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 8

HFD during puberty mitigated β cell proliferation and GH/5-HT pathway hormone levels and gene expression, and it reduced β cell mass in adulthood.

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HFD during puberty mitigated β cell proliferation and GH/5-HT pathway ho...
(A) β Cell proliferation and mass, plasma hormone and islet gene expression, and 5-HT content were assessed in male rats fed a HFD (HFD, red) or a chow diet (CHOW, black) from 4 to 8 wk of age followed by a switch to a chow diet for both groups (HFD-CHOW, red; CHOW-CHOW, black) until 12 wk of age. (B and C) β Cell proliferation was assessed at 5 (B) (n = 3) and 8 (C) (n = 7–8) wk of age by immunofluorescent staining of pancreatic sections for MKI67 and insulin (INS) and presented as the percentage of MKI67+INS+ cells over INS+ cells. (D and E) Body weight (D) and β cell mass per 100 g of body weight (E) at 12 wk of age (n = 8–10). (F) Ghr, Tph1, Htr1d, and Htr2b mRNA levels in islets isolated from rats at 5 wk of age (n = 3–6). mRNA was quantified by RT-PCR and normalized to cyclophilin (Ppia). Data are presented as the fold change over the CHOW diet group. (G–I) Plasma GH (G) and IGF1 (H) levels and islet 5-HT content normalized to total protein (I) in rats at 8 wk of age (n = 6-7). Data represented individual values and are expressed as mean ± SEM. *P < 0.05, **P < 0.01 following unpaired Student’s t test as compared with the control CHOW or CHOW-CHOW group.