L26/P-778 Targeting ERBB4 activates adipose progenitor cells to enhance brown fat formation and its therapeutic potential for PCOS

Abstract Study question How can targeting adult de novo brown adipogenesis improve metabolic and reproductive outcomes in polycystic ovary syndrome (PCOS). Summary answer The ERBB4 is essential for BAT preadipocyte differentiation. Its blockade induces BAT whitening and elevates androgen sensitivity. Androgen intervention suppresses ERBB4 and de novo adipogenesis. What is known already Brown adipose tissue (BAT) holds therapeutic potential for disorders like PCOS and obesity, primarily through improving metabolic and reproductive parameters. Current understanding posits that adult BAT function relies mainly on the activation of existing adipocytes or the interconversion between different adipose cell subtypes. Although a latent population of preadipocytes with differentiation capacity persists in adults, safe and effective clinical strategies to robustly stimulate de novo brown adipogenesis and thereby enhance endogenous BAT mass and function remain a significant unmet challenge in the field. Study design, size, duration This study identified key targets via single-cell RNA sequencing of adult mouse BAT and validated them using cellular and lineage-tracing models. Pharmacological agents were then developed to assess BAT function and its therapeutic potential in PCOS mice.The total duration was three years. Participants/materials, setting, methods We identified ERBB4 as a key regulatory target. To assess its role in differentiation, preadipocytes were treated with ERBB4 agonists or inhibitors in vitro. For in vivo validation, we employed lineage-tracing mice to monitor adipocyte differentiation and established complementary mouse models: one with BAT-specific ERBB4 inhibition and another recapitulating PCOS. BAT formation and function were then analyzed using multiple approaches, including but not limited to immunohistochemistry, qPCR. Main results and the role of chance Analysis of single-cell RNA sequencing data from adult mouse BAT revealed a potential role for ERBB4 in regulating preadipocyte proliferation and differentiation. This finding prompted us to hypothesize that the ERBB4 pathway controls adipocyte precursor cell differentiation—a hypothesis we subsequently validated. We found that ERBB4 expression is markedly upregulated during differentiation. Its inhibition robustly blocks adipogenesis (∼60% reduction; p < 0.01), concurrently downregulating thermogenic gene programs and upregulating androgen receptor (AR) expression, confirming its indispensable role. In a PCOS mouse model, BAT displayed attenuated ERBB4 signaling (p < 0.05) and a reduced proportion of new adipocytes, directly linking impaired ERBB4 activity to PCOS-associated BAT dysfunction. Mechanistically, androgens suppress ERBB4 phosphorylation, thereby disrupting differentiation. This provides direct evidence for how hyperandrogenemia compromises BAT biogenesis in PCOS. Collectively, these statistically robust results establish the ERBB4-androgen axis as a central regulator of BAT homeostasis. Limitations, reasons for caution As a preclinical study, this work is limited by its sample size and the lack of validation in human-derived cells. Future studies employing human preadipocytes and BAT-specific ERBB4-activated mouse models are warranted to confirm the therapeutic potential of this approach. Wider implications of the findings This study establishes ERBB4 as a novel target for stimulating adult brown adipogenesis. This finding provides a foundational rationale for developing BAT activation-based therapies for PCOS and suggests its potential applicability to related metabolic disorders. Trial registration number No