The hepatokine FGF21 is crucial for peroxisome proliferator-activated receptor-α agonist-induced amelioration of metabolic disorders in obese mice

Abstract

Obesity causes excess fat accumulation in white adipose tissues (WAT) and also in other insulin-responsive organs such as the skeletal muscle, increasing the risk for insulin resistance, which can lead to obesity-related metabolic disorders. Peroxisome proliferator-activated receptor-α (PPARα) is a master regulator of fatty acid oxidation whose activator is known to improve hyperlipidemia. However, the molecular mechanisms underlying PPARα activator-mediated reduction in adiposity and improvement of metabolic disorders are largely unknown. In this study we investigated the effects of PPARα agonist (fenofibrate) on glucose metabolism dysfunction in obese mice. Fenofibrate treatment reduced adiposity and attenuated obesity-induced dysfunctions of glucose metabolism in obese mice fed a high-fat diet. However, fenofibrate treatment did not improve glucose metabolism in lipodystrophic A-Zip/F1 mice, suggesting that adipose tissue is important for the fenofibrate-mediated amelioration of glucose metabolism, although skeletal muscle actions could not be completely excluded. Moreover, we investigated the role of the hepatokine fibroblast growth factor 21 (FGF21), which regulates energy metabolism in adipose tissue. In WAT of WT mice, but not of FGF21-deficient mice, fenofibrate enhanced the expression of genes related to brown adipocyte functions, such as ,, and Fenofibrate increased energy expenditure and attenuated obesity, whole body insulin resistance, and adipocyte dysfunctions in WAT in high-fat-diet-fed WT mice but not in FGF21-deficient mice. These findings indicate that FGF21 is crucial for the fenofibrate-mediated improvement of whole body glucose metabolism in obese mice via the amelioration of WAT dysfunctions.

A Phytol‐Enriched Diet Activates PPAR‐α in the Liver and Brown Adipose Tissue to Ameliorate Obesity‐Induced Metabolic Abnormalities

“…While PPAR‐α activation is widely recognized for its effects on improving lipid metabolism disorders, the results of the present study show that phytol intake may improve the abnormal glucose tolerance, insulin resistance, and other carbohydrate metabolism disorders associated with obesity. The beneficial effects of PPAR‐α agonists on carbohydrate metabolism disorders are well reported . The mechanism underlying improved glucose tolerance by PPAR‐α agonists may be related to attenuated adiposity and adipocyte hypertrophy .…”

“…The beneficial effects of PPAR‐α agonists on carbohydrate metabolism disorders are well reported . The mechanism underlying improved glucose tolerance by PPAR‐α agonists may be related to attenuated adiposity and adipocyte hypertrophy . Improvements in adiposity and adipocyte hypertrophy may increase adiponectin levels and ectopic lipid accumulation in the liver .…”

“…Immunoblotting was carried out as previously described . After separating proteins based on size by gel electrophoresis and transferring proteins onto polyvinylidene difluoride membranes, the membranes were incubated with antibodies specific for the target of interest, and antibody binding was visualized using secondary antibodies and detection reagents.…”

“…PPAR‐α agonists such as fibrate drugs are currently used for treating dyslipidemia. Fibrates have been shown to improve obesity‐induced insulin resistance, indicating the usefulness of PPAR‐α agonists for managing obesity‐induced metabolic disorders …”

Dyslipidemia in retinal metabolic disorders

“…FGF21 functions through modulating the activities of PPAR and PGC-1a. FGF21 is crucial for PPARa agonists to ameliorate metabolic disorders in obese mice (Goto et al, 2017). FGF21 regulates PPARc activity and controls body fat (Dutchak et al, 2012).…”