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. 2011 Jun;337(3):734-46.
doi: 10.1124/jpet.111.179960. Epub 2011 Mar 11.

Mechanistic modeling of the effects of glucocorticoids and circadian rhythms on adipokine expression

Siddharth Sukumaran  1 , William J Jusko, Debra C DuBois, Richard R Almon
Affiliations

Mechanistic modeling of the effects of glucocorticoids and circadian rhythms on adipokine expression

Siddharth Sukumaran et al. J Pharmacol Exp Ther. 2011 Jun.

Abstract

A mechanism-based model was developed to describe the effects of methylprednisolone (MPL), circadian rhythms, and the glucose/free fatty acid (FFA)/insulin system on leptin and adiponectin expression in white adipose tissue in rats. Fifty-four normal Wistar rats received 50 mg/kg MPL intramuscularly and were sacrificed at various times. An additional set of 54 normal Wistar rats were sacrificed at 18 time points across the 24-h light/dark cycle and served as controls. Measurements included plasma MPL, glucocorticoid receptor (GR) mRNA, leptin mRNA, adiponectin mRNA, plasma leptin, adiponectin, glucose, FFA, and insulin. MPL pharmacokinetics was described by a two-compartment model with two absorption components. All measured plasma markers and mRNA expression exhibited circadian patterns except for adiponectin and were described by Fourier harmonic functions. MPL caused significant down-regulation in GR mRNA with the nadir occurring at 5 h. MPL disrupted the circadian patterns in plasma glucose and FFA by stimulating their production. Plasma glucose and FFA subsequently caused an increase in plasma insulin. Furthermore, MPL disrupted the circadian patterns in leptin mRNA expression by stimulating its production. This rise was closely followed by an increase in plasma leptin. Both leptin mRNA and plasma leptin peaked at 12 h after MPL and eventually returned back to their circadian baselines. MPL and insulin had opposing effects on adiponectin mRNA expression and plasma adiponectin, which resulted in biphasic pharmacodynamic profiles. This small systems model quantitatively describes, integrates, and provides additional insights into various factors controlling adipokine gene expression.

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Figures

Fig. 1.
Fig. 1.
Model schematic for the effects of methylprednisolone, circadian rhythms, and glucose/free fatty acids/insulin system on leptin and adiponectin expression. Curved input represents circadian pattern in production, open boxes reflect stimulation, and shaded boxes depict inhibition of production rate of a turnover process. The model is described by eqs. 1 to 25. Definitions of parameters are provided in Tables 1 to 5.
Fig. 2.
Fig. 2.
Plasma concentrations versus time after 50 mg/kg i.m. injection of MPL. Solid line represents model simulations (eqs. 1 and 2). Parameter estimates are listed in Table 1. Circles are mean data with error bars indicating 1 S.D. of the mean.
Fig. 3.
Fig. 3.
GR mRNA expression in white adipose tissue in control rats (A) and rats treated with 50 mg/kg i.m. MPL (B). Circles depict mean data with error bars representing 1 S.D. of the mean, and the solid lines show model fitting (parameter estimates given in Table 2). Shaded areas are dark periods, and unshaded areas are light periods.
Fig. 4.
Fig. 4.
Circadian patterns in plasma glucose (A), FFA (B), and insulin (C) in control rats. Circles depict the mean data with error bars representing 1 S.D. of the mean and the solid lines showing model fitting (parameter estimates given in Table 3). Shaded areas are dark periods, and unshaded areas are light periods.
Fig. 5.
Fig. 5.
A, C, and D, plasma glucose (A), FFA (C), and insulin (D) in rats given 50 mg/kg i.m. MPL. Circles depict the mean data with error bars representing 1 S.D. of the mean and the solid lines showing model fitting (parameter estimates given in Table 3). B, the first 24 h of plasma glucose in animals treated with 50 mg/kg i.m. MPL (solid line) and control animals (dotted line).
Fig. 6.
Fig. 6.
Circadian pattern in leptin mRNA expression in white adipose tissue (A) and plasma leptin (B) in control animals. Circles depict the mean data with error bars representing 1 S.D. of the mean and the solid lines showing model fitting (parameter estimates given in Table 4). Shaded areas are dark periods, and unshaded areas are light periods.
Fig. 7.
Fig. 7.
Leptin mRNA expression in white adipose tissue (A) and plasma leptin (B) in rats given 50 mg/kg i.m. MPL. Circles depict the mean data with error bars representing 1 S.D. of the mean and the solid lines showing model fitting (parameter estimates given in Table 4).
Fig. 8.
Fig. 8.
Adiponectin mRNA expression in white adipose tissue (A) and plasma adiponectin (B) in rats given 50 mg/kg i.m. MPL. Circles depict the mean data with error bars representing 1 S.D. of the mean and the solid lines showing model fitting (parameter estimates given in Table 5).
Fig. 9.
Fig. 9.
Simulated profiles of free cytosolic receptor (A), drug-receptor complex in cytosol (DR) (B), and nucleus (DRn) (C) in rats given 50 mg/kg i.m. MPL. The inset in B shows DR truncated at 5 h.
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