Increased mitochondrial ROS generation mediates the loss of the anti‐contractile effects of perivascular adipose tissue in high‐fat diet obese mice

Abstract

BACKGROUND AND PURPOSEObesity is associated with structural and functional changes in perivascular adipose tissue (PVAT), favouring release of reactive oxygen species (ROS), vasoconstrictor and proinflammatory factors. The cytokine TNF-α induces vascular dysfunction and is produced by PVAT. We tested the hypothesis that obesity-associated PVAT dysfunction was mediated by augmented mitochondrial ROS (mROS) generation due to increased TNF-α production in this tissue. EXPERIMENTAL APPROACHC57Bl/6J and TNF-α receptor-deficient mice received control or high fat diet (HFD) for 18 weeks. We used pharmacological tools to determine the participation of mROS in PVAT dysfunction. Superoxide anion (O 2 .-) and H 2 O 2 were assayed in PVAT and aortic rings were used to assess vascular function. KEY RESULTSAortae from HFD-fed obese mice displayed increased contractions to phenylephrine and loss of PVAT anti-contractile effect. Inactivation of O 2 .-, dismutation of mitochondria-derived H 2 O 2 , uncoupling of oxidative phosphorylation and Rho kinase inhibition, decreased phenylephrine-induced contractions in aortae with PVAT from HFD-fed mice. O 2 .-and H 2 O 2 were increased in PVAT from HFD-fed mice. Mitochondrial respiration analysis revealed decreased O 2 consumption rates in PVAT from HFD-fed mice. TNF-α inhibition reduced H 2 O 2 levels in PVAT from HFD-fed mice. PVAT dysfunction, i.e. increased contraction to phenylephrine in PVAT-intact aortae, was not observed in HFD-obese mice lacking TNF-α receptors. Generation of H 2 O 2 was prevented in PVAT from TNF-α receptor deficient obese mice. CONCLUSION AND IMPLICATIONSTNF-α-induced mitochondrial oxidative stress is a key and novel mechanism involved in obesity-associated PVAT dysfunction. These findings elucidate molecular mechanisms whereby oxidative stress in PVAT could affect vascular function.

Chemerin receptor blockade improves vascular function in diabetic obese mice via redox-sensitive and Akt-dependent pathways

“…Insulin sensitivity was calculated using the homeostasis model assessment-insulin resistance (HOMA-IR) index, which takes into account insulin and fasting blood glucose levels, using the following mathematical formula: HOMA-IR ϭ fasting insulin ϫ fasting glucose/22.5. Additional nutritional and metabolic information from the mouse models can be found in previous studies (6,7,42). At the end of treatment, animals were maintained under anesthesia with 2.5% isoflurane for blood collection and then culled by CO 2 inhalation.…”

C1q/TNF‐related protein 9 improves the anti‐contractile effects of perivascular adipose tissue via the AMPK‐eNOS pathway in diet‐induced obese mice

“…The most important role of PVAT is to reduce vasoconstrictive responses to noradrenaline or phenylephrine (PHE) by releasing various relaxation factors; this is called an anti‐contractile property . However, in obesity there are structural and functional changes in PVAT, which can result in vascular dysfunction by influencing endothelial and smooth muscle cells . Previously, we have shown that this anti‐contractile property of PVAT was abolished in obesity because of high free fatty acids (FFA), which attenuated the anti‐contractile response through an endothelium‐dependent pathway.…”

“…4 However, in obesity there are structural and functional changes in PVAT, which can result in vascular dysfunction by influencing endothelial and smooth muscle cells. [5][6][7] Previously, we have shown that this anti-contractile property of PVAT was abolished in obesity because of high free fatty acids (FFA), which attenuated the anti-contractile response through an endothelium-dependent pathway. The mechanism involves an increase in inflammation and oxidative stress.…”

Molecular mechanisms regulating perivascular adipose tissue – potential pharmacological targets?

“…Indeed, a clear link between loss of anti‐contractile activity in obese murine aortic PVAT and increased mitochondrial ROS in the PVAT is shown by da Costa et al . () in this issue. Interestingly, in their study, obese mice lacking the TNF‐α receptor were protected from the deleterious effects of the high‐fat diet on PVAT function.…”