β Cell mass expansion during puberty involves serotonin signaling and determines glucose homeostasis in adulthood
Anne-Laure Castell, Clara Goubault, Mélanie Ethier, Grace Fergusson, Caroline Tremblay, Marie Baltz, Dorothée Dal Soglio, Julien Ghislain, Vincent Poitout
Anne-Laure Castell, Clara Goubault, Mélanie Ethier, Grace Fergusson, Caroline Tremblay, Marie Baltz, Dorothée Dal Soglio, Julien Ghislain, Vincent Poitout
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Research Article Endocrinology Metabolism

β Cell mass expansion during puberty involves serotonin signaling and determines glucose homeostasis in adulthood

Abstract

Puberty is associated with transient insulin resistance that normally recedes at the end of puberty; however, in overweight children, insulin resistance persists, leading to an increased risk of type 2 diabetes. The mechanisms whereby pancreatic β cells adapt to pubertal insulin resistance, and how they are affected by the metabolic status, have not been investigated. Here, we show that puberty is associated with a transient increase in β cell proliferation in rats and humans of both sexes. In rats, β cell proliferation correlated with a rise in growth hormone (GH) levels. Serum from pubertal rats and humans promoted β cell proliferation, suggesting the implication of a circulating factor. In pubertal rat islets, expression of genes of the GH/serotonin (5-hydroxytryptamine [5-HT]) pathway underwent changes consistent with a proliferative effect. Inhibition of the pro-proliferative 5-HT receptor isoform HTR2B blocked the increase in β cell proliferation in pubertal islets ex vivo and in vivo. Peripubertal metabolic stress blunted β cell proliferation during puberty and led to altered glucose homeostasis later in life. This study identifies a role of GH/GH receptor/5-HT/HTR2B signaling in the control of β cell mass expansion during puberty and identifies a mechanistic link between pubertal obesity and the risk of developing type 2 diabetes.

Authors

Anne-Laure Castell, Clara Goubault, Mélanie Ethier, Grace Fergusson, Caroline Tremblay, Marie Baltz, Dorothée Dal Soglio, Julien Ghislain, Vincent Poitout

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Figure 2

β Cell proliferation and mass were increased during puberty in rats, and β cell proliferation was blocked by GNRH1 antagonism.

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β Cell proliferation and mass were increased during puberty in rats, and...
(A–C) β cell proliferation as assessed by immunofluorescent staining of pancreatic sections for MKI67 and insulin (INS) (A and B) or NKX6-1 (C) in male and female rats from 3–9 wk of age. (A) Representative sections showing Ins (green), MKI67 (red), and nuclei (DAPI, blue) from male (top) and female (bottom) rats at weaning (3 wk of age), puberty (~5 wk of age), or young adulthood (9 wk of age). Arrows show positive nuclei for MKI67. Scale bars: 50 μm. (B and C) β Cell proliferation as a percentage of MKI67+INS+ cells over INS+ cells in males (black square) (n = 3–5) and females (red circle) (n = 3–5) (B), or as a percentage of MKI67+NKX6-1+ cells over NKX6-1+ cells in males (black square) (n = 6–8) and females (red circle) (n = 6–8) (C). (D) β Cell mass in males (black square) (n = 5–6) and females (red circle) (n = 5–6). (E–G) Male rats treated with Cetrorelix (CETRO; 100 μg/d) or vehicle (VEH) from D25 to D37 (n = 8–9). Right testicular weight (E), body weight (F), and β cell proliferation (G) were assessed at D38. β Cell proliferation was measured by immunofluorescent staining of pancreatic sections for MKI67 and NKX6-1 and presented as a percentage of MKI67+NKX6-1+ cells over NKX6-1+ cells. Data represent individual or mean values and are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.005, ****P < 0.001 following 1-way ANOVA with Tukey’s multiple-comparison test (B–D) or following unpaired Student’s t test compared with the VEH group (E–G).