The contribution of the recent paper by Chiefari et al.
] is to offer a partial explanation for this observation. The new work draws on growing appreciation that insulin-sensitive tissues communicate not only through substrate fluxes, but also by secreting factors that signal specifically to distant tissues. Adipose tissue, in particular, is now seen as a highly dynamic endocrine organ producing many so-called 'adipokines', including leptin, which has a thoroughly validated metabolic role, adiponectin, and many other factors with varying credentials as bona fide
signaling molecules. One of the more recent of these is retinol binding protein (RBP), product of the Rbp4
gene in mice. Although mostly produced by the liver, RBP also comes from white adipose tissue, and its expression there is inversely related to Glut4 expression [9
]. Furthermore, Rbp4-/-
mice show enhanced insulin sensitivity, and providing RBP either exogenously or by overexpression induces IR [9
Chiefari et al.
] hypothesized that altered Rbp4 expression might explain the discordance between reduced Insr expression and enhanced insulin sensitivity in Hmga1-/-
mice. The first key evidence that this may be partly true comes from the demonstration that these mice do have severely reduced levels of Rbp4
mRNA and circulating RBP. Furthermore, the enhanced expression of Glut4 in muscle of the knockout mice is normalized by exogenous RBP, and the enhanced glucose-lowering effect of insulin in the knockout animals is markedly attenuated by the same treatment (Figure ). In wild-type mice glucagon strongly stimulates expression of Hmga1 and then Rbp4, an effect absent in Hmga1-/-
mice. This suggests that Hmga1 is at least permissive for glucagon-induced stimulation of Rbp4 via a direct effect of Hmga1 on the Rbp4 promoter. Glucagon exerts cellular effects largely through the second messenger cAMP, and together with previous in vitro
studies, this implicates cAMP as a proximal cellular regulator of both genes. However, exactly how RBP impairs insulin signaling is unclear: insulin-stimulated phosphorylation of phosphatidylinositol 3-kinase (PI3K), a key proximal step in insulin's metabolic signaling, was said previously to be severely blunted in Hmga1-/-
], whereas phosphorylation of Akt, the next step in the pathway, is increased in these mice according to Chiefari et al.
] (Figure ). Moreover, Rbp-/-
mice show enhanced insulin-induced phosphorylation of insulin receptor substrate 1 and activation of PI3K, also seemingly at odds with the new findings [9
]. These considerations should motivate further signaling studies.
Figure 1 Model of the divergent consequences of HMGA1 deficiency. All actions that lower blood glucose are in green and influences that raise blood glucose are in red. Ins, insulin; GNG, gluconeogenesis. (a) In the normal physiological state, insulin action dominates, (more ...)