The Role of Lymphatic Vessel Dysfunction in Glucocorticoid-Induced Visceral Adiposity

The anti-inflammatory and immunosuppressive actions of glucocorticoids (GCs) provide beneficial treatment in numerous diseases. However, GCs also have common side effects such as increased visceral fat that raise metabolic and cardiovascular risks. The accumulation of visceral fat reflects an imbalance between lipid storage and clearance. The lymphatic system has a vital role in lipid clearance, with lymphatic smooth muscle cells (LMCs) being essential for the pumping action that propels lymph away from the interstitium. This study examined the effects of GCs on LMCs and the contractile functions of lymphatic collecting vessels, and their relation to visceral adiposity. We visualized the lymphatic network in perirenal adipose tissue of control rats by whole-mount staining using LYVE-1 and podoplanin antibodies. Evans Blue, a tracer dye used to characterize lymphatic drainage, was injected into the perirenal adipose tissue and monitored to measure the extent of clearance. Primary LMCs were isolated from rat renal collecting lymphatic vessels and established in culture. The LMCs were exposed to either dexamethasone (DXMS) or vehicle. RNA sequencing was performed to analyze gene expression in these cells. In complementary in vivo studies, rats were treated with either DXMS or a vehicle for two weeks and the renal lymphatic collecting vessels were isolated to evaluate their contractile function using ex vivo pressure myography analysis. First, we demonstrated the presence of lymphatic capillaries and collecting vessels in the perirenal adipose tissue of control rats. Our studies also showed that Evans Blue injected into the perirenal adipose tissue was cleared within three hours, suggesting that lymphatic vessels have a role in transporting macromolecules from adipose tissue. Next, we found that perirenal lymphatics isolated from rats treated with DXMS for two weeks had compromised pumping dynamics (reduced contraction amplitude and ejection fraction, with minimal changes in contraction frequency) compared to untreated control rats. In primary cultured LMCs, RNA sequencing identified 1,704 differentially expressed genes in LMCs treated with DXMS compared to controls, with 858 genes upregulated and 846 genes downregulated. Gene Ontology enrichment and KEGG pathway analysis indicated that DXMS affected key signaling pathways involving calcium and potassium, which are essential for LMC contraction, as well as kinesin family genes that regulate microtubule depolymerization. Lastly, we documented an increase in the weight of perirenal adipose tissue and adipocyte density in DXMS-treated rats compared to normal rats. We conclude that GCs profoundly modulate lymphatic muscle cell function that blunts lymphatic vessel contractility. We propose that diminished lymphatic pumping results in ineffective lipid clearance, which promotes the accumulation of visceral fat. NIH 1P01HL116263 RO1 DK135764J This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.