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

Abstract

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.

Butyrate Modulates Inflammation in Chondrocytes via GPR43 Receptor

“…Recently, we demonstrated the beneficial effect of butyrate in a mice model of dietinduced obesity, not only on the weight loss, but also restoring adipokine dysfunction, and reducing inflammation [15]. Interestingly, adipokine dysregulation is a clear component of metabolic-triggered inflammation in OA and RA [30,37].…”

“…Recent experimental evidence suggested different therapeutic applications for butyrate, including its ability to treat metabolic and inflammatory diseases [14,15]. Butyrate effects include epigenetic modifications due to its inhibitory effects on histone deacetylases (HDAC), inhibition of NF-κB signalling [16], and the direct agonism on the SCFA G-protein coupled receptors, GPR41 and GPR43 [17].…”

Mitochondrial network responses in oxidative physiology and disease

“…In this, we delineate nuclear omics and intestinal microbial omics as separate entities, but these are extensively integrated with mitochondrial systems at multiple levels as nutrients and metabolic fuels from food are assimilated and delivered as energy precursors for use by mitochondria. Extensive evidence is available, for instance, on functional interactions of the mitogenome with the nuclear genome (nucleogenome), [63,64] and metagenome of the intestines with mitochondrial function in metabolic diseases of fatty liver and type 2 diabetes [65,66]. …”

Aldehyde Dehydrogenase-2 Attenuates Myocardial Remodeling and Contractile Dysfunction Induced by a High-Fat Diet

“…We observed reduced EF and FS, enlarged LVEDD and LVESD, elevated IVSd and LVPWd, and excessive apoptosis, deposition of lipid droplets, and collagen fibers in cardiomyocytes of MS mice. Several mechanisms may be responsible for these MS-related abnormalities, including impaired insulin resistance and increased oxidative stress [23,24]. In this study, impaired insulin resistance may underscore the accelerated apoptosis and myocardial fibrosis in cardiac tissue of MS mice induced by a HF diet.…”