Bolus, W. R. | Search bioRxiv

bioRxiv2026

ApoE-Dependent Lipid Handling by Median Eminence Microglia Preserves Myelin Integrity and Metabolic Function

Microglia regulate hypothalamic control of systemic metabolism, but the mechanisms underlying their contribution remain unclear. Here, we identify a distinct apolipoprotein E (ApoE) microglial population enriched in the median eminence (ME), a brain region involved in sensing peripheral cues and metabolic regulation. These microglia engage multiple functional programs related to lipid handling, interferon signaling, and stress responses that are differentially regulated within the ME. Consumption of a Western diet (WD) increased interferon signaling and lipid accumulation in ME microglia. Expression of the human APOE4 isoform in mice exacerbated microglial lipid dysregulation, interferon signaling, and impaired ME myelin organization. Deleting APOE in microglia attenuated their ability to couple lipid accumulation to interferon signaling, identifying microglial APOE as a cell-intrinsic determinant of interferon responses. Finally, selective activation of liver X receptor signaling using synthetic HDL nanoparticles restored microglial lipid homeostasis, improved hypothalamic leptin responsiveness, and limited weight gain in WD-fed mice. Together, these findings define an Apoe-dependent regulatory program in ME microglia that is therapeutically targetable and clarify how nutritional stress disrupts hypothalamic control of metabolic homeostasis.

neuroscience↗

bioRxiv2026

Osteoprotegerin-Enabled Immune Evasion by Pathological Adipose Stromal Cells Drives Metabolic Dysfunction in Obesity

Diet-induced obesity (DIO) promotes the accumulation of stromal cells with senescent characteristics in the adipose tissue (AT). Selectively clearing these cells--either through chemical senolytics or activation of invariant natural killer T (iNKT) cells--improves glucose homeostasis in obese mice, however the identity of the responsible stromal population remains unknown. Here, we use transcriptional profiling of AT stromal cells coupled with C12FDG-based enrichment of senescent populations in mice with DIO and healthy controls to identify a distinct subset of adipose progenitor cells (APCs) with robust senescence signatures that accumulate in DIO across multiple AT depots. We show that these cells, which we term senescent APCs (sAPCs), are not merely passive markers of metabolic stress but are instead active stromal organizers, accumulating in parallel with the emergence of lipid-associated macrophages (LAMs) and the diminution of multipotent mesenchymal progenitors. sAPCs promoted CCR2-dependent macrophage chemotaxis, directly linking stromal senescence to chemokine-mediated remodeling of the AT immune niche. Comparative transcriptional analysis revealed a remarkable similarity between sAPCs and inflammatory cancer-associated fibroblasts (iCAFs), including the strong induction of periostin (POSTN) and the production of osteoprotegerin (OPG), a decoy receptor for RANKL and TRAIL that enables tumoral immune evasion. Indeed, OPG production by AT stromal cells was induced by DIO across AT depots. Exogenous OPG inhibited the ability of iNKT cells to kill senescent APCs in vitro, whereas antibody-mediated OPG neutralization reciprocally enhanced such cytotoxic killing. In vivo, systemic OPG neutralization both reduced sAPC accumulation in AT and normalized glucose homeostasis in obese mice. Together, these findings identify sAPCs as a pathological stromal population that expands in obesity through elaboration of immunomodulatory factors. In particular, secreted OPG enables sAPCs to evade iNKT-mediated immune surveillance and contributes to metabolic dysfunction, highlighting OPG and sAPCs as promising therapeutic targets for restoring AT immune and metabolic homeostasis.

immunology↗