Noninsulin‐dependent diabetes mellitus occurs in mice ectopically expressing the human Axl tyrosine kinase receptor

Abstract

The axl tyrosine kinase receptor is aberrantly expressed on myeloid cells of many individuals afflicted with chronic myelogenous leukemia (CML) and other myeloid leukemias. Although previous studies demonstrated this kinase to have oncogenic potential, it is not known whether axl actively participates in the onset and/or progression of CML. We addressed this question by generating transgenic mice possessing constitutive ectopic expression of human axl throughout cells of the myeloid hematopoietic lineage through the use of the granulocyte colony-stimulating factor (GCSF) receptor promoter. The transgenics did not exhibit hematopoietic malignancies, but did exhibit phenotypic characteristics associated with noninsulin-dependent diabetes mellitus (NIDDM) including hyperglycemia and hyperinsulinemia, severe insulin resistance, progressive obesity, hepatic lipidosis, and pancreatic islet dysplasia. The obese-diabetes phenotype was similar to that observed in the agouti and melanocortin-4(-/-) mutants, however the axl transgenics were not hyperphagic. Axl transgenic animals expressed elevated serum tumor necrosis factor (TNF)-alpha levels that were further enhanced upon in vitro lipopolysaccharide (LPS) stimulation of peripheral blood. Administration of the axl ligand, gas6, to peripheral transgenic blood samples eliminated excessive TNF-alpha production in response to LPS stimulation. As a means to better understand axl-gas6 biology, transgenic animals were produced which systemically expressed the gas6-binding axl proteolytic cleavage product. A more severe NIDDM phenotype occurred in these mice. The observed phenotypes may be related to the axl receptor or proteolytic cleavage product competing with related axl family receptors for binding of the gas6 ligand. We conclude that axl expression in myeloid cells in itself does not lead to the onset or progression of leukemia and suggest that ectopic axl expression affects endogenous modulation of TNF-alpha production indirectly resulting in the NIDDM phenotype.

Circulating Growth Arrest-Specific 6 Protein Is Associated With Adiposity, Systemic Inflammation, and Insulin Resistance Among Overweight and Obese Adolescents

“…In 1995, Shugart et al (21) found that Gas6 plays a pivotal role in enhancing 3T3-L1 adipocyte proliferation. Augustine et al (25) accidentally found that transgenic mice with overexpression of Gas6/TAM signaling exhibit progressive obesity. Moreover, adipose tissue is highly vascularized, and its growth depends on vascularization (38).…”

“…In addition, some studies of transgenic mice found that Gas6/ TAM signaling might recruit macrophages from the bone marrow into the adipose tissue, implying that Gas6/TAM signaling may play a potential role in the pathogenesis of adipose tissue inflammation (14,23,24). Interestingly, transgenic animals that ectopically express the TAM family of receptors also develop progressive obesity with elevated circulating TNF-␣ concentrations and severe systemic insulin resistance (25). This preclinical evidence indicates that the Gas6/TAM system likely represents an important pathogenic mechanism for obesity and obesityassociated inflammation and insulin resistance.…”

Growth arrest specific protein (GAS) 6: a role in the regulation of proliferation and functional capacity of the perinatal rat beta cell

“…A recent study reported an association between high plasma GAS6 concentrations and a decreased risk of developing of type 2 diabetes mellitus [24]. Additionally, a transgenic mouse strain possessing a constitutive active AXL receptor throughout cells of the myeloid haematopoietic linage, showed a non-insulin dependent diabetes mellitus phenotype with gradual age-dependent reduction in the number of insulin-positive cells, possibly due to sequestering of free GAS6-ligand present in plasma [25]. However, the possible role of GAS6 in regulation of beta cell mass or whether any receptors for GAS6 are present in beta cells has never been investigated.…”

Association of plasma growth arrest-specific protein 6 (Gas6) concentrations with albuminuria in patients with type 2 diabetes

“…Transgenic mice ectopically expressing AXL in myeloid cells, were observed to develop phenotypes similar to noninsulin-dependent diabetes mellitus. 39 These animals displayed hyperglycemia, severe insulin resistance, hyperinsulinemia, hepatic lipids and pancreatic islet dysplasia, progressive obesity, but did not exhibit hyperphagia.…”