Butyrate Regulates Liver Mitochondrial Function, Efficiency, and Dynamics in Insulin-Resistant Obese Mice

Diabetes. 2017 May;66(5):1405-1418. doi: 10.2337/db16-0924. Epub 2017 Feb 21.


Fatty liver, oxidative stress, and mitochondrial dysfunction are key pathophysiological features of insulin resistance and obesity. Butyrate, produced by fermentation in the large intestine by gut microbiota, and its synthetic derivative, the N-(1-carbamoyl-2-phenyl-ethyl) butyramide, FBA, have been demonstrated to be protective against insulin resistance and fatty liver. Here, hepatic mitochondria were identified as the main target of the beneficial effect of both butyrate-based compounds in reverting insulin resistance and fat accumulation in diet-induced obese mice. In particular, butyrate and FBA improved respiratory capacity and fatty acid oxidation, activated the AMPK-acetyl-CoA carboxylase pathway, and promoted inefficient metabolism, as shown by the increase in proton leak. Both treatments consistently increased utilization of substrates, especially fatty acids, leading to the reduction of intracellular lipid accumulation and oxidative stress. Finally, the shift of the mitochondrial dynamic toward fusion by butyrate and FBA resulted in the improvement not only of mitochondrial cell energy metabolism but also of glucose homeostasis. In conclusion, butyrate and its more palatable synthetic derivative, FBA, modulating mitochondrial function, efficiency, and dynamics, can be considered a new therapeutic strategy to counteract obesity and insulin resistance.

MeSH terms

  • AMP-Activated Protein Kinases / drug effects
  • AMP-Activated Protein Kinases / metabolism
  • Acetyl-CoA Carboxylase / drug effects
  • Acetyl-CoA Carboxylase / metabolism
  • Animals
  • Blotting, Western
  • Body Composition / drug effects
  • Butyrates / pharmacology*
  • Diet, High-Fat
  • Energy Metabolism / drug effects
  • Fatty Acids / metabolism
  • Glucose / metabolism
  • Glucose Tolerance Test
  • Hep G2 Cells
  • Homeostasis / drug effects
  • Humans
  • Insulin Resistance*
  • Lipid Metabolism / drug effects*
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / ultrastructure
  • Male
  • Mice
  • Microscopy, Electron, Transmission
  • Mitochondria, Liver / drug effects*
  • Mitochondria, Liver / metabolism
  • Mitochondrial Dynamics / drug effects
  • NF-E2-Related Factor 2 / drug effects
  • NF-E2-Related Factor 2 / metabolism
  • Obesity / metabolism*
  • Oxidation-Reduction / drug effects
  • Oxidative Stress / drug effects*
  • Real-Time Polymerase Chain Reaction


  • Butyrates
  • Fatty Acids
  • N-(1-carbamoyl-2-phenyl-ethyl)butyramide
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • AMP-Activated Protein Kinases
  • Acetyl-CoA Carboxylase
  • Glucose