Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion
Nadejda Bozadjieva, … , Patrick E. MacDonald, Ernesto Bernal-Mizrachi
Nadejda Bozadjieva, … , Patrick E. MacDonald, Ernesto Bernal-Mizrachi
Published November 6, 2017
Citation Information: J Clin Invest. 2017;127(12):4379-4393. https://doi.org/10.1172/JCI90004.
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Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion

Abstract

Glucagon plays a major role in the regulation of glucose homeostasis during fed and fasting states. However, the mechanisms responsible for the regulation of pancreatic α cell mass and function are not completely understood. In the current study, we identified mTOR complex 1 (mTORC1) as a major regulator of α cell mass and glucagon secretion. Using mice with tissue-specific deletion of the mTORC1 regulator Raptor in α cells (αRaptorKO), we showed that mTORC1 signaling is dispensable for α cell development, but essential for α cell maturation during the transition from a milk-based diet to a chow-based diet after weaning. Moreover, inhibition of mTORC1 signaling in αRaptorKO mice and in WT animals exposed to chronic rapamycin administration decreased glucagon content and glucagon secretion. In αRaptorKO mice, impaired glucagon secretion occurred in response to different secretagogues and was mediated by alterations in KATP channel subunit expression and activity. Additionally, our data identify the mTORC1/FoxA2 axis as a link between mTORC1 and transcriptional regulation of key genes responsible for α cell function. Thus, our results reveal a potential function of mTORC1 in nutrient-dependent regulation of glucagon secretion and identify a role for mTORC1 in controlling α cell–mass maintenance.

Authors

Nadejda Bozadjieva, Manuel Blandino-Rosano, Jennifer Chase, Xiao-Qing Dai, Kelsey Cummings, Jennifer Gimeno, Danielle Dean, Alvin C. Powers, George K. Gittes, Markus A. Rüegg, Michael N. Hall, Patrick E. MacDonald, Ernesto Bernal-Mizrachi

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Figure 3

mTORC1 signaling is necessary for maintenance of postnatal α cells.

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mTORC1 signaling is necessary for maintenance of postnatal α cells. (A) ...
(A) Immunofluorescent staining for insulin and glucagon in pancreatic sections from control, αRaptorKO, and αRaptorHET mice (α cells depicted with white arrows). Scale bars: 50 μm. (B) Quantification of α cell fraction at postnatal day 1 (newborn) control, αRaptorKO, and αRaptorHET mice (n = 3). (C) Quantification of α cell mass at 2 weeks (n = 4), (D) in 1-month-old (n = 4), and (E) 2-month-old control, αRaptorKO, and αRaptorHET mice (n = 4–5). (F) Pancreatic glucagon content (n = 4–6) in 2-month-old mice. (G) Quantification of α cell mass (n = 3–4) and (H) pancreatic glucagon content (n = 3–4) in 8-month-old mice. (I) Quantification of β cell fraction at postnatal day 1 (newborn) (n = 3) and (J) β cell mass in 2-month-old mice (n = 4–5). (K) Electron microscopy of α cells from 1-month-old control and αRaptorKO mice. Scale bars: 800 nm (control) and 600 nm (αRaptorKO). (L) Quantification of α cell size by morphometric analysis in control and αRaptorKO mice at 1 month of age (n = 3). (M) Analysis of glucagon content by flow cytometric analysis in dispersed α cells from control and αRaptorKO mice at 3 weeks of age (n = 3–4). MFI, mean fluorescence intensity. (N) Quantification of GFP-LC3 puncta and representative images of dispersed α cells from 3-week-old control and αRaptorKO mice (n = 50 cells) crossed to an in vivo reporter of autophagy (GFP-LC3 mice). Scale bars: 10 μm. Data for C, D, L, and N are shown as means ± SEM. *P ≤ 0.05 (Student’s 2-tailed t test). Data for B and E–J are shown as means ± SEM. *P ≤ 0.05 (1-way ANOVA with Dunnett’s post-test).