Editors' ChoiceDiabetes

PPAR for the Course in Type 2 Diabetes

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Science Translational Medicine  30 Nov 2011:
Vol. 3, Issue 111, pp. 111ec192
DOI: 10.1126/scitranslmed.3003484

Insulin resistance and chronic inflammation are hallmarks of type 2 diabetes and obesity. Li and colleagues report that deleting the nuclear receptor corepressor (NCoR) in adipocytes resulted in enhanced insulin sensitivity and decreased systemic inflammation in mice. These results resemble the effects induced by the thiazolidinedione class of insulin-sensitizing drugs used to treat type 2 diabetes and provide evidence for the potential therapeutic utility of tissue-specific peroxisome proliferator–activated receptor γ (PPARγ) agonists. PPARγ is a nuclear hormone receptor expressed in adipose tissue, liver, kidney, and skeletal muscle and is a key player in glucose metabolism. In the presence or absence of ligand, coactivators or corepressors, respectively, regulate PPARγ activity by modulating PPARγ-mediated gene expression. In their new study, Li et al. selectively delete NCoR expression in mouse adipose tissue in order to assess the role of this corepressor in glucose metabolism, insulin sensitivity, and inflammation.

Li and colleagues report that when they fed mice engineered to have adipocytes lacking NCoR a high-fat diet, the animals became more obese than did their wild-type counterparts. Despite their increased adiposity, these mice were protected against insulin resistance and experienced improved glucose tolerance when given a high-fat diet. These mice were also shown to acquire enhanced systemic insulin sensitivity in muscle and liver as compared with control animals. Moreover, when the authors analyzed adipose tissue for macrophage accumulation—a known contributor to chronic inflammation and insulin resistance—they found that the mice lacking the adipocyte NCoR had reduced macrophage infiltration and decreased proinflammatory gene expressions in their adipose tissue. Last, the researchers demonstrated that administration of rosiglitazone, a PPARγ agonist drug, improved the insulin sensitivity of obese wild-type mice fed a high-fat diet but not that of mice lacking adipocyte NcoR fed a high-fat diet. These results demonstrate that activation of the PPARγ-mediated transcription program in adipocytes is a principal contributor to systemic insulin sensitivity and glucose metabolism.

Managing type 2 diabetes with thiazolidinedione drugs is often confounded by fluid retention and cardiovascular side effects. These effects are likely due to nonspecific activation of PPARγ in other tissues such as the kidney. The findings of the study by Li et al. now suggest that targeted activation of PPARγ in adipocytes but not other tissues could provide therapeutic benefits together with an improved side effect profile, which is welcome news indeed for the treatment of type 2 diabetes.

P. Li et al., Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity. Cell 4, 815–826 (2011). [PubMed]

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