The Maternal Impact of AdGHRKO Mice on Glucose Metabolism

Abstract

Genetically modified mouse models provide effective tools to explore the occurrence development and therapy of various diseases, especially the metabolic diseases such as diabetes. In line with the reported maternal inheritance of glucose homeostasis via maternally expressed gene activity, we found that a tissue-specific knockout exhibited maternal influence on insulin sensitivity, resulting in a lower liability for diabetes in the offsprings. Using the Cre/LoxP system, we constructed a mouse model of adipose tissue-specific growth hormone receptor (GHR) knockout (AdGHRKO). Unlike other tissue-specific GHR knockouts, AdGHRKO was found to be maternally inheritable. Compared with female AdGHRKO mice born from Flox mothers, female KO mice born from KO mothers displayed resistance to diet-induced obesity from a high-fat diet for 8 weeks. and the difference in body weight was exclusively due to a significant reduction in white fat tissue, especially from decreased subcutaneous deposition. Moreover, KO mice from KO mothers had better insulin sensitivity and glucose tolerance after high-fat treatment for 8 weeks. Our data suggests that the phenotype of metabolic stability in progeny is strongly affected by the maternal genotype. To support this, we also found that Flox mice born from KO mothers presented similar phenotypic traits (improved glucose tolerance and insulin resistance) of protection from high fat induced diabetes, which was comparable to the KO mice born from KO mothers. Our ongoing studies are to determine if this phenomenon is caused by alterations in maternal hormone levels or some unknown mitochondrial activities. Nonetheless, how adipose tissue specific ablation of GHR exerts its effects on metabolic syndromes through maternal cues is of high interest not only to pure genetic studies but also to medical practice. Disclosure X. Wang: None. A. Mi: None. Y. Liu: None. D. Wang: None. L. Ran: None. Y. Wu: None.