Mechanisms linking beige adipogenesis and angiogenic remodeling in white adipose tissue

Abstract

A hallmark feature of adipose tissue as a central metabolic organ is its capacity for expansion and remodeling in response to physiological demand, with roles beyond simply serving as lipid storage. One striking form of this remodeling is beige or brown-like adipogenesis, the process by which thermogenically active adipocytes arise within white adipose depots in response to cold or adrenergic stimulation, increasing the capacity of the tissue for non-shivering heat production. Integral to this beige adipogenesis, and tissue plasticity as a whole, is the adipose vasculature, which facilitates oxygen, nutrient, and lipid exchange in accordance with local and systemic metabolic state. In response to cold or adrenergic stimulation, beige adipocyte biogenesis is accompanied by increased microvascular growth in inguinal white adipose tissue (iWAT), yet whether this angiogenic response is driven by the beige adipogenic program itself or reflects an independent endothelial response to adrenergic stimulation remained unknown. Here, our central goal was to define the spatiotemporal dependencies between beige adipogenesis and angiogenesis and to identify the molecular signals that coordinate vascular outgrowth within the thermogenic niche. A major limitation in studying the spatiotemporal organization of adipose tissue remodeling has been the reliance on traditional two-dimensional imaging, which fails to capture the finer details of the adipose tissue which is highly heterogenous. To overcome this, we employed Adipo-Clear, a whole-tissue clearing approach that enables visualization of the intact adipose microvasculature in three dimensions. We found that blunting beige adipocyte biogenesis, whether by disrupting adipocyte lipolysis, thermogenic transcriptional programming, or de-novo beige progenitor differentiation, significantly suppresses cold-induced angiogenesis in iWAT, while leaving the visceral depot unaffected. The pro-angiogenic signal was shown to be lipid-borne and its release was ATGL-dependent. Linoleic acid emerged as the key mediator: it accumulates selectively in cold-exposed iWAT, is depleted when lipolysis is disrupted, and is sufficient to drive endothelial proliferation and tube formation. Mechanistically, we found that these endothelial effects are transduced through COX2-dependent prostaglandin synthesis and EP2 receptor signaling, suggesting that a single lipolysis-derived lipid coordinates both progenitor expansion and vascular remodeling within the thermogenic niche. Together, these data define a paracrine lipid circuit linking cold-activated adipocyte lipolysis to angiogenic remodeling of the iWAT vasculature. Identification of this axis advances our understanding of how beige adipose tissue remodeling is coordinated at the tissue level and opens new avenues for therapeutic strategies targeting the thermogenic adipose niche in the context of metabolic disease.