Effect of High-fat Diet on KKA^yandob/obMouse Liver and Adipose Tissue Corticosterone and 11-dehydrocorticosterone Concentrations

Abstract

The present study was performed to compare glucocorticoid levels in obese KKA (y) and ob/ob mice with those in normal C57BL/6J mice, and the effect of high-fat diet on glucocorticoids in KKA (y) and ob/ob mice. Liver, mesenteric and epididymal adipose tissue corticosterone and 11-dehydrocorticosterone concentrations as well as circulating corticosterone concentrations were measured. The KKA (y) and ob/ob mice displayed elevated serum corticosterone levels compared to normal mice, 2.0 to 2.8-fold in KKA (y), and 11 to 16-fold in ob/ob mice. Liver corticosterone levels were 3.0 to 5.1 and 6.2 to 8.1-fold, and 11-dehydrocorticosterone levels were 3.4 to 3.6 and 6.7 to 8.2-fold higher in KKA (y) and ob/ob mice compared to normal mice. Mesenteric adipose tissue corticosterone levels were 2.7 to 4.2-fold higher, and 11-dehydrocorticosterone levels were 2 to 4-fold higher in ob/ob than in KKA (y) mice. Epididymal adipose tissue corticosterone levels were 3.0 to 6.2-fold higher, and 11-dehydrocorticosterone levels were 1.8 to 2.0-fold higher in ob/ob than in KKA (y) mice. Circulating, hepatic, and mesenteric and epididymal adipose tissue glucocorticoid concentrations were low in the normal C57BL/6J mouse, high in the ob/ob mouse, and intermediate in the KKA (y) mouse. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA levels were doubled in ob/ ob compared to KKA (y) mice in all three tissues. Glucocorticoid concentrations correlated with 11beta-HSD1 mRNA levels. High-fat diet had no effect on the tissue glucocorticoid concentrations.

Compound library development guided by protein structure similarity clustering and natural product structure

“…11␤HSD1 may be a promising therapeutic target for the antagonization of glucocorticoid actions (39,41). Its inhibition is considered to be a promising approach to the treatment of obesity (30,42), the metabolic syndrome (43,44), diabetes type 2 (45,46), and cognitive dysfunction (47). The 11␤HSD2 isoform catalyzes exclusively the oxidation of cortisol, and inhibition of 11␤HSD2 causes sodium retention resulting in hypertension (48).…”

Chronic mild stress alters circadian expressions of molecular clock genes in the liver

“…In addition, circadian expressions of hepatic clock genes are impaired in young ob/ob mice even before the onset of metabolic abnormalities, and this impairment in rhythmic expressions of hepatic clock genes was restored by leptin treatment (2). Serum corticosterone levels are increased in ob/ob mice (1,52), and leptin treatment depresses corticosterone levels via suppression of the HPA axis (17). Taking these previous reports and our present results together, HPA axis activation may contribute to alterations in circadian clock gene expressions in the liver, not only under chronic stress conditions, but also in states of excess nutrition.…”

“…Genetically obese strains such as KK-Ay (3) and db/db mice (28), and mice with high-fat diet-induced obesity (27), exhibit attenuated circadian expressions of several clock genes in the liver. Intriguingly, in all of these murine models, serum corticosterone levels were shown to be altered (1,27). In addition, circadian expressions of hepatic clock genes are impaired in young ob/ob mice even before the onset of metabolic abnormalities, and this impairment in rhythmic expressions of hepatic clock genes was restored by leptin treatment (2).…”

Glucocorticoids, metabolism and metabolic diseases

“…In this respect, hepatic fat accumulation has been demonstrated in patients with Cushing's syndrome [134,135], and GC levels have been found to be dramatically increased in various animal models of obesity, dyslipidemia, and hepatic steatosis, such as the db/db, ob/ob, and KKA(y) mouse [136,137]. Indeed, treatment of rats with GCs leads to increased triglyceride synthesis, decreased fatty acid oxidation, and to the subsequent accumulation of lipids in the liver [138].…”