Endocrine Abstracts

Background: Glucocorticoids (GCs) modulate glucose homeostasis by acting on metabolic tissues including liver, adipose, and skeletal muscle. ABCC1 is a transmembrane ‘drug-resistance’ transporter expressed in adipose tissue and skeletal muscle with previously unknown physiological function. We recently showed that ABCC1 modulates intracellular GC concentrations and action in adipose. Here, we tested the hypothesis that Abcc1 regulates GC concentrations in skeletal muscle as well as adipose, andinfluences glucose metabolism and insulin sensitivity.

Methods: Global Abcc1 knockout (Abcc1^-/-)and wild-type mice were fed with chow diet or high-fat diet (HFD; 58% fat and sucrose) for 9 weeks before glucose and insulin tolerance tests and sampling for plasma and tissue GC concentrations measured by Liquid Chromatography Tandem Mass Spectrometry, and tissue GC-responsive markers (mRNA and protein) by RT-qPCR and Western blot.

Results: On chow diet, deletion of Abcc1 increased levels of corticosterone in plasma, subcutaneous adipose tissue (sWAT), and gastrocnemius muscle. This was accompanied by reduced total body fat mass (sWAT, gWAT and BAT) and lower fasting plasma insulin, with normal glucose tolerance. Reduced LplmRNA in sWAT, but not muscle, suggests Abcc1^-/-mice have lower lipid uptake in adipose. On HFD fat mass gain was comparable between genotypes, but Abcc1^-/-mice developed impaired glucose and insulin tolerance, and hyperinsulinemia. Strikingly, this worsened metabolic phenotype presents without measurable alterations in plasma or tissue GC levels.

Conclusions: These results suggest that ABCC1 influences adiposity, glucose metabolism, and insulin sensitivity by mechanisms which are likely to be GC-dependent only in part. These results introduce ABC transmembrane transporters as novel regulators of metabolic function.