Maternal protein restriction leads to pancreatic failure in offspring: role of misexpressed microRNA-375.
The intrauterine environment of the fetus is a preeminent actor in long-term health. Indeed, mounting evidence shows that maternal malnutrition increases the risk of type 2 diabetes (T2D) in progeny. Although the consequences of a disturbed prenatal environment on the development of the pancreas are known, the underlying mechanisms are poorly defined. In rats, restriction of protein during gestation alters the development of the endocrine pancreas and favors the occurrence of T2D later in life. Here we evaluate the potential role of perturbed microRNA (miRNA) expression in the decreased β-cell mass and insulin secretion characterizing progeny of pregnant dams fed a low-protein (LP) diet. miRNA profiling shows increased expression of several miRNAs, including miR-375, in the pancreas of fetuses of mothers fed an LP diet. The expression of miR-375 remains augmented in neoformed islets derived from fetuses and in islets from adult (3-month-old) progeny of mothers fed an LP diet. miR-375 regulates the proliferation and insulin secretion of dissociated islet cells, contributing to the reduced β-cell mass and function of progeny of mothers fed an LP diet. Remarkably, miR-375 normalization in LP-derived islet cells restores β-cell proliferation and insulin secretion. Our findings suggest the existence of a developmental memory in islets that registers intrauterine protein restriction. Hence, pancreatic failure after in utero malnutrition could result from transgenerational transmission of miRNA misexpression in β-cells.
INSERM, U1081, Institute for Research on Cancer and Aging of Nice (IRCAN), Aging and Diabetes Team, Nice, France CNRS, UMR7284, IRCAN, Nice, France University of Nice Sophia Antipolis, Nice, France.
Olivier
O
Dumortier
INSERM, U1081, Institute for Research on Cancer and Aging of Nice (IRCAN), Aging and Diabetes Team, Nice, France CNRS, UMR7284, IRCAN, Nice, France University of Nice Sophia Antipolis, Nice, France Clinical Chemistry Laboratory, University Hospital, Nice, France.
Charlotte
C
Hinault
INSERM, U1081, Institute for Research on Cancer and Aging of Nice (IRCAN), Aging and Diabetes Team, Nice, France CNRS, UMR7284, IRCAN, Nice, France University of Nice Sophia Antipolis, Nice, France.
Nadine
N
Gautier
Central Pathology Laboratory, University Hospital, Nice, France.
Stéphanie
S
Patouraux
INSERM, U1081, Institute for Research on Cancer and Aging of Nice (IRCAN), Aging and Diabetes Team, Nice, France CNRS, UMR7284, IRCAN, Nice, France University of Nice Sophia Antipolis, Nice, France.
Virginie
V
Casamento
INSERM, U1081, Institute for Research on Cancer and Aging of Nice (IRCAN), Aging and Diabetes Team, Nice, France CNRS, UMR7284, IRCAN, Nice, France University of Nice Sophia Antipolis, Nice, France Clinical Chemistry Laboratory, University Hospital, Nice, France vanobbeg@unice.fr.
Emmanuel
E
Van Obberghen
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018753:Diet, Protein-Restricted; D005260:Female; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011488:Protein Deficiency / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
C574979:MIRN375 microRNA, rat; D035683:MicroRNAs