Impaired glucose homeostasis and neonatal mortality in hepatocyte nuclear factor 3alpha-deficient mice. Proc Natl Acad Sci U S A 1999 Aug 31;96(18):10152-7
Date
09/01/1999Pubmed ID
10468578Pubmed Central ID
PMC17858DOI
10.1073/pnas.96.18.10152Scopus ID
2-s2.0-0033621155 (requires institutional sign-in at Scopus site) 127 CitationsAbstract
Hepatocyte nuclear factors 3 (HNF-3) belong to an evolutionarily conserved family of transcription factors that are critical for diverse biological processes such as development, differentiation, and metabolism. To study the physiological role of HNF-3alpha, we generated mice that lack HNF-3alpha by homologous recombination in embryonic stem cells. Mice homozygous for a null mutation in the HNF-3alpha gene develop a complex phenotype that is characterized by abnormal feeding behavior, progressive starvation, persistent hypoglycemia, hypotriglyceridemia, wasting, and neonatal mortality between days 2 and 14. Hypoglycemia in HNF-3alpha-null mice leads to physiological counter-regulatory responses in glucocorticoid and growth hormone production and an inhibition of insulin secretion but fails to stimulate glucagon secretion. Glucagon-producing pancreatic alpha cells develop normally in HNF-3alpha-/- mice, but proglucagon mRNA levels are reduced 50%. Furthermore, the transcriptional levels of neuropeptide Y are also significantly reduced shortly after birth, implying a direct role of HNF-3alpha in the expression of these genes. In contrast, mRNA levels were increased in HNF-3 target genes phosphofructo-2-kinase/fructose-2,6-bisphophatase, insulin growth factor binding protein-1, and hexokinase I of HNF-3alpha-null mice. Mice lacking one or both HNF-3alpha alleles also show impaired insulin secretion and glucose intolerance after an intraperitoneal glucose challenge, indicating that pancreatic beta-cell function is also compromised. Our results indicate that HNF-3alpha plays a critical role in the regulation of glucose homeostasis and in pancreatic islet function.
Author List
Shih DQ, Navas MA, Kuwajima S, Duncan SA, Stoffel MMESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Newborn
DNA-Binding Proteins
Death
Feeding Behavior
Feeding and Eating Disorders
Genotype
Glucose
Hepatocyte Nuclear Factor 3-alpha
Homeostasis
Hypoglycemia
Mice
Mice, Knockout
Nuclear Proteins
Pancreas
Restriction Mapping
Starvation
Transcription Factors
Triglycerides
Wasting Syndrome
