Endocrine Abstracts

Background: Glucocorticoids (GCs) modulate glucose homeostasis by acting on metabolic tissues including liver, adipose and skeletal muscle. GC access to corticosteroid receptors in these tissues is regulated e.g. by pre-receptor metabolism. We recently identified a role for ABCC1, a transmembrane ‘drug-resistance’ transporter, as a GC exporter which limits intracellular GC concentrations and action in adipose tissue. Here, we tested the hypothesis that ABCC1, which is also highly expressed in skeletal muscle, influences glucose metabolism and insulin sensitivity, through regulation of tissue GC action.

Methods

Male global Abcc1 knockout (Abcc1^-/-) and wild-type (WT) littermate mice were fed chow diet or high-fat diet (HFD - 58% fat and sucrose) for 9 weeks, starting at 8-12 weeks of age (n=10-13 each group). Glucose and insulin tolerance tests were performed (week 7-8), all procedures were done with ethical approval. Plasma and tissue GC concentrations were measured by Liquid Chromatography Tandem Mass Spectrometry, and tissue GC-responsive genes and metabolic markers (mRNA and protein) by RT-qPCR and Western blot.

Results: Our findings show that on chow diet, Abcc1^-/- mice have similar body weight, despite reduced fat mass (subcutaneous, gonadal and brown adipose tissue), normal glucose tolerance in the presence of reduced fasting insulin levels, and increased levels of corticosterone in plasma, subcutaneous adipose tissue (sWAT) and gastrocnemius muscle compared to WT mice, By contrast, on HFD, Abcc1^-/- mice had similar body weight gain and fat mass to WT mice, but impaired glucose and insulin tolerance and fasting hyperinsulinemia, without measurable alterations in plasma or tissue GC levels. Interestingly, on HFD, WT mice protein levels of ABCC1 were upregulated in sWAT but not in skeletal muscle. Further, we investigated a number of genes and pathways that might be affected by the changes in insulin e.g GSK-3β We identified upregulation on the levels of pGSK-3β in skeletal muscle, but not in adipose tissue from Abcc1^-/- mice on chow diet. By contrast, on HFD, the levels of pGSK-3β were upregulated in skeletal muscle from WT mice but not in Abcc1^-/-. These changes were absent in adipose tissue.

Conclusions: Abcc1 influences adiposity, insulin sensitivity and glucose homeostasis differently according to diet and obesity, and by mechanisms which are likely to be only in part GC-dependent. Further dissection of the substrates for ABCC1 which mediate these effects may reveal new avenues for therapy in metabolic disease.