<p>Peroxisome proliferator-activated receptors are nuclear hormone receptors with three subtypes (PPARα, PPARβ/δ, and PPARγ) that exhibit distinct tissue expression and biological activities. PPARγ is a key target for insulin-sensitizing thiazolidinediones, which are PPARγ full agonists that are used to treat type 2 diabetes. Unfortunately, despite the excellent anti-diabetic effects of thiazolidinediones, their clinical use is limited due to their adverse effects. For this reason, an approach targeting PPARγ partial agonists instead of full agonists has been proposed in an effort to develop new anti-diabetic agents without adverse effects. Marine organism-associated microbes have been recognized as a potential reservoir to provide diverse bioactive natural products, including antibiotics, anti-tumor compounds, and anti-infective compounds, often linked to their functional roles in host organisms. In this study, we aimed to identify potential PPARγ partial agonists with anti-diabetic potential and reduced side effects. Using bioactivity-guided fractionation, PPARγ transactivation assays, and molecular docking simulations, macrolactin A and 7-<i>O</i>-succinyl macrolactin A, isolated from the ascidian-associated <i>Bacillus subtilis</i> J08J-1-B’-4, were identified as PPARγ and dual PPARα/γ partial agonists, respectively. These compounds enhanced insulin-stimulated glucose uptake in adipocytes and HepG2 cells without inducing adipogenesis. Furthermore, macrolactin A showed neuroprotective and anti-inflammatory effects in <i>in vitro</i> assays. These findings highlight two microbial polyketides macrolactin A and 7-<i>O</i>-succinyl macrolactin A as promising candidates for type 2 diabetes treatment with potential multi-target bioactivities.</p> Graphical Abstract <p></p>