Open AccessFat‐Specific Protein 27 Regulation of Vascular Function in Human Obesity
Author(s) -
Karki Shakun,
Farb Melissa G.,
Sharma Vishva M.,
Jash Sukanta,
Zizza Elaina J.,
Hess Donald T.,
Carmine Brian,
Carter Cullen O.,
Pernar Luise I.,
Apovian Caroline M.,
Puri Vishwajeet,
Gokce Noyan
Publication year - 2019
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.118.011431
Subject(s) - adipose tissue , endocrinology , medicine , angiogenesis , insulin resistance , lipolysis , vasodilation , gene knockdown , endothelium , obesity , biology , gene , biochemistry
Background Pathophysiological mechanisms that connect obesity to cardiovascular disease are incompletely understood. FSP27 (Fat‐specific protein 27) is a lipid droplet‐associated protein that regulates lipolysis and insulin sensitivity in adipocytes. We unexpectedly discovered extensive FSP 27 expression in human endothelial cells that is downregulated in association with visceral obesity. We sought to examine the functional role of FSP 27 in the control of vascular phenotype. Methods and Results We biopsied paired subcutaneous and visceral fat depots from 61 obese individuals (body mass index 44±8 kg/m 2 , age 48±4 years) during planned bariatric surgery. We characterized depot‐specific FSP 27 expression in relation to adipose tissue microvascular insulin resistance, endothelial function and angiogenesis, and examined differential effects of FSP 27 modification on vascular function. We observed markedly reduced vasodilator and angiogenic capacity of microvessels isolated from the visceral compared with subcutaneous adipose depots. Recombinant FSP 27 and/or adenoviral FSP 27 overexpression in human tissue increased endothelial nitric oxide synthase phosphorylation and nitric oxide production, and rescued vasomotor and angiogenic dysfunction ( P <0.05), while si RNA ‐mediated FSP 27 knockdown had opposite effects. Mechanistically, we observed that FSP 27 interacts with vascular endothelial growth factor‐A and exerts robust regulatory control over its expression. Lastly, in a subset of subjects followed longitudinally for 12±3 months after their bariatric surgery, 30% weight loss improved metabolic parameters and increased angiogenic capacity that correlated positively with increased FSP 27 expression ( r =0.79, P <0.05). Conclusions Our data strongly support a key role and functional significance of FSP 27 as a critical endogenous modulator of human microvascular function that has not been previously described. FSP 27 may serve as a previously unrecognized regulator of arteriolar vasomotor capacity and angiogenesis which are pivotal in the pathogenesis of cardiometabolic diseases linked to obesity.