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Secretin activates brown fat and induces satiation


Brown adipose tissue (BAT) thermogenesis is activated by feeding. Recently, we revealed a secretin-mediated gut–BAT–brain axis, which stimulates satiation in mice, but the purpose of meal-induced BAT activation in humans has been unclear. In this placebo-controlled, randomized crossover study, we investigated the effects of intravenous secretin on BAT metabolism (measured with [18F]FDG and [15O]H2O positron emission tomography) and appetite (measured with functional magnetic resonance imaging) in healthy, normal weight men (GUTBAT trial no. NCT03290846). Participants were blinded to the intervention. Secretin increased BAT glucose uptake (primary endpoint) compared to placebo by 57% (median (interquartile range, IQR), 0.82 (0.77) versus 0.59 (0.53) μmol per 100 g per min, 95% confidence interval (CI) (0.09, 0.89), P = 0.002, effect size r = 0.570), while BAT perfusion remained unchanged (mean (s.d.) 4.73 (1.82) versus 6.14 (3.05) ml per 100 g per min, 95%CI (−2.91, 0.07), P = 0.063, effect size d = −0.549) (n = 15). Whole body energy expenditure increased by 2% (P = 0.011) (n = 15). Secretin attenuated blood-oxygen level-dependent activity (primary endpoint) in brain reward circuits during food cue tasks (significance level false discovery rate corrected at P = 0.05) (n = 14). Caloric intake did not significantly change, but motivation to refeed after a meal was delayed by 39 min (P = 0.039) (n = 14). No adverse effects were detected. Here we show in humans that secretin activates BAT, reduces central responses to appetizing food and delays the motivation to refeed after a meal. This suggests that meal-induced, secretin-mediated BAT activation is relevant in the control of food intake in humans. As obesity is increasing worldwide, this appetite regulating axis offers new possibilities for clinical research in treating obesity.

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Fig. 1: Study protocol.
Fig. 2: Secretin increases GU in human BAT.
Fig. 3: Secretin induces satiation when measured by fMRI.
Fig. 4: Secretin induces satiation when measured by CSS.
Fig. 5: SCTR expression in BAT negatively correlates with body weight in fasted participants.
Fig. 6: Secretin changes circulating metabolite and hormone levels.

Data availability

All statistical parametric images of the fMRI study (including the effect size maps) can be found from NeuroVault at The accession number for the RNA-Seq data presented in this article is GEO GSE113764. SCTR expression in human tissues is available in the Online Biology Gene Portal System (BioGPS) at Datasets that support the findings of this study are available in the Supplementary Information. Source data are provided with this paper. The data that support the plots within this paper, as well as other findings of this study, are available from the corresponding author (P.N.) upon reasonable request.


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The study was conducted within the Centre of Excellence into Cardiovascular and Metabolic Diseases supported by the Academy of Finland (grant no. 307402), University of Turku, Åbo Akademi University; and funded by the Instrumentarium Science Foundation (grant no. 190014) (S.L.), The Paulo Foundation (S.L.), Turku University Hospital Foundation (S.L.) and The Finnish Medical Foundation (grant no. 2985) (S.L.). TUM researchers were supported by the Else Kröner-Fresenius Stiftung (M.K.) and the German Research Foundation (grant no. DFG-CRC 1371: P13 (M.K.), Z02 (K. Steiger)).

Author information




M.K., P.N., K.A.V. and S.L. conceived and designed the study. S.L., L.S. and M.L. performed the human experiments. K. Schnabl conceived the study design for the SCTR expression and regulation study and carried out animal and cell culture experiments. S.L., L.S., K. Schnabl, K.L., M.U.-D. and R.K analysed data. L.N., L.L.E. and T.V. helped with statistical analysis. O.E. and A.K.K. contributed to PET/CT data collection. K. Steiger conducted the immunohistochemical studies. L.N. conceived the fMRI study design. T.N. and M.T. provided BAT biopsies from study participants. M.B. and C.W. provided the analysis of fasted human BAT biopsies. K. Schnabl, Y.L and M.K edited the paper and contributed physiological aspects of secretin-activated brown fat in mouse studies complementing the human study. S.L. wrote the paper with input from authors. All authors read and approved the paper.

