title: Maternal diet-induced microRNAs and mTOR underlie β cell dysfunction in offspring.
abstract: A maternal diet that is low in protein increases the susceptibility of offspring to type 2 diabetes by inducing long-term alterations in β cell mass and function. Nutrients and growth factor signaling converge through mTOR, suggesting that this pathway participates in β cell programming during fetal development. Here, we revealed that newborns of dams exposed to low-protein diet (LP0.5) throughout pregnancy exhibited decreased insulin levels, a lower β cell fraction, and reduced mTOR signaling. Adult offspring of LP0.5-exposed mothers exhibited glucose intolerance as a result of an insulin secretory defect and not β cell mass reduction. The β cell insulin secretory defect was distal to glucose-dependent Ca2+ influx and resulted from reduced proinsulin biosynthesis and insulin content. Islets from offspring of LP0.5-fed dams exhibited reduced mTOR and increased expression of a subset of microRNAs, and blockade of microRNA-199a-3p and -342 in these islets restored mTOR and insulin secretion to normal. Finally, transient β cell activation of mTORC1 signaling in offspring during the last week of pregnancy of mothers fed a LP0.5 rescued the defect in the neonatal β cell fraction and metabolic abnormalities in the adult. Together, these findings indicate that a maternal low-protein diet alters microRNA and mTOR expression in the offspring, influencing insulin secretion and glucose homeostasis.
authors.forename: Emilyn U
authors.initials: EU
authors.lastname: Alejandro
authors.forename: Brigid
authors.initials: B
authors.lastname: Gregg
authors.forename: Taylor
authors.initials: T
authors.lastname: Wallen
authors.forename: Doga
authors.initials: D
authors.lastname: Kumusoglu
authors.forename: Daniel
authors.initials: D
authors.lastname: Meister
authors.forename: Angela
authors.initials: A
authors.lastname: Chen
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Merrins
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Satin
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Peter
authors.initials: P
authors.lastname: Arvan
authors.forename: Ernesto
authors.initials: E
authors.lastname: Bernal-Mizrachi
mesh_terms: D000818:Animals; D001835:Body Weight; D002118:Calcium / Q000378:metabolism; D018753:Diet, Protein-Restricted; D005260:Female; D018149:Glucose Intolerance; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000473:pathology; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D011247:Pregnancy; D011270:Pregnancy, Animal; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D019076:Transgenes
chemical_list: D007328:Insulin; D035683:MicroRNAs; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D002118:Calcium