Partial agonists of peroxisome proliferator-activated receptor-γ (PPARγ), also termed selective PPARγ modulators, are expected to uncouple insulin sensitization from triglyceride (TG) storage in patients with type 2 diabetes mellitus. These agents shall thus avoid adverse effects, such as body weight gain, exerted by full agonists such as thiazolidinediones. In this context, we describe the identification and characterization of the isoquinoline derivative PA-082, a prototype of a novel class of non-thiazolidinedione partial PPARγ ligands. In a cocrystal with PPARγ it was bound within the ligand-binding pocket without direct contact to helix 12. The compound displayed partial agonism in biochemical and cell-based transactivation assays and caused preferential recruitment of PPARγ-coactivator-1α (PGC1α) to the receptor, a feature shared with other selective PPARγ modulators. It antagonized rosiglitazone-driven transactivation and TG accumulation during de novo adipogenic differentiation of murine C3H10T1/2 mesenchymal stem cells. The latter effect was mimicked by overexpression of wild-type PGC1α but not its LXXLL-deficient mutant. Despite failing to promote TG loading, PA-082 induced mRNAs of genes encoding components of insulin signaling and adipogenic differentiation pathways. It potentiated glucose uptake and inhibited the negative cross-talk of TNFα on protein kinase B (AKT) phosphorylation in mature adipocytes and HepG2 human hepatoma cells. PGC1α is a key regulator of energy expenditure and down-regulated in diabetics. We thus propose that selective recruitment of PGC1α to favorable PPARγ-target genes provides a possible molecular mechanism whereby partial PPARγ agonists dissociate TG accumulation from insulin signaling.