Dietary methionine depletion and hydrogen sulfide producing genes in perivascular adipose tissue of male wistar rats

Authors: CORKEN, ADAM - University Arkansas For Medical Sciences (UAMS); DAVIS, LEE - University Arkansas For Medical Sciences (UAMS); WAHL, ELIZABETH - Arkansas Children'S Nutrition Research Center (ACNC); SIKES, JAMES - Arkansas Children'S Nutrition Research Center (ACNC); THAKALI, KESHARI - University Arkansas For Medical Sciences (UAMS)

Submitted to: Physiological Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/4/2025
Publication Date: 12/19/2025
Citation: Corken, A., Davis, L., Wahl, E.C., Sikes, J.D., Thakali, K.M. 2025. Dietary methionine depletion and hydrogen sulfide producing genes in perivascular adipose tissue of male wistar rats. Physiological Reports. 13(24): article e70702. https://doi.org/10.14814/phy2.70702.
DOI: https://doi.org/10.14814/phy2.70702

Interpretive Summary: Perivascular adipose tissue (PVAT) surrounds blood vessels and is important for keeping blood vessels open. In obesity, PVAT loses its ability to keep blood vessels open, thus contributing to high blood pressure. Hydrogen sulfide (H2S) is a gas made by blood vessels that is important for keeping blood vessels open. Methionine is an essential amino acid, meaning that we need to get this amino acid from the food we eat. Others have shown that reducing methionine in the diet improves metabolism and markers of diabetes. Here we asked if reducing methionine in food could increase the amount of H2S in blood vessels through increasing expression of specific genes. Using rodents, we fed rats one of four diets: the first had normal fat and normal methionine levels, the second had normal fat and low methionine levels, the third had high fat and normal methionine levels, and the fourth had high fat and low methionine levels. We found that low methionine in the diet prevented weight over time in male rats, but had no effect on blood pressure or blood vessel function. In our study, a high fat diet per se did not cause PVAT dysfunction or increased weight gain. We saw that the expression of the gene Activating Transcription Factor 4 (ATF4) was increased in PVAT, but we did not see a corresponding increase in expression of ATF4 downstream targets in PVAT. Our findings give us important information about new ways to treat obesity and obesity-associated cardiovascular disease.

Technical Abstract: Perivascular adipose tissue (PVAT) regulates vascular tone and high fat diets reportedly lead to the loss of it’s anti-contractile properties. Methionine restriction recapitulates many caloric restriction metabolic effects and increases liver expression of activating transcription factor 4 (ATF4) and downstream targets with anti-contractile properties such as cystathionine-'-synthase (CBS) and cystathionine-'gamma lyase (CSE). We hypothesized that dietary methionine restriction would prevent high fat diet-induced PVAT dysfunction by increasing ATF4 expression. Male Wistar rats were fed control (C, 10% calories from fat) or high fat diets (H, 60% calories from fat) (HFD) that were methionine replete (R, 0.86% methionine) or deplete (D, 0.12% methionine) for 12 weeks. Methionine restriction prevented body mass increases, independent of fat content, and had no effect on blood pressure or arterial contraction to norepinephrine (10 'uM) or relaxation to acetylcholine (10 'uM). In this feeding paradigm, HFD did not induce PVAT dysfunction. CR diet increased ATF4 transcript levels in multiple PVAT depots but did not consistently affect expression of downstream targets. Protein expression of ATF4 and its targets varied largely for all groups. In conclusion, 12 week methionine restriction profoundly affected body mass but not blood pressure or arterial reactivity in the presence or absence of PVAT.