AMPK-derived peptides reduce blood glucose levels but lead to fat retention in the liver of obese mice

Abstract

AMP-activated protein kinase (AMPK) is a regulator of energy balance at both the cellular and the whole-body levels. Direct activation of AMPK has been highlighted as a potential novel, and possibly safer, alternative to treat type II diabetes and obesity. In this study, we aimed to design and characterize novel peptides that mimic the aG region of the a2 AMPK catalytic domain to modulate its activity by inhibiting interactions between AMPK domains or other interacting proteins. The derived peptides were tested in vivo and in tissue culture. The computationally predicted structure of the free peptide with the addition of the myristoyl (Myr) or acetyl (Ac) moiety closely resembled the protein structure that it was designed to mimic. Myr-peptide and Ac-peptide activated AMPK in muscle cells and led to reduced adipose tissue weight, body weight, blood glucose levels, insulin levels, and insulin resistance index, as expected from AMPK activation. In addition, triglyceride, cholesterol, leptin, and adiponectin levels were also lower, suggesting increased adipose tissue breakdown, a result of AMPK activation. On the other hand, liver weight and liver lipid content increased due to fat retention. We could not find an elevated pAMPK:AMPK ratio in the liver in vivo or in hepatocytes ex vivo, suggesting that the peptide does not lead to AMPK activation in hepatocytes. The finding that an AMPK-derived peptide leads to the activation of AMPK in muscle cells and in adipose tissue and leads to reduced glucose levels in obese mice, but to fat accumulation in the liver, demonstrates the differential effect of AMPK modulation in various tissues.

Hemin Improves Insulin Sensitivity in Skeletal Muscle in High Fat–Fed Mice

“…The cause of the differential effect of hemin on AMPK phosphorylation depending on tissues is unclear in the present study, although the divergent regulation of AMPK has been reported previously. Novel peptides mimicking the a2 AMPK domain increase the AMPK phosphorylation in the skeletal muscle but not in the liver, which leads to reduced adipose tissue mass and triglyceride levels in the skeletal muscle and increased liver triglyceride levels (44). Furthermore, AMPK activity in skeletal muscle and liver is differentially regulated in lipodystrophic A-ZIP/F-1 mice, in which AMPK activity in the skeletal muscle of A-ZIP/F-1 mice is unchanged, while AMPK activity in liver is reduced (45).…”

Pharmacological Targeting of AMP-Activated Protein Kinase and Opportunities for Computer-Aided Drug Design

“…Interestingly, the strategy of targeting this binding site has already been followed with the computational design of peptides resembling the αG-helix of AMPK. 88 Surprisingly, instead of AMPK inactivation as might be expected from the mutant data, treatment with the peptides activated AMPK in myocyte and ameliorated metabolic parameters in high-fat fed mice. Whether the latter effect was really due to AMPK targeting was not studied, neither was the reason for AMPK activation.…”

“…The αG-helix thus appears as a critical binding site for AMPK interactions. Interestingly, the strategy of targeting this binding site has already been followed with the computational design of peptides resembling the αG-helix of AMPK . Surprisingly, instead of AMPK inactivation as might be expected from the mutant data, treatment with the peptides activated AMPK in myocyte and ameliorated metabolic parameters in high-fat fed mice.…”

AnchorDock: Blind and Flexible Anchor-Driven Peptide Docking

“…Peptides play a pivotal role in the regulation and modulation of the crowded protein network in the cell (Petsalaki and Russell, 2008) and may provide a starting point for drug discovery (Chapnik et al, 2014). Peptides as drug candidates have the potential to combine the advantages of small molecules such as cell permeability and cost-effectiveness with the high specificity of large biological compounds (Vlieghe et al, 2010).…”