Distinct roles for the mTOR pathway in postnatal morphogenesis, maturation and function of pancreatic islets

Abstract

While much is known about the molecular pathways that regulate embryonic development and adult homeostasis of the endocrine pancreas, little is known about what regulates early postnatal development and maturation of islets. Given that birth marks the first exposure to enteral nutrition, we investigated how nutrientregulated signaling pathways influence postnatal islet development in mice. We performed loss-of-function studies of mechanistic target of rapamycin (mTOR), a highly conserved kinase within a nutrientsensing pathway known to regulate cellular growth, morphogenesis and metabolism. Deletion of Mtor in pancreatic endocrine cells had no significant effect on their embryonic development. However, within the first 2 weeks after birth, mTOR-deficient islets became dysmorphic, β-cell maturation and function were impaired, and animals lost islet mass. Moreover, we discovered that these distinct functions of mTOR are mediated by separate downstream branches of the pathway, in that mTORC1 (with adaptor protein Raptor) is the main complex mediating the maturation and function of islets, whereas mTORC2 (with adaptor protein Rictor) impacts islet mass and architecture. Taken together, these findings suggest that nutrient sensing may be an essential trigger for postnatal β-cell maturation and islet development.

Role of mTOR in Glucose and Lipid Metabolism

“…The loss-of-function studies of mTOR signaling in vivo have been examined in mice deficient for mTOR or Raptor specifically in beta cells or pancreatic endocrine progenitor cells (mating with PDX1- or Neurog3-cre mice). These mice consistently exhibit reduced beta cells mass, defective postnatal islet development, hypoinsulinemia, and glucose intolerance [ 54 , 55 , 56 , 57 , 58 ]. Conversely, activation of mTORC1 signaling by deletion of TSC1 leads to beta cell hypertrophy and hyperinsulinemia [ 59 ].…”

Is there a role for the RNA-binding protein LARP1 in β-cells?

“…mTORC1 plays a fundamental role in b-cell physiology by controlling 5' cap-dependent translation of critical proteins in b-cell (Blandino-Rosano, Barbaresso et al 2017, Ni, Gu et al 2017. mTORC1 activity in b-cells is higher during embryological development and in the first week of post-natal maturation, followed by lower activity levels in mature b-cells (Ni, Gu et al 2017, Sinagoga, Stone et al 2017, Jaafar, Tran et al 2019, Helman, Cangelosi et al 2020, Katsumoto and Grapin-Botton 2020. mTORC1 is reactivated in diabetic states and the chronic hyperactivation could play a role in b-cells dysfunction or failure (Yuan, Rafizadeh et al 2017, Ardestani, Lupse et al 2018.…”

“…Whereas the role played by mTORC1 in band a-cells was recently revealed (Alejandro, Bozadjieva et al 2017, Blandino-Rosano, Barbaresso et al 2017, Ni, Gu et al 2017, Sinagoga, Stone et al 2017, the role of the mTORC1 target LARP1 on pancreatic b-cells has never been studied. mTORC1 complexes and phosphorylates LARP1, but whether LARP1 inhibits or stimulates mTORC1-mediated protein translation of TOP mRNAs is still under debate (Burrows, Abd Latip et al 2010, Aoki, Adachi et al 2013, Tcherkezian, Cargnello et al 2014, Fonseca, Zakaria et al 2015, Mura, Hopkins et al 2015, Hong, Freeberg et al 2017, Lahr, Fonseca et al 2017.…”

Targeting Acute Islet Inflammation to Preserve Graft Mass and Long-Term Function

“…However, accumulating evidence indicates that blocking these intracellular targets is not specific to lymphocyte cell types and that CN and mTOR also regulate cytokines in innate immune cells and islet endocrine cells [54,[85][86][87][88]. This is further complicated by the findings that islets require CN and mTOR pathways for physiological adaptation and cellular function [89][90][91][92].…”