Nat Chem Biol: Fbxo48 inhibitors reduce insulin resistance by preventing pAMPK alpha degradation

5'-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is the central regulatory factor of the metabolic pathline, which senses fluctuations in cell energy supply to urgently regulate the balance of the breakdown of metabolism and anabolic processes.
studies have shown that AMPK coordinates overall cellular responses to energy stress in cases of mid-starvation, low oxygen, impaired mitochondrial function, and disease status, such as type 2 diabetes.
amPK activity is considered an attractive therapeutic target for a wide range of diseases.
in the recent study "A Fbxo48 inhibitor prevents pAMPK alpha degradation and ameliorates insulin resistance", researchers say they have identified an orphan Ubithin E3 connective enzyme sub-unit protein Fbxo48 that targets the active phosphorylated AMPK alpha (pAmpk alpha) and induces its multi-ubiction, which in turn is degraded by ponase.
researchers have now synthesized a new Fbxo48 inhibitory compound, BC1618, which stimulates ampk-dependent signaling path pathlines far more effectively than 5-aminominazine-4-pyridine-1-β-furan nucleosides (AICAR) or metformin.
the compound increases Ampk's biological activity not by stimulating ampk, but by preventing the degradation of activated pAmpk alpha mediated by Fbxo48.
researchers have shown that, consistent with enhanced Ampk activity, BC1618 promotes mitochondrial division, promotes autophagy, and increases liver insulin sensitivity in obese mice induced by a high-fat diet.
, the study provides a unique bioactive compound that inhibits the consumption of pAmpk alpha.
, the results define a new path that regulates Ampk's biological activity and demonstrate the potential benefits of regulating that path.