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Differential regulation of adipocytokine mRNAs by rosiglitazone in db/db mice
G B Moore1, H Chapman, J C Holder
1Department of Vascular Biology, GlaxoSmithKline, Harlow, Essex CM19 5AW, United Kingdom. Gary_B_Moore@gsk.com
Abstract:
The precise mechanism by which PPARgamma activation by thiazolidinediones (TZDs) improves insulin sensitivity is still unclear. Recent studies have focused on the role of adipocytokines in metabolic control and their regulation by TZDs. In this study, we compared the chronic effects of antihyperglycemic doses of the TZD rosiglitazone, the beta3-adrenoceptor agonist BRL-35135, and the PPARalpha agonist Wy-14,643 on the mRNA expression of adipocytokines in WAT of db/db mice. Rosiglitazone treatment decreased adiponectin and resistin mRNA levels by 57 and 72%, respectively (P < 0.001), with no effect on the level of TNFalpha or RELMalpha transcripts. In comparison, Wy-14,643 reduced adiponectin transcript levels by 31% (P = 0.015) while BRL-35135 increased RELMalpha mRNA expression by 245% (P < 0.001) without effect on the other transcripts. Our results indicate that although a reduction in adiponectin and resistin mRNA levels in WAT by rosiglitazone treatment of diabetic mice may contribute to the antidiabetic effects, an alteration in TNFalpha, adiponectin, resistin, or RELMalpha mRNA expression is not absolutely required for the regulation of blood glucose concentration in the db/db mouse.
Insights
Thiazolidinediones (TZDs) like rosiglitazone reduce adiponectin and resistin mRNA in diabetic mice, potentially aiding antidiabetic effects. However, these specific adipocytokine changes are not essential for blood glucose regulation in db/db mice.
Area of Science:
- Metabolic Research
- Molecular Endocrinology
- Diabetes Pathophysiology
Background:
- The precise mechanisms by which thiazolidinediones (TZDs) enhance insulin sensitivity remain incompletely understood.
- Adipocytokines play a crucial role in metabolic regulation, and their modulation by TZDs is an active area of research.
Purpose of the Study:
- To investigate the chronic effects of rosiglitazone, BRL-35135, and Wy-14,643 on adipocytokine mRNA expression in white adipose tissue (WAT) of db/db mice.
- To determine if alterations in specific adipocytokine mRNA levels are necessary for the glucose-lowering effects of these compounds.
Main Methods:
- db/db mice were treated with antihyperglycemic doses of rosiglitazone (TZD), BRL-35135 (beta3-adrenoceptor agonist), or Wy-14,643 (PPARalpha agonist).
- Quantitative analysis of mRNA expression for TNFalpha, adiponectin, resistin, and RELMalpha in WAT was performed using RT-PCR.
Main Results:
- Rosiglitazone significantly decreased adiponectin (57%) and resistin (72%) mRNA levels (P < 0.001).
- Wy-14,643 reduced adiponectin mRNA (31%, P = 0.015), while BRL-35135 increased RELMalpha mRNA (245%, P < 0.001).
- No significant effects on TNFalpha or RELMalpha (rosiglitazone), or TNFalpha, resistin, adiponectin (BRL-35135), or TNFalpha, resistin, RELMalpha (Wy-14,643) were observed.
Conclusions:
- Reduced adiponectin and resistin mRNA in WAT by rosiglitazone may contribute to its antidiabetic effects in db/db mice.
- Alterations in TNFalpha, adiponectin, resistin, or RELMalpha mRNA expression are not strictly required for blood glucose regulation in this model.
