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Regulation and Functions of the Renin‐Angiotensin System in White and Brown Adipose Tissue

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ABSTRACT

The renin angiotensin system (RAS) is a major regulator of blood pressure, fluid, and electrolyte homeostasis. RAS precursor angiotensinogen (Agt) is cleaved into angiotensin I (Ang I) and II (Ang II) by renin and angiotensin converting enzyme (ACE), respectively. Major effects of Ang II, the main bioactive peptide of this system, is mediated by G protein coupled receptors, Angiotensin Type 1 (AGTR1, AT1R) and Type 2 (AGTR2, AT2R) receptors. Further, the discovery of additional RAS peptides such as Ang 1‐7 generated by the action of another enzyme ACE2 identified novel functions of this complex system. In addition to the systemic RAS, several local RAS exist in organs such as the brain, kidney, pancreas, and adipose tissue. The expression and regulation of various components of RAS in adipose tissue prompted extensive research into the role of adipose RAS in metabolic diseases. Indeed, animal studies have shown that adipose‐derived Agt contributes to circulating RAS, kidney, and blood pressure regulation. Further, mice overexpressing Agt have high blood pressure and increased adiposity characterized by inflammation, adipocyte hypertrophy, and insulin resistance, which can be reversed at least in part by RAS inhibition. These findings highlight the importance of this system in energy homeostasis, especially in the context of obesity. This overview article discusses the depot‐specific functions of adipose RAS, genetic and pharmacological manipulations of RAS, and its applications to adipogenesis, thermogenesis, and overall energy homeostasis. © 2017 American Physiological Society. Compr Physiol 7:1137‐1150, 2017.

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Figure 1. Figure 1. Origin of different adipocyte types and their association with obesity. Brown adipocytes originate from a subset of dermomyotomal precursors (A). White adipocytes originate from mesodermal stem cells (B and C). Beige adipocytes are hypothesized to be derived from beige precursors (C) or transdifferentiation from mature white adipocytes (B). Beige adipocyte differentiation is induced by cold exposure and beta‐agonists.
Figure 2. Figure 2. Components of the RAS. In the classical RAS pathway, angiotensinogen (Agt) is cleaved by renin into Angiotensin I (Ang I), which is cleaved by angiotensin converting enzyme (ACE) to produce the active hormone, Angiotensin II. Agt is produced mainly by the liver, while WAT also contributes to Agt levels, especially in obese individuals. Ang II binds to G protein coupled receptors ATR1 and ATR2 to mediate its effects. ACE2, homolog of ACE divides this axis into other branch and cleaves Ang I and Ang II into Ang 1‐9 which is then converted to Ang 1‐7, the active peptide. Ang 1‐7 binds to the Mas receptor and opposes the actions of Ang II. The prorenin/renin receptor [(P)RR] is another component of the RAS which upon binding with renin induces nonproteolytic activation of pro/renin and increases the efficiency of the Agt cleavage to Ang I.
Figure 3. Figure 3. Mechanisms of WAT RAS effects. WAT expresses all components of the RAS. Agt and Ang II production are stimulated by nutrients such as long‐chain fatty acids and glucose, hormones such as insulin and cytokines. Ang II binds to AT1R and activates NADPH oxidase to increase reactive oxygen species (ROS) production, which in turn activates the Nf‐kb pathway, leading to transcription of proinflammatory genes such as Resistin, PAI‐1 and MCP‐1. Ang II binding to AT1R also has an inhibitory effect on adipogenesis and lipolysis. Ang II also binds to AT2R, which increases production of key lipogenic enzymes and leads to lipogenesis. Thus, the net effect of RAS on WAT is to increase lipid storage. Renin binds to the pro/renin receptor [(P)RR] which increases the efficiency of Ang II production, thus indirectly promoting lipid storage. Ang 1‐7, produced by subsequent cleavages of Ang I and Ang II, binds to the Mas receptor and exerts anti‐inflammatory actions in WAT.
Figure 4. Figure 4. RAS function in BAT. Brown adipocytes and some white adipocytes respond to cold exposure through actions of the sympathetic nervous system (SNS) to increase Ang II production. Ang II facilitates presynaptic norepinephrine release as well as reduces neuronal uptake, enhancing sympathetic‐mediated cold‐induced thermogenesis of BAT. This contributes to increased Ucp1 expression, nonshivering thermogenesis in BAT, increased energy expenditure, metabolic rate, and fatty acid oxidation.


Figure 1. Origin of different adipocyte types and their association with obesity. Brown adipocytes originate from a subset of dermomyotomal precursors (A). White adipocytes originate from mesodermal stem cells (B and C). Beige adipocytes are hypothesized to be derived from beige precursors (C) or transdifferentiation from mature white adipocytes (B). Beige adipocyte differentiation is induced by cold exposure and beta‐agonists.


