Pregnancy Hyperglycemia in Prolactin Receptor Mutant, but Not Prolactin Mutant, Mice and Feeding-Responsive Regulation of Placental Lactogen Genes Implies Placental Control of Maternal Glucose Homeostasis.
Pregnancy is often viewed as a conflict between the fetus and mother over metabolic resources. Insulin resistance occurs in mothers during pregnancy but does not normally lead to diabetes because of an increase in the number of the mother's pancreatic beta cells. In mice, this increase is dependent on prolactin (Prl) receptor signaling but the source of the ligand has been unclear. Pituitary-derived Prl is produced during the first half of pregnancy in mice but the placenta produces Prl-like hormones from implantation to term. Twenty-two separate mouse genes encode the placenta Prl-related hormones, making it challenging to assess their roles in knockout models. However, because at least four of them are thought to signal through the Prl receptor, we analyzed Prlr mutant mice and compared their phenotypes with those of Prl mutants. We found that whereas Prlr mutants develop hyperglycemia during gestation, Prl mutants do not. Serum metabolome analysis showed that Prlr mutants showed other changes consistent with diabetes. Despite the metabolic changes, fetal growth was normal in Prlr mutants. Of the four placenta-specific, Prl-related hormones that have been shown to interact with the Prlr, their gene expression localizes to different endocrine cell types. The Prl3d1 gene is expressed by trophoblast giant cells both in the labyrinth layer, sitting on the arterial side where maternal blood is highest in oxygen and nutrients, and in the junctional zone as maternal blood leaves the placenta. Expression increases during the night, though the increase in the labyrinth is circadian whereas it occurs only after feeding in the junctional zone. These data suggest that the placenta has a sophisticated endocrine system that regulates maternal glucose metabolism during pregnancy.
Department of Comparative Biology & Experimental Medicine, University of Calgary, Calgary, Alberta, Canada Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
Saara M
SM
Rawn
Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada.
Carol
C
Huang
Department of Comparative Biology & Experimental Medicine, University of Calgary, Calgary, Alberta, Canada.
Martha
M
Hughes
Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
Rustem
R
Shaykhutdinov
Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
Hans J
HJ
Vogel
Department of Comparative Biology & Experimental Medicine, University of Calgary, Calgary, Alberta, Canada Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada jcross@ucalgary.ca.
James C
JC
Cross
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D002940:Circadian Rhythm; D005247:Feeding Behavior; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006943:Hyperglycemia / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D010920:Placenta / Q000378:metabolism*; D010928:Placental Lactogen; D011247:Pregnancy; D011388:Prolactin / Q000235:genetics*; D011981:Receptors, Prolactin / Q000235:genetics*; D014327:Trophoblasts / Q000378:metabolism
D001786:Blood Glucose; D011981:Receptors, Prolactin; D011388:Prolactin; D010928:Placental Lactogen; D005947:Glucose
diabetes; metabolism; placenta; placental lactogen; pregnancy