Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue

Abstract

Glucocorticoids (GCs) are widely prescribed anti-inflammatory agents, but their chronic use leads to undesirable side effects such as excessive expansion of adipose tissue. We have recently shown that the forkhead box protein A3 (Foxa3) is a calorie-hoarding factor that regulates the selective enlargement of epididymal fat depots and suppresses energy expenditure in a nutritional- and age-dependent manner. It has been demonstrated that Foxa3 levels are elevated in adipose depots in response to high-fat diet regimens and during the aging process; however no studies to date have elucidated the mechanisms that control Foxa3’s expression in fat. Given the established effects of GCs in increasing visceral adiposity and in reducing thermogenesis, we assessed the existence of a possible link between GCs and Foxa3. Computational prediction analysis combined with molecular studies revealed that Foxa3 is regulated by the glucocorticoid receptor (GR) in preadipocytes, adipocytes, and adipose tissues and is required to facilitate the binding of the GR to its target gene promoters in fat depots. Analysis of the long-term effects of dexamethasone treatment in mice revealed that Foxa3 ablation protects mice specifically against fat accretion but not against other pathological side effects elicited by this synthetic GC in tissues such as liver, muscle, and spleen. In conclusion our studies provide the first demonstration, to our knowledge, that Foxa3 is a direct target of GC action in adipose tissues and point to a role of Foxa3 as a mediator of the side effects induced in fat tissues by chronic treatment with synthetic steroids.

Ablation of PPARγ in subcutaneous fat exacerbates age‐associated obesity and metabolic decline

“…Plasma glucose levels were measured from tail blood before or 15, 30, 60, 90, and 120 min after insulin or glucose injections via automatic reader (Bayer, Leverkusen, Germany). AUC (area under the curve) was calculated with GraphPad software, as previously described (Ma, Xu & Mueller, ).…”

SGK1/FOXO3 Signaling in Hypothalamic POMC Neurons Mediates Glucocorticoid-Increased Adiposity

“…Tamoxifen (0.15 g/kg; Sigma-Aldrich, St. Louis, MO) suspended in corn oil (Sigma-Aldrich) was intraperitoneally injected into 8-week-old male SGK1 loxp/loxp or SGK1 loxp/loxp 3 POMC-cre:ER T2 littermate mice for five consecutive days to generate mice with adult-onset SGK1 deletion in POMC neurons (PSKO-ER). Dexamethasone (Dex) treatment was administered to male wild-type (WT), control, and PSKO mice, and to male POMC-Cre mice injected with adeno-associated virus (AAV) expressing constitutively active mutant rat SGK1 (S422D) (AAV-CA SGK1)/AAV-null in ARC (control/POMC neuron-specific SGK1 overexpression [PSOE] mice) by intraperitoneal injection of PBS or 5 mg/kg Dex every other day for 6 weeks or for 2 h (1,25). All the mice were on a C57BL/6J background.…”

“…To investigate the metabolic effects of Dex, C57B6J WT mice were intraperitoneally injected with Dex for 6 weeks; this model has been commonly used to study the role of Dex (1,30). Dex treatment did not change body weight, although the total body fat and abdominal fat mass were increased compared with those in mice receiving the control treatment, possibly as a result of decreased lean mass ( Supplementary Fig.…”

“…Despite the overwhelming beneficial anti-inflammatory effects of glucocorticoid, chronic glucocorticoid treatment has been shown to cause numerous adverse metabolic outcomes, including fat mass gain (1). Recent studies have elucidated several peripheral mechanisms underlying glucocorticoid-induced increase in fat mass.…”

“…Recent studies have elucidated several peripheral mechanisms underlying glucocorticoid-induced increase in fat mass. For example, glucocorticoid induces adipocyte differentiation (1)(2)(3), alters lipid metabolism in adipose tissue (1)(2)(3), and inhibits browning of white adipose tissue (WAT) or thermogenesis of brown adipose tissue (BAT) (4,5). In fact, body fat mass is largely controlled by the central nervous system (CNS) (6)(7)(8).…”