Figure 2. Components of the RAS. In the classical RAS pathway, angiotensinogen (Agt) is cleaved by renin into Angiotensin I (Ang I), which is cleaved by angiotensin converting enzyme (ACE) to produce the active hormone, Angiotensin II. Agt is produced mainly by the liver, while WAT also contributes to Agt levels, especially in obese individuals. Ang II binds to G protein coupled receptors ATR1 and ATR2 to mediate its effects. ACE2, homolog of ACE divides this axis into other branch and cleaves Ang I and Ang II into Ang 1‐9 which is then converted to Ang 1‐7, the active peptide. Ang 1‐7 binds to the Mas receptor and opposes the actions of Ang II. The prorenin/renin receptor [(P)RR] is another component of the RAS which upon binding with renin induces nonproteolytic activation of pro/renin and increases the efficiency of the Agt cleavage to Ang I.


Figure 3. Mechanisms of WAT RAS effects. WAT expresses all components of the RAS. Agt and Ang II production are stimulated by nutrients such as long‐chain fatty acids and glucose, hormones such as insulin and cytokines. Ang II binds to AT1R and activates NADPH oxidase to increase reactive oxygen species (ROS) production, which in turn activates the Nf‐kb pathway, leading to transcription of proinflammatory genes such as Resistin, PAI‐1 and MCP‐1. Ang II binding to AT1R also has an inhibitory effect on adipogenesis and lipolysis. Ang II also binds to AT2R, which increases production of key lipogenic enzymes and leads to lipogenesis. Thus, the net effect of RAS on WAT is to increase lipid storage. Renin binds to the pro/renin receptor [(P)RR] which increases the efficiency of Ang II production, thus indirectly promoting lipid storage. Ang 1‐7, produced by subsequent cleavages of Ang I and Ang II, binds to the Mas receptor and exerts anti‐inflammatory actions in WAT.


Figure 4. RAS function in BAT. Brown adipocytes and some white adipocytes respond to cold exposure through actions of the sympathetic nervous system (SNS) to increase Ang II production. Ang II facilitates presynaptic norepinephrine release as well as reduces neuronal uptake, enhancing sympathetic‐mediated cold‐induced thermogenesis of BAT. This contributes to increased Ucp1 expression, nonshivering thermogenesis in BAT, increased energy expenditure, metabolic rate, and fatty acid oxidation.
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Teaching Material

M. Pahlavani, N. S. Kalupahana, L. Ramalingam, N. Moustaid-Moussa. Regulation and Functions of the Renin-Angiotensin System in White and Brown Adipose Tissue. Compr Physiol 7: 2017, 1137-1150. doi:10.1002/cphy.c160031

Didactic Synopsis

Major teaching points:

  1. Understanding the role of renin angiotensin system (RAS) beyond regulation of blood pressure, fluid and electrolyte balance.
  2. In addition to the classically known systemic RAS, several local RAS exist in other tissues including both white and brown adipose tissue.
  3. Adipose tissue RAS is an important regulator not only of adipose tissue metabolism, but also of whole body energy, blood pressure and glucose homeostasis.
  4. Adipose tissue dysfunction is associated with increased Ang II levels and obesity. Various inhibitors of the RAS pathway have been tested in clonal adipocytes, rodent models, and clinical studies, which consistently demonstrate that reducing angiotensin levels decreases obesity-associated inflammation.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: Two functionally different types of adipose tissues, which originate from different precursor cells coexist. White and brown adipocytes develop from specific precursors. Beige adipocytes, on the other hand, can transdifferentiate from white adipocytes due to external stimuli.

Figure 2. Teaching points: The renin angiotensin system is a hormonal system. It starts with the precursor angiotensinogen (Agt), initially known to be secreted by the liver. Agt is cleaved by two different enzymes (renin then angiotensin converting enzyme) leading to synthesis of biologically active peptide angiotensin (Ang) II. Ang II then binds to different angiotensin receptors to mediate its biological effects. The contemporary understanding of RAS has expanded with the discovery of other enzymes, Ang peptides and receptors in this system.

Figure 3. Teaching points: RAS pathway is abnormally activated in obesity leading to increased reactive oxygen species production, higher lipogenesis causing increased lipid storage and elevated inflammation, primarily in white adipose tissue.

Figure 4. Teaching points: RAS is activated by external stimuli in brown adipose tissue, which increases the brown fat specific protein, uncoupling protein 1 (UCP1) expression, and thermogenesis. These effects may increase energy expenditure and can potentially reduce obesity.


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How to Cite

Mandana Pahlavani, Nishan. S Kalupahana, Latha Ramalingam, Naima Moustaid‐Moussa. Regulation and Functions of the Renin‐Angiotensin System in White and Brown Adipose Tissue. Compr Physiol 2017, 7: 1137-1150. doi: 10.1002/cphy.c160031