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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., (Copyright © 2017 John Wiley & Sons, Inc.)

Background: We have previously shown that antagonism of the mineralocorticoid receptor (MR) results in a potent antiadipogenic activity, in vitro and in vivo. Excessive glucocorticoid exposure is associated with obesity and related disorders in humans and mice., Methods: In this study, responses to a novel combined glucocorticoid receptor (GR)/MR antagonist were investigated in a model of diet-induced obesity. Female 10-week-old C57BL/6J mice were fed with normal chow or a high-fat diet (HFD) for 9 weeks. Mice fed a HFD were concomitantly treated for 9 weeks with the GR antagonist mifepristone (80 mg kg(-1) per day) or the novel combined GR/MR antagonist CORT118335 (80 mg kg(-1) per day). Male, juvenile 6-week-old C57BL/6J mice fed HFD were treated with CORT118335 for 4 weeks., Results: Mice fed a HFD showed a significant increase in total body weight and white fat mass, with impaired glucose tolerance and increased fat infiltration in livers. Interestingly, only CORT118335 completely prevented the HFD-induced weight gain and white fat deposition, whereas mifepristone showed no effect on body weight and modestly increased subcutaneous fat mass. Importantly, food intake was not affected by either treatment, and CORT118335 dramatically increased PGC-1α protein expression in adipose tissue, without any effect on UCP1. Both CORT118335 and mifepristone produced metabolic benefit, improving glucose tolerance, increasing adiponectin plasma levels, decreasing leptin and reducing mean adipocyte size. When tested in vitro, CORT118335 markedly reduced 3T3-L1 differentiation and reversed MR-mediated pro-adipogenic effects of aldosterone; differently, GR-mediated effects of dexamethasone were not antagonized by CORT118335, suggesting that it mostly acts as an antagonist of MR in cultured preadipocytes., Conclusions: Combined GR/MR pharmacological antagonism markedly reduced HFD-driven weight gain and fat mass expansion in mice through the increase in adipose PGC-1α, suggesting that both receptors represent strategic therapeutic targets to fight obesity. The effects of CORT118335 in adipocytes seem predominantly mediated by MR antagonism.

White adipose tissue (WAT) is no longer considered a depot for energy storage in the form of triglycerides, but is a secretory organ that releases factors, known as adipokines, capable of regulating several physiological processes. Alteration of WAT function with subsequent dysfunctional expression and secretion of adipokines plays a key role in the pathogenesis of obesity, diabetes, and other metabolic diseases. For this reason, a deeper understanding of the molecular mechanisms regulating adipocyte function is deemed necessary for planning strategies to treat and prevent obesity and its metabolic complications. This review examines cell culture models currently available for studying adipocyte biology. We focus on advantages, disadvantages and main differences between established preadipocyte cell lines and primary preadipocyte cultures. We revise protocols used to promote adipocyte differentiation and mature adipocytes dedifferentiation into preadipocytes. Finally, we briefly describe co-cultures of adipocytes with other cell types and three-dimensional adipocyte culture systems. These models allow investigation of cell-cell interactions with the cross-talk physiologically occurring between adipocytes and other cell types residing within or outside adipose tissue., ((c) 2010 Wiley-Liss, Inc.)

Beside their role in the control of water and electrolyte homeostasis, recent data clearly indicate that aldosterone and the mineralocorticoid receptor (MR) are involved in adipocyte biology. It has been recently shown that aldosterone promotes white and brown adipocyte differentiation in vitro through specific activation of the MR. In addition, a non-epithelial pro-inflammatory role for MR activation has been recently inferred from studies on mineralocorticoid/salt administration in experimental animal models and from clinical studies. The mineralocorticoid system could hence represent a potential target for new therapeutic strategies in obesity and the metabolic syndrome. Progesterone has high affinity for the MR and is a natural antagonist of aldosterone. Differently from classic synthetic progestins, which are devoid of antimineralocorticoid properties, progesterone and new progestogens show remarkable antimineralocorticoid effects. Here, we discuss the potential role of the antimineralocorticoid properties of progestogens in the control of body weight, adipose tissue proliferation and salt sensitivity; their therapeutic use in postmenopausal women, as well as in women affected by polycystic ovary syndrome, may open new and unexpected possibilities in the treatment of related metabolic disorders.