Dual Mode Action of Mangiferin in Mouse Liver under High Fat Diet

Abstract

Chronic over-nutrition is a major contributor to the spread of obesity and its related metabolic disorders. Development of therapeutics has been slow compared to the speedy increase in occurrence of these metabolic disorders. We have identified a natural compound, mangiferin (MGF) (a predominant component of the plants of Anemarrhena asphodeloides and Mangifera indica), that can protect against high fat diet (HFD) induced obesity, hyperglycemia, insulin resistance and hyperlipidemia in mice. However, the molecular mechanisms whereby MGF exerts these beneficial effects are unknown. To understand MGF mechanisms of action, we performed unbiased quantitative proteomic analysis of protein profiles in liver of mice fed with HFD utilizing 15N metabolically labeled liver proteins as internal standards. We found that out of 865 quantified proteins 87 of them were significantly differentially regulated by MGF. Among those 87 proteins, 50% of them are involved in two major processes, energy metabolism and biosynthesis of metabolites. Further classification indicated that MGF increased proteins important for mitochondrial biogenesis and oxidative activity including oxoglutarate dehydrogenase E1 (Dhtkd1) and cytochrome c oxidase subunit 6B1 (Cox6b1). Conversely, MGF reduced proteins critical for lipogenesis such as fatty acid stearoyl-CoA desaturase 1 (Scd1) and acetyl-CoA carboxylase 1 (Acac1). These mass spectrometry data were confirmed and validated by western blot assays. Together, data indicate that MGF upregulates proteins pivotal for mitochondrial bioenergetics and downregulates proteins controlling de novo lipogenesis. This novel mode of dual pharmacodynamic actions enables MGF to enhance energy expenditure and inhibit lipogenesis, and thereby correct HFD induced liver steatosis and prevent adiposity. This provides a molecular basis supporting development of MGF or its metabolites into therapeutics to treat metabolic disorders.

Mangiferin modulation of metabolism and metabolic syndrome

“…Scd1 catalyzes the conversion of stearoyl‐CoA to oleoyl‐CoA, which is a major substrate for TG synthesis. Ingenuity pathway analysis (IPA) of these proteomics data predicted that MGF suppressed SREBPs . This data corroborates a report by Guo et al showing that MGF treatment in hamster resulted in reduced SREBP‐1c transcripts in liver .…”

“…We recently provided evidence that MGF activates PDH . Our proteomics study also predicts other molecular targets and signaling pathways affected by MGF . While these studies advanced our understanding of the mechanisms of action of MGF, more mechanistic studies are in great need to provide clear pictures of how MGF exerts its beneficial effects.…”

Consumption of a Mango Fruit Powder Protects Mice from High-Fat Induced Insulin Resistance and Hepatic Fat Accumulation

“…The effect may be due to the active molecule MGF, which is present in our mango fruit powder [18]. It has been reported that MGF may ameliorate high-fat diet-induced hepatic TG accumulation and may decrease FFA and TG while increasing plasma beta-hydroxybutyrate levels in rodents [37-39], partly by modulating the expression of genes involved in lipid oxidation and mitochondrial bioenergetics in key metabolic tissues [37-40]. In a randomized, double-blind, controlled trial in humans, MGF supplementation (150 mg/day 12 weeks) improved serum lipid profiles in overweight patients with hyperlipidemia [17].…”

Pharmacological Effects of Aquilaria spp. Leaves and Their Chemical Constituents

“…Simultaneously, it signifi cantly increased the levels of proteins important for mitochondrial biogenesis and oxidative activity, including oxoglutarate dehydrogenase E1 and cytochrome c oxidase subunit 6B1, and decreased the levels of those critical for lipogenesis, such as fatty acid stearoylCoA desaturase 1 and acetyl-CoA carboxylase 1 (Lim et al 2014 ).…”