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Pax6 Haploinsufficiency Causes Abnormal Metabolic Homeostasis by Down-Regulating Glucagon-Like Peptide 1 in Mice

Model Animal Research Center (J.D., Y.G., J.Z., H.Y., S.G., X.G.), Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Research, Medical School of Nanjing University, Nanjing 210061, China; School of Basic Medicine (Y.G., Q.Z., X.G.), Zhengzhou University, Zhengzhou, Zhengzhou 450001, China; and Peking University Stem Cell Research Center (L.L.), Beijing 100083, China

Address all correspondence and requests for reprints to: Xiang Gao, Model Animal Research Center, Nanjing University, 12 Xuefu Road, Nanjing 210061, China. E-mail: Gaoxiang{at}nju.edu.cn.

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.