Ucp1 Vehicle PCPA Vehicle PCPA iwat: inguinal (subcutaneous) WAT 18

19 Relative expression PCPA increases thermogenic gene expressions in iwat 1 Ucp1 1.5 Ucp2 5 Dio2 1.5 Ppargc1a 3 Prdm SCD SCD+PCPA +PCPA. SCD SCD+PCPA +PCPA SCD SCD+PCPA +PCPA. SCD SCD+PCPA +PCPA SCD SCD+PCPA +PCPA 19

20 Relative expression SCD PCPA increases thermogenic gene expressions in BAT Vehicle PCPA Ucp Dio Ppargc1a Cidea SCD SCD+PCPA +PCPA SCD SCD+PCPA +PCPA SCD SCD+PCPA +PCPA. SCD SCD+PCPA +PCPA 2

21 % Injected dose / body weight PCPA increases glucose uptake into BAT Vehicle 1.5 BAT 1. PCPA.5. Vehicle PCPA 21

22 PCPA treatment increases mitochondrial number and size in BAT Vehicle PCPA 65x 22

23 LP53341, a synthetic Tph inhibitor that does not cross BBB Yadav VK, et al., Nature Medicine, 21 23

24 Body weight (g) Body weight (g) Weight gain by was lower in LP53341 treated mice LP PCPA Age (wks) Age (wks) 24

25 LP decreases size of adipocytes Vehicle LP ewat iwat BAT 25

26 Glucose (mg/dl) Glucose (% of initial) LP improves glucose homeostasis and insulin tolerance LP LP Time (min) Time (min) 26

27 Relative expression Relative expression LP increases thermogenic gene expressions in BAT 8 6 Ucp1 8 6 Dio Vehicle LP SCD SCD 27

28 Summary I PCPA treatment protected from diet induced obesity reduced adipose fat pad and size of adipocytes increased browning of iwat and thermogenic gene expressions increased glucose tolerance and insulin sensitivity increased whole body energy expenditure Inhibition of Tph1 by LP showed similar phenotypes like PCPA 28

29 Gut derived serotonin has no effect on body weight gain Sumara G, et al. Cell Metabolsim,

30 Tph1 is expressed in 3T3-L1 adipocytes Kinoshita M et al., Mol Endocrinol,21 3

31 Serotonin modulates adipocyte differentiation Kinoshita M et al., Mol Endocrinol,21 31

32 Serotonin (ng/mg) increases 5-HT contents in adipose tissues SCD 5 25 ewat iwat BAT 32

33 increases 5-HT expressions in adipose tissues Tph1 Tph2 Fabp4 ewat iwat BAT Tph1 relative expression SCD Actb ewat iwat BAT 33

34 Weight gain (g) Glucose (mg/dl) Fat-specific Tph1 KO (FKO) shows resistance to obesity 1 WT Tph1 FKO Age (wks) WT Tph1 FKO Time (min) 34

35 KO WT Fat-specific Tph1 KO mice shows decreased fat size ewat iwat BAT 35

36 Fat-specific Tph1 KO mice shows increased Ucp1 expression in iwat Ucp1 WT Tph1 FKO 36

37 Fat-specific Tph1 KO mice shows increased Ucp1 expression in SVF from BAT BAT SVF Ucp1 Relative expression WT Tph1 FKO Control 5-HT β3 agonist 37

38 Serotonin receptors Lam DD et al, Expert Rev Mol Med, 27 38

39 Body weight (g) VO 2 (ml/h/kg) Heat (kcal/h/kg) Htr3a KO mice are resistant to and shows increased energy expenditure WT, Htr3a KO, Age (wks) 5, 4, 3, 2, 1, Light Dark WT Htr3a KO Light Dark 39

40 Relative expression SCD Htr3a KO mice shows reduced lipid droplet and increased thermogenic gene expression in BAT WT Htr3a KO WT Htr3a KO Ucp1 Dio2 4

41 WT There is no significant difference in WAT of Htr3a KO mice ewat iwat WT Htr3a KO Htr3a KO 41

42 camp (pmol/ml) camp-pka pathway is activated by Htr3a antagonist Vehicle Ondan m-cpbg Ondan+CL Ondan: Ondansetron, Htr3a antagonist m-cpbg: Htr3a agonist CL: CL316243, b3 AR agonist 42

43 Relative expression Relative expression Htr3a antagonist increased thermogenic gene expression in brown adipocytes Vehicle Ondan Ucp1 2 Ppara Hsl Ppargc1a Prdm16 Dio2 Ucp1.5. Vehicle m-cpbg 43

44 OCR (pmoles/min) Htr3a antagonist increased O2 consumption in brown adipocytes Ondansetron CL Rotenone/Antimycin A Oligomycin 1,5 1, Vehicle CL Ondan + CL Time (min) 44

45 Conclusions and Questions 1. Serotonin is synthesized in adipose tissues. 2. Expression of serotonin is increased by high fat diet in adipose tissues. 3. Chemical or genetic inhibition of serotonin synthesis improves glucose homeostasis, and induces browning of subcutaneous WAT. 4. Inhibition of Htr3 increased thermogenesis in BAT. 5. Which mechanisms are involved in browning of WAT? Htr browning 45

46 Acknowledgements KAIST Chang-Myung Oh Ko Eun Shong Kyuho Kim Hail Kim Jun Namkung Hyungseok Kim Hee-Saeng Jung Kyungbook National University Yonghoon Go In-Kyu Lee Chungnam National University Minho Shong Seoul National University Junghan Song Hak Chul Jang Sung Hee Choi UCSF Shingo Kajimura 46

47 Thank you for your attention! 47