Endocrine Abstracts

Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy and insulin resistance. Although there is a strong inverse correlation between intramuscular triglyceride (IMTG) levels and insulin sensitivity, the impact of glucocorticoids upon the processes that regulate skeletal muscle lipid metabolism has not been explored.

Mouse C2C12 skeletal myocytes were grown to confluence and differentiated into myotubes in chemically defined media. Expression of key components of the lipogenic and β-oxidation pathways were examined by RT-PCR. Functional impact of glucocorticoids upon de novo lipogenesis (ACC activity) was assessed by measuring 1-[14C]acetate incorporation into intramuscular lipids and β-oxidation was assessed by measuring the accumulation of [3H]water following 9,10-[3H]palmitate treatment. Experiments were performed using synthetic glucocorticoid dexamethasone (DEX) in the presence and absence of insulin.

C2C12 myotubes treated with DEX has reduced expression of the key lipogenic genes: FAS (1.90±0.18 vs 1.25±0.15 AU, P<0.01), ACC1 (1.03±0.09 vs 0.83±0.06 AU, P<0.05) and GPAT (0.56±0.06 vs 0.35±0.03 AU, P<0.05). The effect of DEX was reversed when cells were coincubated with the glucocorticoid receptor antagonist RU38486. Endorsing these findings, de novo lipogenesis was decreased by DEX in a dose dependent manner (2.9±0.04 vs 1.9±0.03 (5 nM) versus 1.3±0.02 d.p.m.×10⁴ (500 nM), P<0.05). DEX conversely increased the rate of β-oxidation (25.8±2.1 vs 27.7±2.9 (5 nM) versus 28.9±3.1 d.p.m.×10⁴ (500 nM), P<0.05). Importantly, an increase PDK4 expression was observed with DEX (0.66±0.08 vs 7.36±1.11 AU, P<0.001) and reversed by RU38486, suggesting metabolic switching from glucose to fatty acids as fuel.

In the presence of insulin, low dose DEX was without effect upon lipid accumulation (3.1±0.05 vs 3.2±0.06 d.p.m.×10⁴ (5 nM), P=NS), but increased β-oxidisation (25.8±2.1 vs 27.7±2.9 (5 nM) versus 28.9±3.1 d.p.m.×10⁴ (500 nM), P<0.05).

These data highlight the impact of glucocorticoids to decrease lipid accumulation and increase β-oxidation in the absence of insulin. In contrast, in the presence of insulin they act together to promote IMTG accumulation.