Comparative study between the effect of the peroxisome proliferator activated receptor-α ligands fenofibrate and n-3 polyunsaturated fatty acids on activation of 5′-AMP-activated protein kinase-α1 in high-fat fed rats

Abstract

Abstract Objectives Obesity is a risk factor for type 2 diabetes mellitus. It results from an energy imbalance in which energy intake exceeds energy expenditure. The cellular fuel gauge 5′-AMP-activated protein kinase (AMPK) is a heterotrimeric protein consisting of one catalytic subunit (α) and two non-catalytic subunits (β and γ), and approximately equal levels of α1 and α2 complexes are present in the liver. AMPK regulates metabolic pathways in response to metabolic stress and in particular ATP depletion to switch on energy-producing catabolic pathways such as β-oxidation of fatty acids and switch off energy-depleting processes such as synthesis of fatty acid and cholesterol. A high-fat diet alters AMPK-α1 gene expression in the liver and skeletal muscle of rats and results in body weight gain and hyperglycaemia. The aim of this study was to investigate and compare the potential effects of peroxisome proliferator-activated receptor (PPAR)-α agonists fenofibrate and n-3 polyunsaturated fatty acids (PUFAs) in modulation of AMPK-α1 activity in liver and skeletal muscle of high-fat diet fed rats. Methods Reverse transcription–polymerase chain reaction was used for determination of AMPK-α1 in liver and soleus muscle and both PPAR-α and CPT-1 in hepatic tissues. Serum, total cholesterol, triacylglycerol, fatty acid and fasting blood glucose were determined colorimetrically. Key findings Both PPAR-α agonists, fenofibrate and n-3 PUFA, increased the mRNA expression of AMPK-α1 activity in liver and skeletal muscle of obese diabetic rats. Fenofibrate was superior in its activation of hepatic mRNA expression of AMPK-α 1 to exert more lipolytic effect and body weight reduction, as estimated through the decrease of triacylglycerol output and serum levels of fatty acid on the one hand and the increase in CPT-1 mRNA expression, the key enzyme in β-oxidation of fatty acid, on the other hand. n-3 PUFA activated AMPK-α1 mRNA expression in skeletal muscle much more than fenofibrate to reveal more hypoglycaemic effect. Conclusions The PPAR-α agonists fenofibrate and n-3 PUFA could efficiently activate AMPK-α1 mRNA expression in liver and skeletal muscle to exert body weight reduction and hypoglycaemic effect, respectively.