The cell wall of wild-type (WT) Mycobacterium tuberculosis (Mtb) and the Mtb strain disrupted in a 13-gene operon mce1 (Δmce1) varies by more than 400 lipid species. In a recent work it was observed that non-polar lipid extracts from Δmce1 enhanced the mRNA expression of lipid-sense nuclear receptors TR4 and PPAR-γ in murine macrophage relative to WT-Mtb cell wall lipids. Accumulated evidence over the last decade indicates that PPARs influence multiple facets of inflammation and immunity, thereby providing important crosstalk between metabolism and immune system. Here, we used GW9662, the PPAR-γ blocking agent, and applied the mass spectrometry-based targeted eicosanoid, and untargeted lipidomics and metabolomics analysis to assess the role of this nuclear receptor in regulating the lipid and metabolic alterations in Δmce1 Mtb lipid- induced murine macrophages. Under Δmce1-Mtb lipid stimulation, macrophages produced high levels of phosphatidylglycerol, diacyl and triacylglycerols, and low levels of free fatty acids (FFAs) compared to unstimulated control. In contrast, macrophage stimulated with Δmce1-Mtb lipid and PPAR-γ-blocking produced high levels of FFAs, as arachidonic acid (ARA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) among others. In the culture supernatants, Δmce1-Mtb lipid and PPAR-γ-blocking macrophages demonstrated a reduction in the levels of prostaglandin-E2 (PGE2), prostaglandin-D2 (PGD2), and prostaglandin-A2 (PGA2) molecules, when compared to Δmce1-Mtb lipid counterparts. Additionally, metabolomics analysis revealed a significant elevation in the level of 2-monopalmitin in Δmce1-Mtb and PPAR- γ-blocking lipid macrophages compared to Δmce1-Mtb lipid counterparts. Collectively, these results unveil an intricate mechanism involving PPAR-γ in macrophages, controlled by Mtb, in the synthesis of prostaglandins and free fatty acid molecules.