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Impact of Adrenal Steroids on Regulation of Adipose Tissue

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ABSTRACT

Corticosteroids are secreted by the adrenal glands and control the functions of adipose tissue via the activation of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). In turn, adipocytes release a large variety of adipokines into the bloodstream, regulating the function of several organs and tissues, including the adrenal glands, hereby controlling corticosteroid production. In adipose tissue, the activation of the MR by glucocorticoids (GC) and aldosterone affects important processes such as adipocyte differentiation, oxidative stress, autophagic flux, adipokine expression as well as local production of GC through upregulation of the enzyme 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1). Notably, the proinflammatory responses induced by the MR are counteracted by activation of the GR, whose activity inhibits the expression of inflammatory adipokines. Both GR and MR are deeply involved in adipogenesis and adipose expansion; hence pharmacological blockade of these two receptors has proven effective against adipose tissue dysfunction in experimental models of obesity and metabolic syndrome (MetS), suggesting a potential use for MR and GR antagonists in these clinical settings. Importantly, obesity and Cushing's syndrome (CS) share metabolic similarities and are characterized by high levels of circulating corticosteroids, which in turn are able to deeply affect adipose tissue. In addition, pharmacological approaches aimed at reducing aldosterone and GC levels, by means of the inhibition of CYP11B2 (aldosterone synthase) or 11β‐HSD1, represent alternative strategies to counter the detrimental effects of excessive levels of corticosteroids, which are often observed in obesity and, more general, in MetS. © 2017 American Physiological Society. Compr Physiol 7:1425‐1447, 2017.

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Figure 1. Figure 1. MR hyperactivation leads to detrimental effects on adipose tissue metabolism. Different cell types are present in adipose tissue, including adipocytes and macrophages (both expressing MR). Activation of MR in the adipocyte promotes adipogenesis, ROS production, and autophagic flux. Notably, MR activity represses conversion of white into brown adipocytes, a phenomenon that has been shown to display a protective role against obesity and insulin resistance, at least in experimental murine models. Adipocyte MR activation promotes inflammation through increased expression of TNF‐α, IL‐6, and MCP‐1, that in turn favors macrophage recruitment into adipose tissue. MR activation also up‐regulates the expression of the enzyme 11β‐HSD1, with a subsequent increase in local production of glucocorticoids (GC) (). Interestingly, macrophage MR activity promotes polarization toward the M1 phenotype, which exhibits proinflammatory functions. Thus, hyperactivation of MR, both in adipocytes and in macrophages, has deleterious effects on adipose tissue. In addition, local production of aldosterone has been recently described in adipose tissue, with potential enhancement of MR activation in resident cell types expressing MR.
Figure 2. Figure 2. Novel fat‐adrenal axis. Both aldosterone and GC, released by the adrenal glands, are able to activate MR and GR in the adipose tissue where, considering the lack of 11β‐HSD2, a prevalent activation of MR by GC is expected. MR activation promotes adipose tissue expansion, oxidative stress, inflammation, and autophagic flux. Of note, GC activate GR, which induces anti‐inflammatory effects through inhibition of TNF‐α, IL‐6, and MCP‐1 expression. On the other hand, adipose tissue releases into the bloodstream CTRP1, leptin, and other factors capable to increase aldosterone synthesis by the adrenal gland. In particular, activation of the adipocyte MR leads to increased leptin expression that, once released into circulation, can reach the adrenal cortex and stimulate transcription of the CYP11B2 gene, thereby increasing aldosterone production.
Figure 3. Figure 3. In vitro and in vivo effects of pharmacological antagonism of MR and GR on adipose tissue. (A) Differentiating 3T3‐L1 preadipocytes treated with aldosterone show increased accumulation of intracellular lipids (as displayed by Oil‐Red‐O staining). Conversely, treatment with MR antagonist (spironolactone) inhibits intracellular lipid accumulation. These data suggest that MR is important for adipogenesis. (B) Treatment of differentiating 3T3‐L1 preadipocytes with either MR antagonist (spironolactone), GR antagonist (mifepristone), or combined GR/MR antagonist (CORT118335) blocks intracellular lipid accumulation, showing that both MR and GR play a relevant role in adipocyte maturation. (C, D) Treatment of mice fed an HFD with CORT118335 leads to a remarkable reduction of body weight (C) and abdominal fat mass (D), indicating that combined GR/MR antagonism powerfully prevents HFD‐induced adipose tissue expansion.


Figure 1. MR hyperactivation leads to detrimental effects on adipose tissue metabolism. Different cell types are present in adipose tissue, including adipocytes and macrophages (both expressing MR). Activation of MR in the adipocyte promotes adipogenesis, ROS production, and autophagic flux. Notably, MR activity represses conversion of white into brown adipocytes, a phenomenon that has been shown to display a protective role against obesity and insulin resistance, at least in experimental murine models. Adipocyte MR activation promotes inflammation through increased expression of TNF‐α, IL‐6, and MCP‐1, that in turn favors macrophage recruitment into adipose tissue. MR activation also up‐regulates the expression of the enzyme 11β‐HSD1, with a subsequent increase in local production of glucocorticoids (GC) (). Interestingly, macrophage MR activity promotes polarization toward the M1 phenotype, which exhibits proinflammatory functions. Thus, hyperactivation of MR, both in adipocytes and in macrophages, has deleterious effects on adipose tissue. In addition, local production of aldosterone has been recently described in adipose tissue, with potential enhancement of MR activation in resident cell types expressing MR.


