SAT-651 - Balancing Fat: Innovations in Adipose Tissue Engineering and Function

Adipose tissue (AT) is a dynamic endocrine organ that integrates hormonal, mechanical, and microenvironmental signals to regulate systemic metabolism. However, existing models lack the ability to capture these coupled inputs, limiting mechanistic insight into sex-specific metabolic regulation and therapeutic response. Here, we engineer human-relevant, three-dimensional (3D) adipose tissue platforms that incorporate vascular, immune, and extracellular matrix components to interrogate AT function under controlled, physiologically relevant conditions.

Using a vascularized, immune-competent fat-on-chip system, we examine how β-estradiol and dietary fatty acids coordinate adipocyte metabolism. We observe dose-dependent endocrine effects, where low β-estradiol enhances fatty acid uptake gene expression, moderate levels promote lipogenesis, and high levels suppress lipolysis and overall metabolic activity. These nonlinear responses provide a mechanistic framework for understanding hormone-sensitive conditions such as lipedema and metabolic changes across the female lifespan.

To probe the role of physical forces, we developed a 3D adipose model exposed to simulated microgravity (sµg) using a rotating wall vessel. sµg enhances insulin-stimulated glucose uptake and GLUT4 translocation in mature adipocytes, independent of canonical AKT signaling. Instead, this response is mediated through cortical actin remodeling, as inhibition of ARP3 attenuates glucose uptake under sµg conditions, revealing a mechanosensitive regulator of insulin responsiveness.

Integration of immune components further demonstrates that macrophages drive pro-inflammatory cytokine signaling and alter adipokine profiles, while hypoxic conditions increase cellular tension and impair lipid mobilization, recapitulating key features of adipose dysfunction.

Together, these engineered platforms establish a tunable, human-relevant system to dissect how endocrine signals, mechanical cues, and immune interactions converge to regulate adipose tissue function. This work advances a foundation for predictive, sex-aware models of metabolism and enables the development of more effective therapeutic strategies targeting adipose dysfunction in obesity, aging, and women’s health.

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