Adiponectin deficiency leads to hepatic steatosis and contributes to the development of gestational diabetes mellitus

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dc.contributor.authorGruber, Brittany Lynn Moyce
dc.contributor.examiningcommitteeWigle, Jeffrey (Biochemistry and Medical Genetics)en_US
dc.contributor.examiningcommitteeDoucette, Christine (Physiology and Pathophysiology)en_US
dc.contributor.examiningcommitteeHatch, Grant (Pharmacology and Therapeutics)en_US
dc.contributor.examiningcommitteePowell, Theresa (University of Colorado, Pediatrics)
dc.contributor.guestmembersPowell, Theresa (University of Colorado, Pediatrics)en_US
dc.contributor.supervisorDolinsky, Vernon (Pharmacology and Therapeutics)en_US
dc.date.accessioned2021-04-07T20:57:38Z
dc.date.available2021-04-07T20:57:38Z
dc.date.copyright2021-04-07
dc.date.issued2020en_US
dc.date.submitted2021-04-07T19:13:24Zen_US
dc.degree.disciplinePharmacology and Therapeuticsen_US
dc.degree.levelDoctor of Philosophy (Ph.D.)en_US
dc.description.abstractGestational diabetes mellitus (GDM) is a common complication of pregnancy, characterized by hyperglycemia and impaired glucose tolerance with first onset mid-gestation. Genetic predisposition, maternal obesity and diet contribute to development of GDM. In addition, low levels of serum adiponectin are associated with increased risk for GDM. Adiponectin is an adipose tissue derived cytokine that improves systemic insulin sensitivity. Since adiponectin has a role in hepatic lipid metabolism, we hypothesize that adiponectin deficiency leads to fatty liver during pregnancy, worsening insulin resistance and contributing to GDM development. We compared adiponectin KO (strain B6;129-Adipoqtm1Chan/J) mice to WT (C57/B6) controls in the third trimester of pregnancy and evaluated measures of glucose and insulin tolerance when animals were consuming LF or HFS diets in pregnancy. We performed a histological and biochemical evaluation of hepatic steatosis in pregnancy. To investigate underlying mechanisms, we used qPCR, immunoblotting, and immunofluorescence analysis of tissues from pregnant adiponectin KO and WT mice. Adiponectin KO mice were hyperglycemic, had impaired glucose tolerance and dysregulated islet hormone secretion in the third trimester. Mice lacking adiponectin showed unchecked hepatic glucose output in the third trimester, which may contribute to hyperglycemia in pregnancy. Pregnant adiponectin KO mice had reduced mitochondrial respiration, increased lipid synthesis and hepatic steatosis. Supplementation with adiponectin improved glucose tolerance and hepatic steatosis in pregnancy. In a cohort of First Nation’s mothers and newborns, lower serum adiponectin and higher serum leptin were observed in GDM relative to T2D pregnancies and normoglycemic controls. GDM and T2D during pregnancy was associated with increased birthweight and maternal adiponectin was negatively correlated with birthweight, suggesting that adiponectin may have a role in fetal growth. In conclusion, we observed an association between low levels of adiponectin and GDM in pregnant women. In pregnant adiponectin KO mice, lack of adiponectin leads to the development of hepatic steatosis, disruption to islet function and hyperglycemia in pregnancy. Supplementation with adiponectin to mice in the third trimester, mitigated fatty liver and glucose intolerance in the third trimester.en_US
dc.description.noteMay 2021en_US
dc.identifier.urihttp://hdl.handle.net/1993/35412
dc.language.isoengen_US
dc.rightsopen accessen_US
dc.subjectGestational diabetesen_US
dc.subjectPregnancyen_US
dc.subjectHepatic Steatosisen_US
dc.subjectAdiponectinen_US
dc.subjectType 2 Diabetesen_US
dc.subjectNAFLDen_US
dc.titleAdiponectin deficiency leads to hepatic steatosis and contributes to the development of gestational diabetes mellitusen_US
dc.typedoctoral thesisen_US
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