Prohibitin (PHB) is an evolutionarily conserved protein capable of modulating the metabolic status of multiple cell types. Phosphorylation of PHB at tyrosine residues regulates signal transduction and intracellular trafficking by hormones, growth factors and antigen-activated immune cells. Our laboratory has developed two transgenic mouse models by overexpressing PHB and a mutated PHB (Y114F-PHB) under the fatty acid-binding protein 4 (Fabp4) gene promoter, which is selectively expressed in adipocytes and monocytic macrophages. Based on discoveries from these two transgenic mouse models named Mito-Ob and mutant-Mito-Ob, I speculate that PHB plays an important role in modulating macrophage polarization and function in part through its Tyr-114 phosphorylation (Chapter 2). Macrophages can polarize into two major phenotypes: proinflammatory (M1) and anti-inflammatory (M2). This functional plasticity of macrophages is heavily influenced by internal and external signals, which alter their survival and output. In this thesis, I examined the role of PHB in the metabolism and immune function of macrophages. The importance of PHB tyrosine phosphorylation in cell signalling is reviewed in Chapter 3. PHB has proven to be a crucial link in endocrine-immune crosstalk. In Chapter 4, the immunometabolic aspect of PHB function is reviewed in the context of Mito-Ob and mutant-Mito-Ob mice based on their metabolic and immune dysregulations. While PHB function was examined in adipocytes during my master’s thesis, its role in macrophages remains unexplored. In Chapter 5, I investigated the role of PHB under the M1/M2 dichotomy in a murine cell line, RAW 264.7, and the Mito-Ob and mutant-Mito-Ob mouse models. PHB’s involvement in the functional plasticity of macrophages is many folds. Overexpression of PHB in macrophages differentially affected cytokine production in M1 and M2 macrophages in vitro. Mutation of the Tyr-114 phosphorylation site in PHB affected ERK and STAT6 signalling, arginase synthesis and activity, and mitochondrial respiration. In summary, PHB plays a crucial role in integrating cell signalling events with metabolic switches, as uncovered in polarized macrophages. The results of this thesis support the notion that PHB has important functions in regulating immune cell types, and further investigation on targeting PHB or PHB-related pathways in immune cells may yield therapeutic potential.