Impaired glucose homeostasis and neonatal mortality in hepatocyte nuclear factor 3alpha-deficient mice.
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.
Shih
D Q
DQ
Laboratory of Metabolic Diseases, Rockefeller University, New York, NY 10021, USA.
Navas
M A
MA
Kuwajima
S
S
Duncan
S A
SA
Stoffel
M
M
D000818:Animals; D000831:Animals, Newborn; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D003643:Death; D005247:Feeding Behavior; D001068:Feeding and Eating Disorders / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005838:Genotype; D005947:Glucose / Q000378:metabolism*; D051541:Hepatocyte Nuclear Factor 3-alpha; D006706:Homeostasis; D007003:Hypoglycemia / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D015183:Restriction Mapping; D013217:Starvation; D014157:Transcription Factors / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D019282:Wasting Syndrome / Q000235:genetics
D004268:DNA-Binding Proteins; C496500:Foxa1 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D014280:Triglycerides; D005947:Glucose