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.
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).
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).
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.
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We wish to thank staff of the Gastrointestinal Investigation Unit, Royal Adelaide Hospital and Discipline of Surgery, Flinders Medical Center, for their assistance with the study.
DJK and RLY conceived, designed, supervised the study, obtained study support, acquired data, undertook statistical analyses, and wrote the manuscript; they are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. APL and VMJ obtained study support. CKR, NQN, SST, TW, DF, PR, PH, LS, SLD, DAW acquired human duodenal and colon tissues and performed research endoscopy. ALL assisted in study design, acquired data, undertook statistical analyses, and wrote the manuscript. AMM, GS, NP, NJI, NC, and EWLS advised on study design, acquired, and undertook statistical analyses of data. All authors had access to the study data and reviewed and approved the final manuscript.
Australian Research Council (grant no. LP150100419) and Pfizer Inc. (NY, USA). Pfizer Inc. was not involved in the study design, sample collection, or analysis of data.
Conflict of interest
The authors declare that they have no conflict of interest.
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Young, R.L., Lumsden, A.L., Martin, A.M. et al. Augmented capacity for peripheral serotonin release in human obesity. Int J Obes 42, 1880–1889 (2018). https://doi.org/10.1038/s41366-018-0047-8
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