The renin angiotensin system and the metabolic syndrome

Abstract

The renin angiotensin system (RAS; most well-known for its critical roles in the regulation of cardiovascular function and hydromineral balance) has regained the spotlight for its potential roles in various aspects of the metabolic syndrome. It may serve as a causal link among obesity and several co-morbidities. Drugs that reduce the synthesis or action of angiotensin-II (A-II; the primary effector peptide of the RAS) have been used to treat hypertension for decades and, more recently, clinical trials have determined the utility of these pharmacological agents to prevent insulin resistance. Moreover, there is evidence that the RAS contributes to body weight regulation by acting in various tissues. This review summarizes what is known of the actions of the RAS in the brain and throughout the body to influence various metabolic disorders. Special emphasis is given to the role of the RAS in body weight regulation. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.

Figure 1. The classical (endocrine) renin angiotensin system

A-II is formed from liver-synthesized angiotensinogen via a series of proteolytic cleavage events. Angiotensinogen is first cleaved by the rate-limiting enzyme renin (formed in and secreted from the kidney) into A-I. A-I is then processed by ACE (from the lung) into A-II. Circulating A-II activates AT₁ and AT₂ receptors in various tissues, such as the brain, adrenal and vascular tissue to modulate cardiovascular and hydromineral homeostasis.

Figure 2. The updated renin angiotensin system

In addition to the classical enzymatic cascade for A-II synthesis, there are several alternative pathways for A-II synthesis. Binding of prorenin to the (pro)renin receptor activates intracellular signaling pathways and also allows for the conversion of angiotensinogen to A-I by the prorenin/(pro)renin receptor complex. There are also alternative active angiotensin peptides, including angiotensin (1–7) and angiotensin-IV that are formed by other enzymes. These peptides activate the Mas and angiotensin type-4 (AT₄; insulin-regulated aminopetidase [IRAP]) receptors, respectively.

Figure 3. Proposed energy and glucose homeostasis-modulatory actions of A-II in various tissues

These tissues also contain local RASs, indicating that A-II’s influence may be autocrine, paracrine or endocrine.