Blockade of mineralocorticoid receptor reverses adipocyte dysfunction and insulin resistance in obese mice

Abstract

MR blockade attenuates obesity-related insulin resistance partly through reduction of fat ROS production, inflammatory process, and induction of cytokines.

Obesity and corticosteroids: 11β-Hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease

“…11 -HSD2, whilst consistently lower than 11 -HSD1 was also reduced in adipose from obese women (Engeli et al, 2004) and may be expressed predominantly in the stromal compartment M a n u s c r i p t 8 of human visceral fat (Lee et al, 2008). This would make sense as aldosterone has been implicated in preadipocyte differentiation and adipokine expression in adipose, among other functions (Guo et al, 2008, Hirata et al, 2009. If confirmed, this may also account for the increased cortisone levels found in the portal vein (along with intestinal 11 -HSD2) of obese humans (Basu et al, 2008).…”

“…The role and direct effects of 11 -HSD1 in subpopulations of the endocrine pancreas during the inflammatory processes of diabetes (Donath et al, 2005) and in skeletal muscle with insulin resistance also require clarification. Finally, it is important to note that with inhibition of cortisol regeneration as a therapeutic strategy, care must be taken to consider effects in cells also expressing MR and low levels of the cortisol-inactivating 11 -HSD2 enzyme, potentially even the adipocytes and A c c e p t e d M a n u s c r i p t 18 macrophages (Hirata et al, 2009, Gilmour et al, 2006. Notably, cortisol cannot distinguish between MR and GR whereas the potent anti-inflammatory steroid dexamethasone (note: 11keto-dexamethosone activates GR comparably) despite binding MR with higher affinity than GR, does not transactivate MR-mediated gene transcription (Rebuffat et al, 2004).…”

Comparison of eplerenone and spironolactone for the treatment of primary aldosteronism

“…Eplerenone improves obesity-related insulin resistance through the reduction of fat reactive oxygen species (ROS) production, inflammatory processes, and induction of cytokines in ob/ob mice. [13].…”

Marine natural product des-O-methyllasiodiplodin effectively lowers the blood glucose level in db/db mice via ameliorating inflammation

“…In addition, NADPH oxidase-induced highly toxic ROS may cause tissue injury during inflammation [37] . In this respect, the transcription factor PU.1 is essential for NADPH oxidase subunit p47 promoter activity [38] , and PU.1 and p47 subunit expression is closely involved in ROS generation [33] . Here, we discovered that the marine natural product DML showed effective antiinflammatory activity, as indicated by its regulation of TNFα, MCP-1, IL-6, PU.1 and NADPH p47 subunit genes, both in vitro and in vivo.…”

“…Spironolactone (Spir) and eplerenone (Eple), known MR antagonists, have been shown to be useful in the treatment of hypertension and heart failure [29,30] , the reversal of obesity-related changes in pro-inflammatory adipokines and the amelioration of adipocyte dysfunction and insulin resistance [31][32][33] . In addition, the production of pro-inflammatory factors such as TNF-α, MCP-1, and IL-6 was attenuated by Eple both in liver and adipose tissue via the suppression of reactive oxygen species (ROS) [33] , and Spir improved glucose and lipid metabolism by ameliorating inflammation in high-fat and high-fructose diet mice [31] . Many prior studies have addressed the potency of MR antagonists in the regulation of obesity-related pathological processes.…”