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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4379-4393 |
| Number of pages | 15 |
| Journal | Journal of Clinical Investigation |
| Volume | 127 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2017 |
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ASJC Scopus subject areas
- Medicine(all)
Cite this
Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion. / Bozadjieva, Nadejda; Blandino Rosano, Manuel; Chase, Jennifer; Dai, Xiao Qing; Cummings, Kelsey; Gimeno, Jennifer; Dean, Danielle; Powers, Alvin C.; Gittes, George K.; Rüegg, Markus A.; Hall, Michael N.; MacDonald, Patrick E.; Bernal Mizrachi, Ernesto.
In: Journal of Clinical Investigation, Vol. 127, No. 12, 01.12.2017, p. 4379-4393.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion
AU - Bozadjieva, Nadejda
AU - Blandino Rosano, Manuel
AU - Chase, Jennifer
AU - Dai, Xiao Qing
AU - Cummings, Kelsey
AU - Gimeno, Jennifer
AU - Dean, Danielle
AU - Powers, Alvin C.
AU - Gittes, George K.
AU - Rüegg, Markus A.
AU - Hall, Michael N.
AU - MacDonald, Patrick E.
AU - Bernal Mizrachi, Ernesto
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI90004
DO - 10.1172/JCI90004
M3 - Article
VL - 127
SP - 4379
EP - 4393
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 12
ER -