The renin-angiotensin system in obesity : metabolic and hemodynamic effects

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    Abstract

    Abdominal obesity plays a central role in the metabolic syndrome and is a major risk factor for type 2 diabetes mellitus and cardiovascular disease. Unravelling the underlying mechanisms of obesity and obesity-related metabolic and hemodynamic disorders, such as insulin resistance and hypertension, may increase the rationale for dietary and/or pharmacological strategies to prevent or treat type 2 diabetes and cardiovascular disease.
    There is substantial evidence for the involvement of the renin-angiotensin system (RAS) in obesity-related disorders, as extensively reviewed in chapters 1 and 2. Both animal and human studies support the idea that increased RAS activity may lead to insulin resistance and hypertension. With respect to increased RAS activity in obesity, it is tempting to postulate that the RAS in adipose tissue may exert autocrine, paracrine and/or endocrine effects that may contribute to obesity-related disorders. This thesis describes a variety of studies that investigated local (autocrine/paracrine) and systemic (endocrine) metabolic and hemodynamic effects of the RAS in normal-weight and obese subjects, combining in vivo techniques and in vitro approaches.
    In chapter 3, the endocrine function of locally produced angiotensin II (Ang II) in adipose tissue and skeletal muscle was examined in vivo in humans. We demonstrated that there is no net Ang II release across abdominal subcutaneous adipose tissue and the forearm in lean and obese subjects. This suggests that Ang II that is produced by adipocytes and in skeletal muscle acts as an autocrine/paracrine hormone, but does not contribute to the circulating Ang II concentration. Furthermore, we found that '-adrenergic stimulation increased plasma Ang II concentration in obese, but not lean subjects. Our observations imply that the increased plasma Ang II concentration during '-adrenergic stimulation in obese subjects is explained by other factors than Ang II release from abdominal subcutaneous adipose tissue and/or the forearm. The release of other RAS components, such as angiotensinogen (AGT) and renin, from adipose tissue may be increased during -adrenergic stimulation in obese subjects, which may elevate Ang II generation in the circulation. Alternatively, local Ang II secretion from other tissues than abdominal subcutaneous adipose tissue and the forearm, such as the kidney and liver, may explain this observation.
    Ang II is a potent vasoconstrictor and is an important regulator of blood pressure and fluid homeostasis. Therefore, Ang II may exert vasoconstrictive effects in metabolically active tissues, such as adipose tissue and skeletal muscle. In chapter 4, we showed that local Ang II administration decreases blood flow through adipose tissue and skeletal muscle. These Ang II-induced effects were comparable in normal-weight and obese subjects. The Ang II-induced decrease of adipose tissue and skeletal muscle blood flow may have great impact on metabolism, as blood flow determines the delivery of substrates and hormones to each tissue. A decreased adipose tissue blood flow (ATBF) may reduce triacylglycerol (TAG) clearance by adipose tissue, leading to increased circulating TAG concentrations and an increased delivery of TAG to skeletal muscle, liver and pancreas, which may result in lipid accumulation in these tissues. These events may induce insulin resistance in skeletal muscle and liver, and impair insulin secretion by the pancreas. The decrease in skeletal muscle blood flow evoked by Ang II may affect glucose uptake in this tissue, but this depends on the reduction of blood flow through nutritive vessels. Future research is necessary to examine the effects of the Ang II-induced vasoconstriction in adipose tissue and skeletal muscle on metabolism.
    Based on these findings, we decided to investigate the role of Ang II in ATBF regulation into more detail using the recently developed microinfusion technique, as described in chapter 5. First, we confirmed the findings in chapter 4, showing that Ang II markedly decreases blood flow through abdominal subcutaneous adipose tissue. Secondly, it was demonstrated that circulating Ang II that reaches adipose tissue, rather than locally produced Ang II in adipose tissue, decreases fasting ATBF under physiological conditions. Because Ang II is produced by human adipocytes, these data strongly suggest that locally produced Ang II in adipose tissue acts as an autocrine/paracrine rather than an endocrine hormone, which is in line with our finding that there is no net Ang II release from adipose tissue in humans (chapter 3). Furthermore, Ang II does not appear to be involved in postprandial ATBF regulation, which is in accordance with previous investigations showing that the postprandial enhancement of ATBF is predominantly controlled by the '-adrenergic system. However, the Ang II-induced decrease in fasting ATBF may decrease absolute ATBF after a meal in subjects with increased RAS activity. This may reduce TAG clearance and, therefore, contribute to postprandial hyperlipidemia. Finally, we showed that the Ang II-induced decrease in fasting ATBF is predominantly independent of nitric oxide (NO) action, suggesting that the balance between Ang II and NO activity may be an important determinant of the vascular tone and thus ATBF under fasting conditions.
