Augmented capacity for peripheral serotonin release in human obesity

Richard L. Young, Amanda L. Lumsden, Alyce M. Martin, Gudrun Schober, Nektaria Pezos, Sony S. Thazhath, Nicole J. Isaacs, Nada Cvijanovic, Emily W.L. Sun, Tongzhi Wu, Christopher K. Rayner, Nam Q. Nguyen, Dayan De Fontgalland, Philippa Rabbitt, Paul Hollington, Luigi Sposato, Steven L. Due, David A. Wattchow, Alice P. Liou, V. Margaret JacksonDamien J. Keating

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background/objectives: Evidence from animal studies highlights an important role for serotonin (5-HT), derived from gut enterochromaffin (EC) cells, in regulating hepatic glucose production, lipolysis and thermogenesis, and promoting obesity and dysglycemia. Evidence in humans is limited, although elevated plasma 5-HT concentrations are linked to obesity.

Subjects/methods: We assessed (i) plasma 5-HT concentrations before and during intraduodenal glucose infusion (4 kcal/min for 30 min) in non-diabetic obese (BMI 44 ± 4 kg/m2, N = 14) and control (BMI 24 ± 1 kg/m2, N = 10) subjects, (ii) functional activation of duodenal EC cells (immunodetection of phospho-extracellular related-kinase, pERK) in response to glucose, and in separate subjects, (iii) expression of tryptophan hydroxylase-1 (TPH1) in duodenum and colon (N = 39), and (iv) 5-HT content in primary EC cells from these regions (N = 85).

Results: Plasma 5-HT was twofold higher in obese than control responders prior to (P = 0.025), and during (iAUC, P = 0.009), intraduodenal glucose infusion, and related positively to BMI (R2 = 0.334, P = 0.003) and HbA1c (R2 = 0.508, P = 0.009). The density of EC cells in the duodenum was twofold higher at baseline in obese subjects than controls (P = 0.023), with twofold more EC cells activated by glucose infusion in the obese (EC cells co-expressing 5-HT and pERK, P = 0.001), while the 5-HT content of EC cells in duodenum and colon was similar; TPH1 expression was 1.4-fold higher in the duodenum of obese subjects (P = 0.044), and related positively to BMI (R2 = 0.310, P = 0.031).

Conclusions: Human obesity is characterized by an increased capacity to produce and release 5-HT from the proximal small intestine, which is strongly linked to higher body mass, and glycemic control. Gut-derived 5-HT is likely to be an important driver of pathogenesis in human obesity and dysglycemia.

Original languageEnglish
Pages (from-to)1880-1889
Number of pages10
JournalInternational Journal of Obesity
Volume42
Issue number11
DOIs
Publication statusPublished - Nov 2018

Keywords

  • Obesity
  • endoscopy
  • Serotonin
  • Enterochromaffin cells
  • Glucose

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    Young, R. L., Lumsden, A. L., Martin, A. M., Schober, G., Pezos, N., Thazhath, S. S., Isaacs, N. J., Cvijanovic, N., Sun, E. W. L., Wu, T., Rayner, C. K., Nguyen, N. Q., De Fontgalland, D., Rabbitt, P., Hollington, P., Sposato, L., Due, S. L., Wattchow, D. A., Liou, A. P., ... Keating, D. J. (2018). Augmented capacity for peripheral serotonin release in human obesity. International Journal of Obesity, 42(11), 1880-1889. https://doi.org/10.1038/s41366-018-0047-8