The role of leptin and insulin signaling in the hypothalamic control of liver metabolism

Abstract

Background: While hepatic insulin resistance arises as one of the earliest causes of impaired glucose tolerance (IGT) and diabetes mellitus type 2 (DM2), the metabolic pathways involved are still poorly understood. In recent years the hypothalamus has been demonstrated to regulate whole body glucose and lipid metabolism and therefore DM2 and IGT. In an unbiased non-hypothesis driven approach our study aimed to further dissect the metabolic pathways affected by hypothalamic insulin and leptin signaling. Methods: In order to investigate the role of leptin and insulin signaling in the hypothalamus, we infused leptin or insulin into the mediobasal Hypothalamus (MBH) of male Sprague-Dawley rats and measured glucose production, glucose uptake via tracer-dilution technique under euglycemic pancreatic clamp conditions. Western blots, enzyme linked assays and mass spectrometry, were used to simultaneously analyse multiple metabolic pathways. Results: MBH leptin and insulin have similar effects on hepatic energy metabolism. Targeted metabolomics analysis revealed (via measurement of acylcarnitines) that central insulin and leptin suppress long chain fatty acid β-oxidation in the liver and lead to increased levels of several TCA cycle intermediates as well as decreased branched-chain amino acids (BCAAs) in blood plasma. Conclusion: The actions of leptin and insulin in the MBH increased gluconeogenic substrate breakdown in the liver through a decrease in fatty acid B-oxidation and an increase of oxidative phosphorylation of amino acid and glucose metabolites. Moreover, central leptin and insulin improved insulin sensitivity and the metabolic profile through reductions in plasma levels of branched chain AA, which are frequently increased in patients with DM.