    As mentioned earlier, the Ang II-induced decrease in ATBF may reduce TAG clearance by adipose tissue. Furthermore, alterations in tissue blood flow may affect lipolysis and thus storage of TAG in adipose tissue. In addition to indirect effects of tissue blood flow on lipolysis, Ang II may exert direct effects on lipolysis. We therefore examined the effects of Ang II on lipolysis in adipose tissue and skeletal muscle in humans. In chapter 4, we demonstrated that Ang II inhibits lipolysis in both tissues in vivo in normal-weight and obese subjects. The antilipolytic effect of Ang II was comparable between groups. To obtain better insight into the dose-response effect of Ang II on lipolysis in adipose tissue, and to assess whether the inhibition of lipolysis was caused by direct effects of Ang II on adipocytes, in vitro lipolysis experiments were initiated, as described in chapter 6. We demonstrated for the first time that Ang II dose-dependently inhibits lipolysis in abdominal subcutaneous adipocytes in normal-weight and obese subjects (maximum inhibition ~20-25%). The antilipolytic effect of Ang II was completely abolished by Ang II type 1 (AT1) receptor blockade, indicating that the Ang II-induced inhibition of lipolysis is mediated through the AT1 receptor. Thus, these in vitro data are in accordance with our findings in vivo, demonstrating that Ang II inhibits lipolysis in adipose tissue. However, the in vitro findings suggest that a physiological Ang II concentration exerts a tonic suppression of lipolysis in human adipocytes. Therefore, Ang II may not play a prominent role in the physiological regulation of fat cell lipolysis in vivo in humans. These findings, together with the reported inhibitory effect of Ang II on adipocyte differentiation in humans, suggest that Ang II may not be involved in the expansion of fat mass in humans. The Ang II-induced inhibition of lipolysis in skeletal muscle may contribute to lipid accumulation in this tissue, but further research is needed to examine the dose-response effect of Ang II on lipolysis in skeletal muscle.
    Long-term clinical trials have demonstrated that blockade of the RAS reduces the incidence of type 2 diabetes mellitus. As described in chapter 7, we performed a double-blind placebo-controlled randomized trial in obese insulin resistant subjects to examine the effects of short-term angiotensin-converting enzyme (ACE) inhibitor treatment on insulin sensitivity. In addition, several proposed mechanisms that may underlie the beneficial effects of RAS blockade on the development of diabetes were examined. We showed that 2-week ACE inhibitor treatment has no significant effects on whole-body insulin sensitivity, forearm blood flow, glucose uptake across the forearm, whole-body substrate oxidation, and intramuscular TAG content. Therefore, it can be tentatively concluded that short-term RAS blockade has no clinically relevant effects on insulin sensitivity. These findings suggest that the beneficial effects of agents that interfere with the RAS on the development of type 2 diabetes may be explained by long-term effects. It has previously been reported that Ang II inhibits adipocyte differentiation and stimulates lipogenesis. These processes, together with the inhibition of fat cell lipolysis by Ang II (chapters 4 and 6), may decrease the buffering capacity for lipid storage in adipose tissue in the long-term, which may result in an excessive influx of TAG and fatty acids to skeletal muscle, liver, and pancreas, leading to insulin resistance and an impaired insulin secretion. Thus, it is tempting to postulate that structural changes in adipose tissue induced by long-term RAS blockade may underlie the reduced incidence of type 2 diabetes observed in several clinical trials.
    The RAS has been established as a major regulator of blood pressure and fluid homeostasis. Although the RAS may play an important role in obesity-related hypertension, the notion that interference with a sole pathophysiological mechanism will substantially facilitate prevention or treatment of hypertension is an oversimplification that ignores the heterogeneous nature of this disorder. Chapter 8 clearly shows that the treatment of obesity-related hypertension is ambiguous, and highlights the role of RAS blockade in the treatment of hypertension in obese individuals. Prospective studies in obese patients are necessary before deciding on the most suitable antihypertensive treatment in these individuals.
    In summary, from the series of studies described in this thesis the main conclusions are that:
    1. locally produced Ang II in adipose tissue and skeletal muscle does not play an endocrine role in humans, indicating that Ang II that is locally produced in these tissues exerts autocrine/paracrine effects.
    2. Ang II inhibits lipolysis in adipose tissue and skeletal muscle in normal-weight and obese subjects. Because physiological Ang II concentrations evoked near-maximal inhibition of fat cell lipolysis, Ang II may not play a prominent role in the regulation of lipolysis in adipose tissue in humans. The Ang II-induced inhibition of lipolysis in skeletal muscle may contribute to lipid accumulation in this tissue.
    3. Ang II is a major regulator of adipose tissue and skeletal muscle blood flow in normal-weight and obese humans. Circulating Ang II rather than locally produced Ang II in adipose tissue is responsible for the Ang II-induced decrease in adipose tissue blood flow. The effects of Ang II on blood flow through adipose tissue were predominantly independent of NO action.
    4. short-term RAS blockade has no significant effects on insulin sensitivity, forearm blood flow, glucose uptake in skeletal muscle, whole-body substrate oxidation, and IMTG content in obese insulin resistant subjects. Therefore, the reduced incidence of type 2 diabetes after long-term RAS blockade appears to be explained by long-term effects that could affect insulin sensitivity and/or insulin secretion.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • Maastricht University
    Supervisors/Advisors
    • Saris, Wim, Supervisor
    • van Baak, Marleen, Advisor
    • Blaak, Ellen, Advisor
    Award date28 Jun 2006
    Place of PublicationMaastricht
    Publisher
    Publication statusPublished - 1 Jan 2006

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