Corresponding author

Correspondence to Pirjo Nuutila.

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Competing interests

M.K. and Y.L. are inventors on a patent application from the Technical University of Munich (publication no. WO/2017/20285; international application no. PCT/EP2017/062420) addressing the role of SCTR agonists and modulators in the regulation of energy homeostasis. This patent is based on the initial discovery that meal-induced secretin inhibits food intake, and this anorexigenic action of secretin depends on the activation of brown fat12. The remaining authors declare no competing interests.

Additional information

Peer review information Nature Metabolism thanks Andrew Gray, Marc Tittgemeyer and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Christoph Schmitt.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Enrolment and analysis.

CONSORT flowchart on the enrolment and analysis of study participants.

Extended Data Fig. 2 Visual analogue scale –questions.

Composite satiety score calculated with scale 1–100. Composite satiety score = satiety + fullness + (100 − prospective food consumption) + (100 − hunger)).

Extended Data Fig. 3 PET results and secretin receptor expression.

a. Muscle glucose uptake (GU) is increased by secretin compared to placebo. Data were analyzed with two-sided paired samples t-test and included n = 15 subjects. b. Secretin receptor expression in 79 human tissues, retrieved from Data are expressed as fold over the median (M), error bars show standard error. c. There is no significant change in perfusion after secretin infusion as compared to placebo. Data were analyzed with two-sided paired samples t-test and included n = 15 subjects.

Source data

Extended Data Fig. 4 Additional functional magnetic resonance and composite satiety score results.

a, Down-regulated brain reward anticipation response due to injection of secretin. This separate analysis (n = 14) including subjects with high movement artifacts was originally done. In the placebo condition, palatable food led to increased BOLD activity in brain reward circuits. This effect was diminished in the secretin condition. Interaction effect between food categories and conditions were found in the reward circuits. Significance level was FDR-corrected at p value 0.05. MFC = medial frontal cortex, CC = cingulate cortex, OCC = occipital cortex, Cau = caudate, MTG = middle temporal gyrus, Ins = insula, PCC = posterior cingulate cortex. b, composite satiety score area under the curve (AUC) was not increased postprandially, c nor for the entire study day (pre-prandial, prandial and postprandial phases together). Values are normalized, dividing by the value of the first time point. Data were analyzed by two-sided paired samples t-test, n = 14.

Source data

Extended Data Fig. 5 Additional positron emission tomography and secretin receptor gene expression results.

a, Brown adipose tissue (BAT) glucose uptake (GU) in cold and after secretin. There is no correlation between BAT GU in cold exposure and after secretin infusion. Data were analyzed by Spearman’s rank correlation in order to avoid assumptions around linearity of associations (n = 15). b, human secretin receptor (SCTR) expression on mRNA level, assessed by qPCR, in supraclavicular BAT is weakly associated with body-mass-index (BMI) in n = 14 fasted participants. Data were analyzed by Pearson’s correlation. c, SCTR expression analyzed by RNASeq does not correlate with BMI in n = 14 non-fasted participants. Data were analyzed by Pearson’s correlation.

Source data

Extended Data Fig. 6 Changes in circulating bile acids, hormones and carbohydrates.

a. Secretin did not increase serum bile acid levels compared to placebo. Values are normalized, dividing by the value of the first time point. Each timepoint was analyzed by two-sided, paired Wilcoxon signed-rank test. Median values and standard errors are shown on graph, n = 14. b. Serum hormone and c. carbohydrate heatmap secretin vs. placebo. Values are normalized, dividing by the value of the first time point. Each timepoint was analyzed by two-sided paired Wilcoxon signed-rank test, n = 12. * = p < 0.05, ** = p < 0.01, *** p < 0.001.

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Supplementary information

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Laurila, S., Sun, L., Lahesmaa, M. et al. Secretin activates brown fat and induces satiation. Nat Metab 3, 798–809 (2021).

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