Adipose Triglyceride Lipase and Gpr40 Contribute to the Anti‐Contractile Effect of Perivascular Adipose Tissue

OBJECTIVE: Perivascular adipose tissue (PVAT) surrounds most peripheral blood vessels and exerts an anti-contractile influence through paracrine mediators. Although numerous vasoactive factors have been identified, the mechanisms linking adipocyte metabolism to PVAT-dependent modulation of vascular tone remain poorly defined. Because adipocytes store energy as triglycerides hydrolyzed by adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) to generate free fatty acids, we hypothesized that lipolysis-derived fatty acids may contribute to PVAT's anti-contractile actions through activation of long-chain fatty acid-sensing G protein-coupled receptors, Gpr40 and/or Gpr120. METHODS: Mesenteric resistance arteries (MRAs) from adult Wistar rats were studied using wire myography, with or without PVAT, and pharmacological agonists/antagonists and endothelial denudation were used to study signaling. To examine changes in hypertension, PVAT and MRAs from spontaneously hypertensive rats (SHRs) were analyzed by western blotting, and plasma from non-fasting or fasting SHR was assessed by untargeted lipidomics. RESULTS: In Wistar rats, inhibition of ATGL, but not HSL, abolished PVAT's anti-contractile effect, and blockade of Gpr40, but not Gpr120, similarly diminished this response, identifying ATGL and Gpr40 as important mediators. Activation of Gpr40 in PVAT- and endothelium-denuded MRAs further recapitulated the anti-contractile effect in a β-arrestin-dependent manner. In SHR, PVAT ATGL expression was significantly upregulated and MRA Gpr40 expression tended to increase. However, circulating Gpr40 ligand abundance was largely unchanged between strains, suggesting that impaired ligand availability is unlikely to underlie PVAT dysfunction in hypertension. CONCLUSIONS: These findings identify a previously unrecognized ATGL-Gpr40 signaling axis linking adipocyte triglyceride metabolism to PVAT-mediated regulation of vascular tone.