PPAR-γ role in ‘unique’ adipose tissue Treg-cell function
MedWire News: The beneficial effects of T regulatory (Treg) cells in visceral adipose tissue (VAT) are mediated partly by peroxisome proliferator-activated receptor (PPAR)-γ, researchers report in Nature.
Furthermore, the team found that a lack of functional PPAR-γ reduced the ability of the thiazolidinedione drug pioglitazone to restore insulin sensitivity in obese mice.
"Our results provide proof-of-principle that it is possible to target a designated population of Treg cells for a particular therapeutic goal," say Diane Mathis (Harvard Medical School, Boston, Massachusetts, USA) and colleagues.
Mathis et al noted much higher levels of the gene encoding PPAR-γ (Pparg) in VAT Treg cells relative to other T-cell populations. They speculated that this increase could underpin the previously noted beneficial effects of VAT Treg cells on inflammatory and metabolic parameters.
Investigating further, they found that a number of other genes were also upregulated or downregulated in Treg cells. Many of these were involved with leukocyte migration and extravasation or lipid metabolism. Notably, when introduced (along with Foxp3) into naïve T cells, both Pparg isoforms provoked upregulation of these genes, but only Pparg1 caused downregulation.
"This constitutes a rare dysjunction in the activities of the two PPAR-γ isoforms, which differ by only an extra 30 amino acids at the amino terminus of PPAR-γ2," say the researchers.
The antidiabetic thiazolidinedione drugs are potent PPAR-γ agonists. Treating obese mice with pioglitazone caused notable upregulation of Treg cells in epididymal adipose tissue, but not in other fat tissues or organs. Gene expression in the upregulated cells shifted toward that of typical VAT Treg cells.
The researchers also report that Treg cells from VAT, but not the spleen, were able to take up lipid droplets, especially in response to pioglitazone treatment. They describe this as "an intriguing adaptation to the tissular environment, not shared by conventional T cells residing at the same site," but say: "It remains to be determined whether this feature promotes Treg cell survival or effector functions, or whether it is an epiphenomenon."
Pioglitazone treatment of mice with a mutated form of Pparg was less effective than in wild-type mice. Treatment failed to expand the VAT Treg-cell population of mutant mice, was less effective at reducing pro-inflammatory immune cells than in wild-type mice, and caused an unexpected reduction in anti-inflammatory cells.
Although pioglitazone treatment had its expected beneficial effects on parameters of insulin and glucose sensitivity, the effects were smaller in mutant than wild-type Pparg mice.
"Delineating the cell type(s) crucial for the protective effect of [pioglitazone] on metabolic disorders is imperative given current concerns over the side effects of the [thiazolidinedione] class of compounds and the resultant search for alternative drugs," concludes the team.
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By Eleanor McDermid