Sex‐Specific Protein Expression Differences in Peri‐Lymphatic Adipose of Obese and Lean Zucker Rats.

Abstract

Lymphatic abnormalities have been reported to accompany obesity, however little is understood about the mechanisms that lead to these changes. To gain novel insight, we performed a proteomic study of the adipose tissue surrounding mesenteric lymphatic vessels in obese and lean Zucker rats of both sexes in combination of a study of passive wall mechanics of isolated mesenteric collecting lymphatic vessels. At 12‐weeks of age, body weights were recorded and the rats were euthanized for collection of mesetneric lymphatic vessels for study plus blood via cardiac puncture and peri‐lymphatic adipose tissue (PLAT) from the mesentery for proteomic analysis. Mesenteric collecting lymphatic vessels were mounted on a pressure myograph and wall thickness and diameter were measured across a physiological pressure range (1–5 cm water). Serum and protein lysate from the adipose were were then analyzed through the RayBiotech Rat Cytokine Array Q67 testing service. The cohort for study included ten obese and ten lean Zucker rats, with equal numbers of males and females in each group. The mean body weights of this cohort were: lean males 275.8 ± 17.9 g; lean females 190.8 ± 6.3 g; obese males 458.4 ± 11.8 g; and obese females 440.0 ± 6.2 g. (P<0.0001). Across both sexes, the lymphatic vessels from obese rats had a significantly greater wall thickness compared to vessels from lean rats. In the proteomic study of PLAT, 5 targets were significantly elevated in obese rats of both sexes (CCL2, galectin‐1, galectin‐3, neuropilin‐1, and PPBP). Additionally, there were 11 targets were elevated in obese males, but not females (b‐NGF, CINC‐3, fractalkine, IL‐6, IL‐13, PDGF‐AA, prolactin receptor, RAGE, TIMP‐1, VEGF‐A, FGF‐BP), and 24 targets that were elevated in obese females, but not males (4‐1BB, adiponectin, B7‐1, CTACK, EphA5, Flt‐3L, Gas‐1, GFR alpha‐1, IL‐1ra, IL‐7, IL‐17F, IL‐22, JAM‐A, neuropilin‐2, NOPE, Notch‐1, Notch‐2, P‐cadherin, prolactin, RANTES, SCF, TIMP‐2, and TWEAK receptor). In serum from obese males, there were 4 targets that were increased (JAM‐A, GM‐CSF, ICAM‐1, neuropilin‐2) and 2 targets decreased (GP130, Ppbp) compared to lean males. In serum from obese females, 1 target was significantly increased (CCL2) and 4 targets were decreased (decorin, fractalkine, NOPE, prolactin) compared to lean females. There were also four targets that were different across the sexes regardless of lean/obese status (FLT‐3L, Gas‐1, GFR‐alpha‐1, TIMP‐1). Analysis of the targets elevated in the PLAT in both males and females with the STRING database revealed that the elevated proteins belong to clusters pertaining to VEGF signaling, positive regulation of cell adhesion, regulation of angiogenesis, and response to stress. Collectively, the results suggest that in addition to some common signaling proteins that are elevated in the PLAT of obese Zucker rats compared to lean counterparts, there are also several differential signals across the sexes. Future studies that may reveal differences in lymphatic function or dysfunction across the sexes are warranted.Support or Funding InformationSupported by NIH R01GM120774 and L40HL097863.