Adipose tissue-specific regulation of angiotensinogen in obese humans and mice: impact of nutritional status and adipocyte hypertrophy

Abstract

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.

Figure 1

Impact of adipose tissue–derived AGT secretion on obesity and blood pressure in humans. (a) Relation between AGT mRNA level and BMI (n = 46). (b) Relationship between adipose tissue–derived AGT secretion (A-AGT-S) and BMI (n = 39). (c) Relationship between A-AGT-S and systolic blood pressure (SBP) (n = 39). (d) Relationship between A-AGT-S and diastolic blood pressure (DBP) (n = 39). AGT, angiotensinogen; BMI, body mass index; LN, natural logarithm.

Figure 2

Expression of genes involved in renin–angiotensin system in obese and weight-losing mouse. AGT mRNA levels in (a) 12W RD (n = 6) and 12W DIO (n = 6) and in (b) 14W DIO (n = 6) and 14W WL (n = 6) in epididymal fat (EF), subcutaneous fat (SF), mesenteric fat (MF), and retroperitoneal fat (RF). AGT mRNA levels in (c) 12W RD and 12W DIO and in (d) 14W DIO and 14W WL in the liver, kidney, and aorta. ACE mRNA levels in (e) 12W RD and 12W DIO and in (f) 14W DIO and 14W WL. AT1aR mRNA levels in (g) 12W RD and 12W DIO and in (h) 14W DIO and 14W WL. White bar, 12W RD; black bar, 12W DIO; vertical striping bar, 14W DIO; diagonal striping bar, 14W WL. *P < 0.01, **P < 0.05. ACE, angiotensin-converting enzyme; AGT, angiotensinogen; AT1aR, angiotensin II type 1a receptor; DIO, diet-induced obesity; WL, weight-losing.

Figure 3

Adipose tissue–derived AGT secretion and plasma AGT level between obese and weight-losing mouse. Adipose tissue–derived AGT secretion (A-AGT-S) in (a) 12W RD (n = 6) and 12W DIO (n = 6) and in (b) 14W DIO (n = 6) and 14W WL (n = 6) in epididymal fat (EF), subcutaneous fat (SF), mesenteric fat (MF), and retroperitoneal fat (RF). Plasma AGT levels in (c) 12W RD and 12W DIO and in (d) 14W DIO and 14W WL. Relationship between A-AGT-S and plasma AGT levels in (e) EF, (f) SF, (g) MF, and (h) RF. White bar, 12W RD; black bar, 12W DIO; vertical striping bar, 14W DIO; diagonal striping bar, 14W WL. *P < 0.01, **P < 0.05, ***P = 0.05. AGT, angiotensinogen; DIO, diet-induced obesity; LN, natural logarithm; WL, weight-losing.

Figure 4

Relationship between cell size and AGT mRNA level in isolated mature adipocytes in humans. (a) AGT mRNA level in stromal-vascular cells (SVCs) and mature adipocytes (MAs) isolated from human subcutaneous abdominal adipose tissue (SAT) (n = 15; BMI: 28 ± 2.5 kg/m²). White bar, SVCs; black bar, MAs. Relationship between BMI and the AGT mRNA level in (b) SVCs or (c) MAs isolated from human SAT. (d) Relationship between the AGT mRNA level in MAs and the average size of large adipocytes in human SAT (n = 15; BMI: 28 ± 2.5 kg/m²). AGT, angiotensinogen; LN, natural logarithm.