Does Dietary Methionine Alter Perivascular Adipose Tissue Function?

Abstract

Perivascular adipose tissue (PVAT) is an adipose depot surrounding blood vessels and is a paracrine regulator of vascular tone. Obesity is associated with the loss of PVAT‐mediated anti‐contractile properties, thus contributing to obesity‐associated hypertension. Hydrogen sulfide (H2S) is a gaseous signaling molecule that is produced in the vasculature and is important for regulating vascular tone. In PVAT, cystathionine gamma lyase (Cse) is the primary source of H2S which acts as an important adipose‐derived relaxing factor. Dietary methionine restriction recapitulates many of the metabolic effects of caloric restriction and leads to preferential expression of activating transcription factor 4 (ATF4) which facilitates Cse transcription. We hypothesized that dietary methionine restriction will prevent high fat diet‐induced loss of PVAT anti‐contractile properties, through activation of the integrated stress response (ISR) and increased ATF4‐mediated transcription of Cse. Male Wistar rats were fed either a control (C, 10% calories from fat) or a high fat diet (HFD) (H, 60% calories from fat) that was either methionine replete (R, 0.86% methionine) or methionine depleted (D, 0.12% methionine) for 12 weeks such that there were four groups: CR, CD, HR, and HD. Dietary methionine restriction prevented body weight gain, while rats fed a methionine replete diet gained weight over the 12 week feeding period. There was no difference in weight gain between control or HFD fed rats. Arterial blood pressure, measured in conscious rats using tail cuff plethysmography, was not different between the four groups over the 12 week feeding period. After 12 weeks on diets, arterial contractility was assessed using wire myography in 2nd order mesenteric arteries (MAs) with and without attached PVAT. In our hands, the presence of PVAT was associated with reduced contraction to norepinephrine (NE, 10 µM) and greater relaxation to acetylcholine (ACh,10 µM) in MAs from all groups, and HFD was not associated with a loss of PVAT anti‐contractile properties. In the presence of PVAT, dietary methionine restriction increased relaxation to ACh in NE‐precontracted MAs, while HFD had no effect on ACh‐induced relaxation. In conclusion, in male Wistar rats, while HFD had no effect on weight gain, blood pressure, or PVAT modulation of MA contractility, dietary methionine restriction for 12 weeks had profound effects on body weight gain, no effect on arterial blood pressure, and a small effect on MA ACh‐induced relaxation in the presence of PVAT. Future studies include examining gene and protein expression of Cse and other ATF4 responsive genes using real time qPCR, Western blot analysis, and immunohistochemical staining of arterial cross‐sections. These studies will provide further insights into dietary interventions to minimize the cardiovascular co‐morbidities associated with obesity.