Figure 2. Novel fat‐adrenal axis. Both aldosterone and GC, released by the adrenal glands, are able to activate MR and GR in the adipose tissue where, considering the lack of 11β‐HSD2, a prevalent activation of MR by GC is expected. MR activation promotes adipose tissue expansion, oxidative stress, inflammation, and autophagic flux. Of note, GC activate GR, which induces anti‐inflammatory effects through inhibition of TNF‐α, IL‐6, and MCP‐1 expression. On the other hand, adipose tissue releases into the bloodstream CTRP1, leptin, and other factors capable to increase aldosterone synthesis by the adrenal gland. In particular, activation of the adipocyte MR leads to increased leptin expression that, once released into circulation, can reach the adrenal cortex and stimulate transcription of the CYP11B2 gene, thereby increasing aldosterone production.


Figure 3. In vitro and in vivo effects of pharmacological antagonism of MR and GR on adipose tissue. (A) Differentiating 3T3‐L1 preadipocytes treated with aldosterone show increased accumulation of intracellular lipids (as displayed by Oil‐Red‐O staining). Conversely, treatment with MR antagonist (spironolactone) inhibits intracellular lipid accumulation. These data suggest that MR is important for adipogenesis. (B) Treatment of differentiating 3T3‐L1 preadipocytes with either MR antagonist (spironolactone), GR antagonist (mifepristone), or combined GR/MR antagonist (CORT118335) blocks intracellular lipid accumulation, showing that both MR and GR play a relevant role in adipocyte maturation. (C, D) Treatment of mice fed an HFD with CORT118335 leads to a remarkable reduction of body weight (C) and abdominal fat mass (D), indicating that combined GR/MR antagonism powerfully prevents HFD‐induced adipose tissue expansion.
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Teaching Material

M. Infante, A. Armani, C. Mammi, A. Fabbri, M. Caprio. Impact of Adrenal Steroids on Regulation of Adipose Tissue. Compr Physiol 7: 2017, 1425-1447. doi:10.1002/cphy.c160037

Didactic Synopsis

Major Teaching Points:

  1. Understanding the physiology of adipose tissue is essential for the comprehension of its complex cross talk with other organs.
  2. Adrenal steroids play a pivotal role in the regulation of adipose tissue through activation of their nuclear receptors, GR and MR.
  3. Activation of GR or MR displays distinct effects on adipose tissue differentiation, inflammation, and browning.
  4. Adipose tissue-derived factors have a strong impact on aldosterone production by the adrenal glands.
  5. The existence of a bidirectional fat-adrenal endocrine axis provides novel therapeutic perspectives for the treatment of obesity and metabolic syndrome.

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: This figure illustrates that MR is expressed in adipocytes and macrophages infiltrating adipose tissue. MR activity in both cell types is modulated by circulating GC and aldosterone; also, it was recently reported that adipose tissue itself is able to synthesize aldosterone, which could further activate MR. A better comprehension of the regulation of adipocyte function and macrophage polarization by MR could clarify mechanisms leading to adipose tissue dysfunction induced by high levels of GC and aldosterone.

Figure 2. Teaching points: This figure shows that the hormonal cross talk between the adrenal gland and adipose tissue is mediated by corticosteroids and adipokines. GC secreted by the adrenal glands lead to MR-mediated inflammation, oxidative stress, and a high autophagic rate. In dysfunctional adipocytes, MR hyperactivation results in increased secretion of adipokines (in particular leptin), which are capable of promoting aldosterone synthesis. The altered function of adipocyte MR is able to affect aldosterone secretion and has a causal role in favoring cardiovascular alterations related to obesity. The recent discovery that MR regulates the expression of adipokines, modulating aldosterone production, suggests that the beneficial effects of MR antagonists in patients with cardiovascular disease could be mediated by adipose MR blockade.

Figure 3. Teaching points: MR has a central role in adipogenesis. Pharmacological activation (by aldosterone) or blockade (by MR antagonist) of MR in preadipocyte cultures promotes or represses, respectively, adipocyte differentiation (Panel A). Because of the extremely low levels of 11β-HSD2, adipocyte MR is mainly activated by GC. However, GC also activate adipocyte GR, whose involvement in adipogenesis is important; in fact, GR antagonism in preadipocyte cultures inhibits adipogenesis. Therefore, it is well established that both MR and GR antagonism are able to regulate preadipocyte differentiation (Panel B), although their reciprocal interplay still needs to be clarified. Treatment of mice fed HFD with the combined GR/MR antagonist CORT118335 markedly represses HFD-induced fat mass expansion, underlying that both MR and GR play a crucial role in adipose tissue plasticity. Indeed, combined GR/MR blockade by CORT118335 prevents HFD-induced body weight gain and excessive expansion of adipose tissue, leading to beneficial systemic metabolic effects (Panel C, D).


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How to Cite

Marco Infante, Andrea Armani, Caterina Mammi, Andrea Fabbri, Massimiliano Caprio. Impact of Adrenal Steroids on Regulation of Adipose Tissue. Compr Physiol 2017, 7: 1425-1447. doi: 10.1002/cphy.c160037