PTEN-L/CD68 axis regulates diet-induced obesity, monocyte-to-macrophage polarization, and signaling via IL-4 and AKT pathways

Obesity has emerged as a major health issue in the developed world, including in the development and treatment of cancer. Immune regulation is crucial for maintaining adipose tissue balance; however, the early events that convert a noninflammatory state to inflammation, contributing to obesity and cancer, remain poorly understood. PTEN is well known as a tumor suppressor that inhibits the PI3K/AKT pathway and has been linked to cancer, obesity, and macrophage (MΦ) function. However, the role of its secreted isoform, PTEN-L, remains unclear. We previously observed that PTEN-L affects the function of MΦs in mice during Pseudomonas aeruginosa infection and tumor development. Here, based upon a yeast two-hybrid screen, we identified that PTEN-L interacts with CD68, a MΦ marker encoding a scavenger receptor with an unknown function. We studied PTEN-L and CD68 in the context of induced obesity with a high-fat diet (HFD) by knocking them out in mice. We observed that CD68 facilitates entry of PTEN-L into MΦs and human tumor cells, and that Pten-l and Cd68 knockout mice fed a HFD are protected from obesity. Adipose tissue from Pten-l and Cd68 knockout mice exposed to a HFD showed similar immune phenotypes, including expansions of CBR2 + and immature monocyte-derived MΦs and depletion of Apoe + and lipid-associated MΦs, which displayed characteristics of IL-4-stimulated polarization and elevation of AKT activation. Our findings suggest that Pten-l and Cd68 play a role in regulating MΦ polarization by attenuating IL-4-AKT signaling and are important factors in the high-fat diet-induced remodeling of white adipose tissue, contributing to obesity and insulin resistance. Interestingly, treating patients with Atopic Dermatitis using an antibody targeting the IL-4 receptor has been demonstrated to be associated with a noteworthy increase in body weight. Meanwhile, IL-4 influences the phenotype of tumor-infiltrating monocyte-derived MΦs and plays a role in mediating resistance to immunotherapy through macrophage regulation. Thus, we define a mechanism of adipose tissue homeostasis controlled by the expression of PTEN-L and CD68 in myeloid populations, which may have clinical relevance for immune and metabolic responses due to PI3K/AKT inhibitor and IL4R targeted therapy.