Impaired glucose homeostasis and neonatal mortality in hepatocyte nuclear factor 3 alpha-deficient mice

Hepatocyte nuclear factors 3 (HNF-3) belong to an evolutionarily conserved family of transcription factors that are critical for diverse biological pr ocesses such as development, differentiation, and metabolism. To study the physiological role of HNF-3 alpha, me generated mice that lack HNF-3 alpha by homologous recombination in embryonic stem cells. Mice homozygous for a null mutation in the HNF-3 alpha gene develop a complex phenotype that is c haracterized by abnormal feeding behavior, progressive starvation, persiste nt hypoglycemia, hypotriglyceridemia, wasting, and neonatal mortality betwe en days 2 and 14. Hypoglycemia in HNF-3 alpha-null mice leads to physiologi cal counter-regulatory responses in glucocorticoid and growth hormone produ ction and an inhibition of insulin secretion but fails to stimulate glucago n secretion. Glucagon-producing pancreatic alpha cells develop normally in HNF-3 alpha-/- mice, but proglucagon mRNA levels are reduced 50%. Furthermo re, the transcriptional levels of neuropeptide Y are also significantly red uced shortly after birth, implying a direct role of HNF-3 alpha in the expr ession of these genes. In contrast, mRNA levels were increased in HNF-3 tar get genes phosphofructo-2-kinase/fructose-2,6-bisphophatase, insulin growth factor binding protein-1, and hexokinase I of HNF-3 alpha-null mice. Mice lacking one or both HNF-3 alpha alleles also show impaired insulin secretio n and glucose intolerance after an intraperitoneal glucose challenge, indic ating that pancreatic beta-cell function is also compromised. Our results i ndicate that HNF-3 alpha plays a critical role in the regulation of glucose homeostasis and in pancreatic islet function.