Glucocorticoid receptor function in hepatocytes is essential to promote postnatal body growth

Abstract

Mice carrying a hepatocyte-specific inactivation of the glucorticoid receptor (GR) gene show a dramatic reduction in body size. Growth hormone signaling mediated by the Stat5 transcription factors is impaired. We show that Stat5 proteins physically interact with GR and GR is present in vivo on Stat5-dependent IGF-I and ALS regulatory regions. Interestingly, mice with a DNA-binding-deficient GR but an unaltered ability to interact with STAT5 (GR dim/dim ) have a normal body size and normal levels of Stat5-dependent mRNAs. These findings strongly support the model in which GR acts as a coactivator for Stat5-dependent transcription upon GH stimulation and reveal an essential role of hepatic GR in the control of body growth. Received September 8, 2003; revised version accepted January 27, 2004. Glucocorticoids (GCs), which are synthesized in the adrenal cortex, act in many if not all cells of the body and play important roles in development and homeostasis. The effects of the hormone are mediated by the glucocorticoid receptor (GR) that is ubiquitously expressed and by the mineralocorticoid receptor that displays a more restricted expression profile. GR activity depends on the binding of its ligand, which is released on physiological, circadian, and stress stimuli, and thus GR participates in coordinating the organism's responses to the environment. GR can both activate and repress transcription of target genes via DNA binding to glucocorticoid responsive elements (GREs) or cross-talk with other transcription factors (Beato et al. 1995;Tronche et al. 1998). Because the liver is a major target organ for GCs in control of glycogen metabolism and gluconeogenesis, we wished to address the function of hepatic GR by genetic means. As shown previously, loss of the receptor leads to lethality (Cole et al. 1995;Tronche et al. 1998). We therefore have generated cell/tissue-specific and functionselective mutations using the Cre/loxP system Tronche et al. 1999). To define the role of GR in hepatocytes, we expressed the recombinase in hepatocytes under the control of the albumin promoter and the albumin and ␣-fetoprotein enhancers to generate mutant mice with selective inactivation of GR in these cells only (GR AlfpCre mice; Kellendonk et al. 2000). This approach allowed us to partially circumvent the perinatal lethality of GR null mutants. Surprisingly, adult mice with the hepatocyte-specific loss of GR have a severe reduction in body weight. Analysis of these mice revealed not only a novel function of GR in growth control, but also an unprecedented mode of activity. Results and DiscussionApproximately 50% of the homozygous mutants died within 48 h after birth, likely due to the metabolic consequences of the hepatocyte-specific GR knock-out (data not shown). No increase in mortality was observed at later stages. Mice lacking GR in hepatocytes were indistinguishable from their littermates until 3-4 wk of age, but later displayed a severe growth deficit that was more pronounced in adult males than in females (reduction by 32%...

Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis

“…Plasma corticosterone levels are high at delivery and rapidly decline during the first 24 h after birth, and epinephrine and norepinephrine levels are increased severalfold in newborns in response to the stresses of birth, such as transient hypoxia, cold exposure, and cord cutting (15). Because GC plays a critical role in the maintenance of neonatal blood glucose levels through the induction of gluconeogenesis, one-half of hepatocyte-specific GC receptor KO mice die shortly after birth as a result of hypoglycemia (17). Here, we demonstrated that MC2R KO mice are defective in this adaptation, consistent with a previous report that 75% of POMC KO mice die shortly after birth (2).…”

Anti-inflammatory functions of glucocorticoid-induced genes

“…In liver, GR is recruited to STAT5 regulated genes such as insulin-like growth factor 1, and is required for normal post-natal growth. Importantly, this GRmediated transcriptional control is intact in liver cells expressing only GR dim (Tronche et al, 2004). In a similar fashion, STAT3 and GR can physically interact and cooperate to activate promoters containing either STAT or GR binding sites (De Miguel et al, 2003;Kordula and Travis, 1996;Lerner et al, 2003;Takeda et al, 1998;Zhang et al, 1997).…”

“…In transfected cells GR dim is capable of inducing at least some GC target genes (Rogatsky et al, 2003), cooperative gene regulation by GCs and STAT5 is spared in the GR dim mouse (Tronche et al, 2004), and at least one antiinflammatory mediator is effectively induced by GCs in murine macrophages expressing only GR dim (Abraham et al, 2006). In the absence of microarray data describing global transcriptional changes in cells expressing GR dim , it is too early to conclude how broadly and how strongly the induction of gene expression by GCs is impaired, therefore it remains a strong possibility that this mutation does not A c c e p t e d M a n u s c r i p t…”

Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration

“…The biological consequences obtained upon the loss of a single transcription factor are probably not only due to a loss-of-function but also due to a gainof-function by other recruited signaling pathways. In addition, because Stat5 interacts either directly or indirectly with other regulatory molecules, such as the glucocorticoid receptor 26 and the hepatocyte nuclear factor 4a, 27 loss of Stat5 might also affect biological responses initiated by these molecules. Thus, developmental and physiological changes observed upon the loss of a single transcription factor are likely the result of a greatly disturbed regulatory network.…”