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, activating AMPK-ACC pathway, and promoted inefficient metabolism, as shown by the increase in proton leak. Consistently, both treatments increase utilization of substrates, especially fatty acids, leading to the reduction of intracellular lipid accumulation and oxidative stress. Finally, the shift of mitochondrial dynamic toward fusion by butyrate and FBA resulting 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 dynamic, can be considered a new therapeutic strategy to counteract obesity and insulin resistance.
- Received July 29, 2016.
- Accepted February 14, 2017.
- © 2017 by the American Diabetes Association.