Attenuation of FGF21 signalling might aggravate the impairment of glucose homeostasis during the high sucrose diet induced transition from prediabetes to diabetes in WNIN/GR-Ob rats

Fibroblast growth factor 21 (FGF21) has emerged as a pleiotropic hormone and is known for its beneficiary roles in the management of diabetes and hyperglycaemia. However, the role of FGF21 during the transition from prediabetes to diabetes still remains unclear. Hence, the present study is aimed to understand the regulation of glucose homeostasis by FGF21 during the transition from prediabetes to diabetes in WNIN/GR-Ob rats.A total of 36 WNIN/GR-Ob obese male rats (28 days old) were divided into control and high sucrose (HS) groups and were fed ad libitum with their respective diets. These groups were sacrificed at different time points (week 1, 6, and 12) and various physical, biochemical, and molecular mediators were assessed to address FGF21 mediated glucose homeostasis.The study results revealed that rats developed impaired glucose tolerance and insulin resistance by exhibiting delayed glucose clearance from circulation, elevated fasting insulin, increased AUC glucose and HOMA-IR scores significantly; thereby rats demonstrated prediabetes by week 6 and diabetes complications by week 12. In line with the above, differential expression of genes attributed to FGF21 mediated glucose homeostasis, i.e., PPARα, FGF21, β-klotho, PPARγ, Adiponectin, Akt, and UCP1 suggest that the acute insulin sensitizing effect of FGF21 was significantly impaired during prediabetes to diabetes transition. In addition, increased gene and protein expression of FGF21 during the transition compared to controls could be a compensatory response to possibly counteract the metabolic stress imposed by high sucrose diet in WNIN/GR-Ob rats of the experimental group.Findings from the current study emphasize the potential role of FGF21 in glucose homeostasis and its attenuation might aggravate glucose impairment during the transition from prediabetes to diabetes in high sucrose diet induced WNIN/GR-Ob rats

Carbenoxolone treatment ameliorated metabolic syndrome in WNIN/Ob obese rats, but induced severe fat loss and glucose intolerance in lean rats.

BACKGROUND: 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates local glucocorticoid action in tissues by catalysing conversion of inactive glucocorticoids to active glucocorticoids. 11β-HSD1 inhibition ameliorates obesity and associated co-morbidities. Here, we tested the effect of 11β-HSD inhibitor, carbenoxolone (CBX) on obesity and associated comorbidities in obese rats of WNIN/Ob strain, a new animal model for genetic obesity. METHODOLOGY/PRINCIPAL FINDINGS: Subcutaneous injection of CBX (50 mg/kg body weight) or volume-matched vehicle was given once daily for four weeks to three month-old WNIN/Ob lean and obese rats (n = 6 for each phenotype and for each treatment). Body composition, plasma lipids and hormones were assayed. Hepatic steatosis, adipose tissue morphology, inflammation and fibrosis were also studied. Insulin resistance and glucose intolerance were determined along with tissue glycogen content. Gene expressions were determined in liver and adipose tissue. CBX significantly inhibited 11β-HSD1 activity in liver and adipose tissue of WNIN/Ob lean and obese rats. CBX significantly decreased body fat percentage, hypertriglyceridemia, hypercholesterolemia, insulin resistance in obese rats. CBX ameliorated hepatic steatosis, adipocyte hypertrophy, adipose tissue inflammation and fibrosis in obese rats. Tissue glycogen content was significantly decreased by CBX in liver and adipose tissue of obese rats. Severe fat loss and glucose- intolerance were observed in lean rats after CBX treatment. CONCLUSIONS/SIGNIFICANCE: We conclude that 11β-HSD1 inhibition by CBX decreases obesity and associated co-morbidities in WNIN/Ob obese rats. Our study supports the hypothesis that inhibition of 11β-HSD1 is a key strategy to treat metabolic syndrome. Severe fat loss and glucose -intolerance by CBX treatment in lean rats suggest that chronic 11β-HSD1 inhibition may lead to insulin resistance in normal conditions

Carbenoxolone Treatment Ameliorated Metabolic Syndrome in WNN/Ob Obese Rats but induced Severe Fat Loss and Glucose Intolerance in Learn Rats

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Effect of carbenoxolone on adipose tissue gene expression quantified by semi quantitative reverse transcription PCR.

<p>(A). Stearoyl CoA desaturase 1 (SCD1). (B). Malic enzyme 1 (ME1). (C). Macrophage expressed gene (MPEG). (D). Lysosomal acid lipase (LIPA). (E). Beta3-Adrenergic receptor (β3-AR). Parameters were measured after 4weeks of treatment with carbenoxolone or vehicle (50 mg/kg body weight/day). Empty bars indicate lean phenotype where as filled bars indicate obese phenotype. Relative gene expression was measured using calnexin gene as internal control. Relative expression of gene of interest in lean control was taken as 1. Values are means ± SEM for 4 animals for group. . #<i>p</i><0.05, ##<i>p</i><0.01 and ### <i>p</i><0.001 comparing vehicle-treated lean and obese rats. *<i>p</i><0.05, **<i>p</i><0.01 and *** <i>p</i><0.001 comparing carbenoxolone-treated animals with vehicle-treated animals of the same phenotype.</p

Effect of carbenoxolone on plasma biochemical parameters in WNIN/Ob lean and obese rats.

<p>(A). Fed-state corticosterone. (B). Fasting corticosterone. (C). Fed-state triglycerides. (D). Fasting triglycerides. (E). Fed-state total cholesterol. (F). Fasting total cholesterol. (G). Fed-state HDL cholesterol. (H). Fasting HDL cholesterol. Plasma parameters were measured after 4weeks of treatment with carbenoxolone or vehicle (50 mg/kg bodyweight/day). Empty bars indicate lean phenotype where as filled bars indicate obese phenotype. Values are means ± SEM for 6 animals for group. #<i>p</i><0.05, ##<i>p</i><0.01 and ### <i>p</i><0.001 comparing vehicle-treated lean and obese rats. *<i>p</i><0.05, **<i>p</i><0.01 and *** <i>p</i><0.001 comparing carbenoxolone-treated animals with vehicle-treated animals of the same phenotype.</p