Endocrine Abstracts

Mice with congenital adrenal hyperplasia due to a null mutation of cyp11b1, the gene encoding the steroidogenic enzyme 11β-hydroxylase, have low glucocorticoid levels, reduced adiposity and increased liver weight. It is notable that null mice are also glucose intolerant. Here, we have investigated these phenotypes in more detail. Plasma corticosterone levels were less responsive to restraint stress and cholesterol and triglyceride levels were not significantly different in cyp11b1-/- compared with wild type (cyp11b1+/+) littermates. Although mesenteric, gonadal and subcutaneous fat pads were all reduced in size by approximately 50% (P<0.001), mRNA expression levels of key genes involved in regulating lipid metabolism including lipoprotein lipase (LPL), fatty acid synthase (FAS) and adiponectin were not affected and nor were genes for glucocorticoid receptor (GR) or 11β hydroxysteroid dehydrogenase type 1 (HSD11b1). In contrast, increased liver weight in null mice was associated with histological evidence of fatty liver and significantly higher hepatic triglyceride levels (P<0.01). There was no evidence of liver fibrosis. qPCR analysis of hepatic gene expression showed that mRNA levels of peroxisome proliferator-activated receptor-alpha (pparα) and gamma (pparγ), LPL and uncoupling protein-2 were increased 2–3 fold (P<0.05, whereas genes associated with glucocorticoid activity (GR, HSD11b1, phosphoenolpyruvate carboxykinase) and cholesterol metabolism (sterol regulatory element-binding protein (SREBP) and SREBP-cleavage activating protein (SCAP), were unaffected. We conclude that when glucocorticoid secretion is impaired in congenital adrenal hyperplasia, glucose intolerance develops which limits triglyceride deposition in adipose tissue. Instead, excess lipid in mice with congenital adrenal hyperplasia is stored in the liver. Under these circumstances, hepatic lipid accumulation is controlled by PPARs.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.