Mechanistic Modeling of the Effects of Glucocorticoids and Circadian Rhythms on Adipokine Expression

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. Fiftyfour 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.

Functional proteomic analysis of corticosteroid pharmacodynamics in rat liver: Relationship to hepatic stress, signaling, energy regulation, and drug metabolism

“…The CS stimulate lipolysis in white adipose tissue producing free fatty acids for use by other tissues [61] and glycerol for gluconeogenesis [62]. In addition, CS also inhibit hepatic fatty acid β-oxidation [63], the process by which fatty acids are broken down in the mitochondria and/or in peroxisomes to generate acetyl-CoA which subsequently feeds into the Krebs cycle.…”

Changes in Adipokine Levels in Autism Spectrum Disorders

“…All procedures were performed between 8 and 10 a.m. to minimize biological differences due to glucocorticoid variation and circadian rhythms [10]. The blood was immediately centrifuged at 3,000 g for 10 min, 4°C, twice.…”

Meta-Modeling of Methylprednisolone Effects on Glucose Regulation in Rats

“…Abdominal fat GR and leptin mRNA were determined by real-time qRT-PCR using TaqMan-based probes in the circadian-nadir study [24]. The GR density and its mRNA in gastrocnemius muscles were also measured previously [33].…”

“…The receptor dynamic parameters governing drug-receptor binding, translocation and recycling obtained previously [4], [24], [33], [34] were fixed. The GC receptor/gene mechanisms are considered to be similar in different tissues.…”