Emerging Concept of Adipogenesis Regulation by the Renin–Angiotensin System
The renin–angiotensin system (RAS) has been the focus of attention not only for its classical action through circulating RAS but also its local actions in tissues such as the brain,1 liver,2 lung,3 and adipose tissue.4 The roles of the local RAS in adipose tissue have recently been highlighted, because obesity is one of the major risks for the metabolic syndrome with hypertension and glucose intolerance. However, there have been inconsistent reports on the role of the adipose tissue RAS. The role of local RAS in adipogenesis has been discussed but is not well elucidated.
In this issue of Hypertension, Matsushita et al5 examined the role of local RAS during adipocyte differentiation using human mesenchymal stem cells (MSCs) instead of preadipocytes in an elegant fashion. They reported the influence of RAS on MSCs as follows (Figure 1): (1) Comparison of the expression of RAS components between MSCs and differentiated adipocytes revealed that mRNA of renin and the angiotensin II (Ang II) type-2 (AT2) receptor were highly expressed, and Ang II concentration was significantly increased in differentiated adipocytes; (2) administration of Ang II with or without an Ang II type-1 (AT1) receptor blocker (ARB), valsartan, in MSC during adipogenesis showed that Ang II inhibited adipogenesis, and AT2 receptor activation by valsartan further inhibited it; and (3) moreover, treatment with valsartan alone also inhibited adipocyte differentiation. These results suggest that the local RAS, especially AT2 receptor signaling, has a crucial role in adipogenesis.
Evidence has accumulated that AT2 receptor stimulation not only opposes the AT1 receptor but also has unique effects independent of an interaction with AT1 receptor signaling. The AT2 receptor is reported to be widely expressed in the fetal-placental unit6 but is observed at low levels in adult tissues and is re-expressed in some pathological conditions,7 indicating important roles of AT2 receptor activation in tissue regeneration. Our recent report demonstrated possible AT2 receptor-induced differentiation of neurospheres to “neurons” but not to “glia cells”1 indicating that AT2 receptor signaling could regulate stem-progenitor cell fate. However, the regulatory effects of the AT2 receptor on other nondifferentiated cells have not been investigated. Many types of cells exist in adipose tissue. Stem cells, including MSCs, constitute a part of the tissue and have the potential to be pluripotential self-renewing cells.8 MSCs are thought to be involved in repair of tissue damage and regeneration because of their ability of “transdifferentiation” to ectodermal lineages and easy expansion in culture. Therefore, the regulatory mechanism of MSC differentiation is expected to contribute to therapeutic approaches to intractable diseases,9 such as dilated cardiomyopathy, neural injury, muscular dystrophy, leukemia, and other cancers. The inhibitory effect of differentiation or activation of dedifferentiation in MSCs by AT2 receptor stimulation via an autocrine or paracrine Ang II demonstrated by Matsushita et al5 may provide a new insight into a crucial role of the local RAS and also impacts on stem cell biology. However, several questions still remain. What is the downstream mediator of the AT2 receptor to inhibit MSC differentiation? What are the AT2 receptor-stimulated MSCs? Are they adipocytes, preadipocytes, progenitor cells with adipocyte characteristics, or a mixture of these various cells? Further investigations, such as examination of the cell characteristics and the transdifferentiation potential of AT2 receptor-stimulated MSCs, are needed.
The association between Ang II and adipogenesis is complicated, based on previous results as shown in Figure 2. There are ≥2 differentiation steps involved in adipogenesis, “from MSC to adipocytes” and “from preadipocytes to adipocytes.” The inhibitory effects of Ang II seem to differ between MSCs and preadipocyte differentiation. Sharma et al4 hypothesized that Ang II inhibits preadipocyte differentiation, thereby resulting in large insulin-resistant adipocytes with increased storage of lipids. In contrast, blockade of RAS promotes recruitment of preadipocytes, thereby increasing the number of small insulin-sensitive adipocytes. This hypothesis is supported by the observation by Furuhashi et al10 that an ARB, olmesartan, significantly reduced adipocyte size in fructose-fed rats, with improvement of glucose intolerance. In association with preadipocyte differentiation, ARB increased well-differentiated adipocytes, which can secrete inflammatory adipocytokines, such as tumor necrosis factor (TNF)-α, and more beneficial adipocytokines, such as adiponectin. On the other hand, in MSC differentiation, ARB increased less differentiated adipocytes, such as progenitors with adipocyte characteristics, which secrete less adipocytokines and may have transdifferentiation potential (Figure 2). ARB has 2 different effects: blockade of AT1 receptors and increased stimulation of AT2 receptors. Matsushita et al5 showed that AT2 receptor activation inhibits stem cell differentiation and prevents them from achieving their cell fate. The effects of an ARB on this differentiation are mediated by AT2 receptor stimulation rather than by AT1 receptor blockade. In contrast, the effect of ARB on preadipocyte differentiation is to increase “well differentiated adipocytes” rather than “poorly differentiated adipocytes.” Poorly differentiated large insulin-resistant adipocytes could exaggerate inflammation and metabolic abnormalities. The effects of ARB in this differentiation seem to be mediated by the AT1 receptor–blocking effect and at least partly by AT2 receptor stimulation. Thus, ARBs have 2 different possible beneficial effects on adipocyte differentiation, resulting in improvement of the metabolic syndrome.
The regulatory mechanisms of the balance of AT1 and AT2 receptor stimulation by endogenous Ang II during MSC differentiation are under consideration. Matsushita et al5 indicate an enhancing effect of AT1 receptor activation on adipogenesis; however, such an effect through endogenous Ang II is weaker than that of AT2 receptor signal blockade. The detailed downstream targets in MSC differentiation through the AT1 and AT2 receptor have not been revealed, and this should be addressed to elucidate the role of RAS in the metabolic syndrome. As the authors indicated, further investigations by in vitro and in vivo assays using Ang II receptor–null mice are needed.
In conclusion, recent clinical studies indicate that blockade of RAS is effective to prevent the primary onset of type-2 diabetes mellitus, and basic research supports these clinical outcomes, although the role of RAS in obesity is still an enigma. In this respect, Matsushita et al5 provide a timely new insight into the local RAS, linking it to the metabolic syndrome, and provide the basis for potential therapeutic benefit to prevent the metabolic syndrome by blockade of RAS with an ARB.
Sources of Funding
This work was supported by grants from the Ministry of Education, Science, Sports, and Culture of Japan, and the Novartis Foundation for Gerontological Research (to M.H.).
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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