FOXO1-dependent up-regulation of MAP kinase phosphatase 3 (MKP-3) mediates glucocorticoid-induced hepatic lipid accumulation in mice

Abstract

Long-term treatment with glucocorticoids (GCs) or dysregulation of endogenous GC levels induces a series of metabolic diseases, such as insulin resistance, obesity and type 2 diabetes. We previously showed that MAP kinase phosphatase-3 (MKP-3) plays an important role in glucose metabolism. The aim of this study is to investigate the role of MKP-3 in GC-induced metabolic disorders. Dexamethasone (Dex), a synthetic GC, increases MKP-3 protein expression both in cultured hepatoma cells and in the liver of lean mice. This effect is likely mediated by forkhead box protein O1 (FOXO1) because disruption of endogenous FOXO1 function by either interfering RNA mediated FOXO1 knockdown or overexpression of a dominant negative FOXO1 mutant blocks Dex-induced upregulation of MKP-3 protein. In addition, overexpression of FOXO1 is sufficient to induce MKP-3 protein expression. MKP-3 deficient mice are protected from several side effects of chronic Dex exposure, such as body weight gain, adipose tissue enlargement, hepatic lipid accumulation, and insulin resistance. The beneficial phenotypes in mice lacking MKP-3 are largely attributed to the absence of MKP-3 in the liver since only hepatic insulin signaling has been preserved among the three insulin target tissues (liver, muscle and adipose tissue).

How much we know about the attenuation of insulin signaling in the adipose tissue caused by glucocorticoid treatment?

“…Furthermore, rats treated with dexamethasone [15] and corticosterone [10] for 5 or 10 consecutive days, respectively, also develop augmented lipolysis rate preferentially under basal condition. This dual effect of GCs on visceral fat (induction of adipogenesis and lipolysis) corroborates to the expansion of abdominal fat and to the increase of hepatic flux of lipids that may lead to hepatosteatosis [10,17] . For comprehensive reviews about the effects of GCs in the adipose tissue biology and the development of central obesity refers to [12,13] .…”

“…Studies performed in vitro (hepatocytes) and in vivo (lean mice) revealed that mitogen-activated protein (MAP) kinase phosphatase (MKP)-3 is a downstream component of dexamethasone effects [17] . In this study the authors demonstrated that several metabolic adverse effects caused by chronic GC treatment can be attributed to induction of MKP-3 expression and it was dependent on forkhead box protein O1 (FOXO1).…”

Metabolic comorbidities in Cushing's syndrome

“…GCs, via FOXO1, increase the expression of MKP3. Mice lacking MKP3 are protected from some GC-related metabolic effects such as weight gain, increased adiposity, liver lipid accumulation and insulin resistance (93). In mice, an impairment of mitochondrial function has been related to increased epididymal adiposity after GC treatment (94).…”

“…Lack of 11BHSD1 decreases hepatic steatosis, but the extent of the contribution of 11BHSD1 expression and activity in the liver to the lipid accumulation is controversial (73,118,119). MKP3 deficiency has been shown to protect mice from GC-induced fatty liver (93).…”

Modulation of SIRT1-Foxo1 Signaling axis by Resveratrol: Implications in Skeletal Muscle Aging and Insulin Resistance

“…Genetic ablation of Foxo1 in hypothalamus is known to enhance glucose uptake in gastrocnemius muscle [33]. Recent efforts have demonstrated that reducing the endogenous level of Foxo1 by knockdown approach abolished the elevation of MAPK phosphatase-3 (MKP-3), a factor known to induce transcriptional activation of gluconeogenic phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase complex (G6pase) in dexamethasone-treated hepatoma cells [34,35]. Hepatic activation of mitogen-activated protein kinase (MAPK) by injection of mitogen-activated protein kinase kinase (MEK)-expressing adenovirus increased protein expression of MKP-3 and fasting blood glucose despite that reduced nuclear localization of Foxo1 was noted [36].…”