Pax6 haploinsufficiency causes abnormal metabolic homeostasis by down-regulating glucagon-like peptide 1 in mice.
Heterozygosity for the Pax6 allele is associated with impaired glucose tolerance in humans. With a Pax6 mutant mouse model, we found many of the metabolic abnormalities were consistent with the effects of down-regulating the expression of glucagon-like peptide 1 (GLP-1). In addition to impaired glucose tolerance, adult heterozygous mutant mice (Pax6(m/+)) secreted less insulin responding to glucose and arginine administration compared with control mice. Moreover, Pax6(m/+) mice showed increased food intake compared with control mice, although they were resistant to diet-induced fat accumulation. Indeed, levels of circulating GLP-1 and intestinal transcription of Gcg/Proglucagon were dramatically reduced in Pax6(m/+) mice. Mutated Pax6 also failed to activate the Gcg/Proglucagon promoter by in vitro transfection assay. Finally, administering the GLP-1 receptor agonist exendin-4 to Pax6(m/+) mice largely reversed their abnormal food intake, glycemic excursion, and insulin secretion. Our studies suggested that disruption of metabolic homeostasis mainly caused by Pax6 haploinsufficiency was mainly mediated by down-regulation of GLP-1. Administration of exendin-4 may be a useful therapy in humans with a similar mutation.
Ding
Jun
J
Model Animal Research Center, Ministry of Education Key Laboratory of Model Animal for Disease Research, Medical School of Nanjing University, Nanjing 210061, China.
Gao
Yan
Y
Zhao
Jing
J
Yan
Hong
H
Guo
Shi-ying
SY
Zhang
Qin-xian
QX
Li
Ling-song
LS
Gao
Xiang
X
D000367:Age Factors; D000818:Animals; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology; D004622:Embryo, Mammalian; D005136:Eye Proteins / Q000235:genetics* / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000235:genetics* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D006706:Homeostasis / Q000235:genetics*; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D019656:Loss of Heterozygosity / Q000502:physiology*; D008297:Male; D008659:Metabolic Diseases / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009929:Organ Size / Q000235:genetics; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics* / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology
D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D052216:Glucagon-Like Peptide 1