Effect of Obesity On Adipogenic Differentiation of Adipose Tissue-derived Human Mesenchymal Stem Cells

Jiegen Chen, PhD, Anna Spagnoli, MD, Alfonso Torquati, MD MSCI. Duke University and University of North Carolina – Chapel Hill


Introduction: Adipose tissue dysfunction is an important feature of obesity characterized by marked changes in secretion of adipokines. These result in chronic vascular inflammation, oxidative stress, and activation of the renin-angiotensin system (RAS), eventually leading to cardiovascular disease (CVD). In several trials, bariatric surgery has been demonstrated to significantly reduce the risk of CVD. However there is a gap in knowledge about the molecular mechanisms by which bariatric surgery reduce the burden of CVD in obese individuals. Therefore, the aim of the present work is to study whether surgical induced weight loss regulates the expression of RAS-related genes during adipogenesis.
Method: Mesenchymal stem cells (MSCs) were isolated from adipose tissue collected from the following three groups: 1) non-obese (mean BMI=28) controls (n=11); 2) obese subjects (mean BMI=51) undergoing gastric bypass surgery (GBS); and 3) subjects 1 year or more status post-GBS (mean BMI=30) undergoing elective surgery (n=3). These MSCs were induced to adipogenic differentiation. MSCs were treated with Angiotensin II in combination with Losartan (Angiotensin II receptor 1 blocker) and/or PD123319 (Angiotensin II receptor 2 blocker) during differentiation. Differentiation and RAS-related gene expression were analyzed by quantitative RT-PCR.  GraphPad Prism was used for data analysis.  Student’s t-test was used for group comparisons.
Results: As shown in the Figure, Angiotensinogen mRNA levels in MSCs and differentiated adipocytes were significantly higher (p<0.05) in the obese group than in the non-obese controls. Renin mRNA levels were significantly higher (p<0.05) in the obese group MSCs than in the non-obese and post-GBS groups. Angiotensin converting enzyme (ACE) mRNA levels were significantly lower (p<0.05) in the MSCs and adipocytes derived from the post-GBS group than in obese and non-obese controls. Serum angiotensin II levels were significantly lower (p<0.05) in the post-GBS group (52.1±4.2 pg/ml) than in the non-obese (85.4±12.4 pg/ml) and obese (84.7±10 pg/ml) groups. Angiotensin II treatment inhibited adipose MSCs differentiation into adipocytes in a dose dependent manner. The effect of Angiotensin II was mediated by both receptors. However, the receptor 2 blocker (PD123319) was more effective (p<0.05) in inhibiting Angiotensin II effects than the receptor 1 blocker (Losartan).
Conclusion: The adipogenic differentiation of adipose-derived MSCs is regulated by the RAS. We demonstrated that obese subjects are characterized by an up-regulation of the RAS related gene expressions in the adipose tissue. On the contrary, post-GBS subjects exhibit a pattern of RAS related gene expression similar to non-obese controls. This post-bariatric surgery change in RAS related genes can be one of the mechanism responsible for the CVD risk reduction induced by GBS.

 Figure. Renin-angiotensin system (RAS)-related gene expression during MSCs adipogenesis. Data expressed as mean±S.E.M.  * for p<0.05, non-obese vs. obese in MSCs; # for p<0.05, non-obese vs. post-GBS in MSCs; † for p<0.05, obese vs. post-GBS in MSCs; ‡ for p<0.05, non-obese vs. obese in adipocytes; § for p<0.05, non-obese vs. post-GBS in adipocytes.

Session Number: SS01 – Basic Science
Program Number: S003

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