Obesity-related hypertension: the contribution of PPAR gamma acetylation and asprosin - Abstract
Obesity affects 1 in 3 adults in the US and is a major risk factor for the development of hypertension, a leading
cause of cardiovascular disease and death worldwide. While obesity accounts for 70% of cases of essential
hypertension, the mechanisms governing obesity-related hypertension remain unresolved. Currently there are
no anti-hypertensive drugs designed to treat hypertension specifically in obese patients and targeted therapy to
treat this at-risk population is urgently needed. Studies have also associated obesity to stiffening of large arteries,
an independent predictor for cardiovascular events that appears to precede the development of hypertension.
The goal of this application is to elucidate the mechanism(s) by which obesity increases arterial stiffness and
blood pressure. Clinical and experimental evidence shows that the fat surrounding arteries, termed perivascular
adipose tissue (PVAT), and peroxisome proliferator-activated receptor gamma (PPARγ) possess physiologically
protective effects on the vascular system. Our preliminary data shows that western diet-induced obese mice
exhibited aortic stiffness and high blood pressure, which was accompanied by hyperacetylation of PPARγ in
PVAT. Furthermore, levels of asprosin, a newly discovered adipokine, is increased in the serum and thoracic
aorta and mesenteric PVAT from obese mice. Our preliminary functional data in mesenteric arteries reveal that
asprosin potentiates vasoconstriction and impairs vasodilation, indicating a direct effect of asprosin in the
vascular function. Strikingly, aortic stiffness was mitigated in our mice genetically engineered to mimic PPARγ
deacetylation (called 2KR mice) fed a western diet. Our central hypothesis is that the PPARγ hyperacetylation-
asprosin pathway in adipose tissue contributes to obesity-related aortic stiffness and hypertension. Thus, PPARγ
deacetylation would be expected to protect against vascular disorders caused by obesity. The overarching goal
of this work is to provide rigorous scientific evidence to support a therapeutic benefit of PPARγ
deacetylation in obese patients suffering from hypertension. To address our hypothesis, two aims are
proposed: (Aim 1) study whether 2KR mice are protected against obesity-induced aortic stiffness and
hypertension. Aim 2) determine whether asprosin is downstream to PPARγ hyperacetylation and study its effects
on vascular function. We will use a mice model of western diet-induced obesity and 2KR mice. In vivo, ex vivo
and in vitro approaches in combination with pharmacological and genetic approaches will be employed to study
the effects of PPARγ deacetylation and asprosin in vascular functionality. Successful completion of this project
will provide novel insights into the mechanisms of the PPARγ acetylation-asprosin pathway, contribute to our
understanding of obesity-related hypertension and aortic stiffness, and identify PPARγ deacetylation as a
potential new therapeutic target for the treatment of hypertension. Support of this proposal by REAP will promote
an innovative research environment at NYIT, enhance diversity in science and provide opportunities for our
students to participate in clinically relevant research that may change the course of patient care.
