Energy restriction enhances therapeutic efficacy of the PPARγ agonist, rosiglitazone, through regulation of visceral fat gene expression

Aim:  Consumption of a palatable diet can induce hyperphagia, leading to weight gain (dietary obesity) and insulin resistance in rats. Thiazolidinediones (TZDs) can also induce hyperphagia in rats but conversely have an insulin-sensitizing effect. The aim of this study was to investigate whether preventing TZD-induced hyperphagia (i.e. energy restriction) in dietary obese (DIO) rats would enhance the insulin-sensitizing effects of treatment at a therapeutic dose; and, within this paradigm, to produce an original survey of candidate TZD-gene targets in the clinically relevant visceral white adipose tissue (WAT) depot. Methods:  DIO rats that were either freely fed or energy restricted (i.e. pair-fed to the level of untreated controls) were treated with rosiglitazone maleate (RSG; 3 mg/kg/day) for 2 weeks, the restricted group controlling for treatment-induced hyperphagia and weight gain. The outcome measures were circulating concentrations of various biochemical markers of insulin resistance, and gene expression was measured in epididymal WAT. Results:  In both freely fed and pair-fed groups, compared to untreated DIO controls, RSG reduced plasma levels of insulin (−29% and −43%; p < 0.05 and p < 0.001, respectively), free fatty acids (FFAs; −45% and −48%; p < 0.01 and p < 0.001, respectively) and triglycerides (TGs; −63% and −72%; both p < 0.001), reflected in improved insulin sensitivity, as measured by homeostasis model assessment (−29% and −43%; p < 0.01 and p < 0.0001). RSG also increased the expression of the fatty acid transport/synthesis genes, fatty acid transport protein (2.4–3.2-fold), epidermal fatty acid–binding protein (FABP; 1.7–2.0-fold), heart FABP (25–29-fold) and fatty acid synthase (2.3–2.9-fold; all p < 0.05) in both groups. Adipocyte FABP was also increased by RSG treatment, but only in combination with energy restriction (1.52-fold; p < 0.05) as was hexokinase II expression (p < 0.001). In contrast, the drug had no effect on expression of several genes associated with lipolysis. Although obesity-induced hyperleptinaemia was normalized only in the energy-restricted group, leptin messenger RNA (mRNA) expression was reduced in both treated groups (all p < 0.01). Resistin and tumour necrosis factor-alpha expression was also reduced, though in the latter case, only with energy restriction (p < 0.05). Other adipokines were unaffected by RSG treatment. Conclusion:  Our results clearly show that energy restriction enhances the therapeutic efficacy of TZDs and suggest that this occurs, at least in part, through a modulatory effect on gene expression in visceral WAT. These findings improve our understanding of the underlying mechanistic basis for the clinical usefulness of dietary restriction as an adjunct to TZD therapy in type 2 diabetes.