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(PPAR) Modulator Blocks Adipocyte Differentiation but Stimulates Glucose Uptake in 3T3-L1 Adipocytes
Departments of Pharmacology (R.M., P.A.H., L.J., J.B., J.R.P.), Endocrine Research (D.E.M.), Medicinal Chemistry (A.F.), Retinoid Research (K.K.), and New Leads Discovery (G.E.C.) Ligand Pharmaceuticals, Inc. San Diego, California 92121
Peroxisome proliferator-activated
receptor-
(PPAR) agonists such as the thiazolidinediones are
insulin sensitizers used in the treatment of type 2 diabetes. These
compounds induce adipogenesis in cell culture models and increase
weight gain in rodents and humans. We have identified a novel PPAR
ligand, LG100641, that does not activate PPAR but selectively and
competitively blocks thiazolidinedione-induced PPAR activation and
adipocyte conversion. It also antagonizes target gene activation as
well as repression in agonist-treated 3T3-L1 adipocytes. This
novel PPAR antagonist does not block adipocyte differentiation
induced by a ligand for the retinoid X receptor (RXR), the
heterodimeric partner for PPAR, or by a differentiation
cocktail containing insulin, dexamethasone, and
1-methyl-3-isobutylxanthine. Surprisingly, LG100641, like the
PPAR agonist rosiglitazone, increases glucose uptake in
3T3-L1 adipocytes. Such selective PPAR antagonists may help
determine whether insulin sensitization by thiazolidinediones is
mediated solely through PPAR activation, and whether there are
PPAR-ligand-independent pathways for adipocyte differentiation. If
selective PPAR modulators block adipogenesis in vivo,
they may prevent obesity, lower insulin resistance, and delay the onset
of type 2 diabetes.
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