Adipose tissue-specific regulation of angiotensinogen in obese humans and mice: impact of nutritional status and adipocyte hypertrophy.
BACKGROUND
The adipose tissue renin-angiotensin system (RAS) has been implicated in the pathophysiology of obesity and dysfunction of adipose tissue. However, neither regulation of angiotensinogen (AGT) expression in adipose tissue nor secretion of adipose tissue-derived AGT has been fully elucidated in humans.


METHODS
Human subcutaneous abdominal adipose tissue (SAT) biopsies were performed for 46 subjects with a wide range of body mass index (BMI). Considering the mRNA level of AGT and indices of body fat mass, the amount of adipose tissue-derived AGT secretion (A-AGT-S) was estimated. Using a mouse model of obesity and weight reduction, plasma AGT levels were measured with a newly developed enzyme-linked immunosorbent assay (ELISA), and the contribution of A-AGT-S to plasma AGT levels was assessed.


RESULTS
A-AGT-S was substantially increased in obese humans and the value was correlated with the plasma AGT level in mice. A-AGT-S and plasma AGT were higher in obese mice, whereas lower in mice with weight reduction. However, the AGT mRNA levels in the liver, kidney, and aorta were not altered in the mouse models. In both humans and mice, the AGT mRNA levels in mature adipocytes (MAs) were comparable to those in stromal-vascular cells. Coulter Multisizer analyses revealed that AGT mRNA levels in the MAs were inversely correlated with the average size of mature adipocytes.


CONCLUSIONS
This study demonstrates that adipose tissue-derived AGT is substantially augmented in obese humans, which may contribute considerably to elevated levels of circulating AGT. Adipose tissue-specific regulation of AGT provides a novel insight into the clinical implications of adipose tissue RAS in human obesity.
Yasue
Shintaro
S
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Masuzaki
Hiroaki
H
Okada
Sadanori
S
Ishii
Takako
T
Kozuka
Chisayo
C
Tanaka
Tomohiro
T
Fujikura
Junji
J
Ebihara
Ken
K
Hosoda
Kiminori
K
Katsurada
Akemi
A
Ohashi
Naro
N
Urushihara
Maki
M
Kobori
Hiroyuki
H
Morimoto
Naoki
N
Kawazoe
Takeshi
T
Naitoh
Motoko
M
Okada
Mitsuru
M
Sakaue
Hiroshi
H
Suzuki
Shigehiko
S
Nakao
Kazuwa
K
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D000808:Angiotensinogen / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D049108:Cell Enlargement / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008875:Middle Aged; D009752:Nutritional Status; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D000808:Angiotensinogen; D012083:Renin