Branched short-chain fatty acids modulate glucose and lipid metabolism in primary adipocytes

Abstract

Short-chain fatty acids (SCFAs), e.g. acetic acid, propionic acid and butyric acid, generated through colonic fermentation of dietary fibers, have been shown to reach the systemic circulation at micromolar concentrations. Moreover, SCFAs have been conferred anti-obesity properties in both animal models and human subjects. Branched SCFAs (BSCFAs), e.g., isobutyric and isovaleric acid, are generated by fermentation of branched amino acids, generated from undigested protein reaching colon. However, BSCFAs have been sparsely investigated when referring to effects on energy metabolism. Here we primarily investigate the effects of isobutyric acid and isovaleric acid on glucose and lipid metabolism in primary rat and human adipocytes. BSCFAs inhibited both cAMP-mediated lipolysis and insulin-stimulated de novo lipogenesis at 10 mM, whereas isobutyric acid potentiated insulin-stimulated glucose uptake by all concentrations (1, 3 and 10 mM) in rat adipocytes. For human adipocytes, only SCFAs inhibited lipolysis at 10 mM. In both in vitro models, BSCFAs and SCFAs reduced phosphorylation of hormone sensitive lipase, a rate limiting enzyme in lipolysis. In addition, BSCFAs and SCFAs, in contrast to insulin, inhibited lipolysis in the presence of wortmannin, a phosphatidylinositide 3-kinase inhibitor and OPC3911, a phosphodiesterase 3 inhibitor in rat adipocytes. Furthermore, BSCFAs and SCFAs reduced insulin-mediated phosphorylation of protein kinase B. To conclude, BSCFAs have effects on adipocyte lipid and glucose metabolism that can contribute to improved insulin sensitivity in individuals with disturbed metabolism.

Maternal prebiotic supplementation reduces fatty liver development in offspring through altered microbial and metabolomic profiles in rats

“…The branched‐chain fatty acid isobutyrate, though primarily a gut microbiota branched chain amino acid fermentation by‐product, also may be produced following ingestion of specific dietary fibers (80). Here, isobutyrate was significantly negatively correlated with steatosis score, insulin AUC, and glucose AUC, and significantly positively correlated with Clostridium cluster XI abundance.…”

“…Notably, higher levels of stool isobutyrate have been found in microbiomes enriched for Clostridium cluster XI (81). Furthermore, in the presence of isobutyrate, primary rat adipocytes displayed reduced lipolysis, decreased hormone‐sensitive lipase phosphorylation, and increased basal and insulin‐stimulated glucose uptake (80). These effects were mediated via reduced phosphorylation of PKB, a key player in insulin signal transduction (80).…”

“…Furthermore, in the presence of isobutyrate, primary rat adipocytes displayed reduced lipolysis, decreased hormone‐sensitive lipase phosphorylation, and increased basal and insulin‐stimulated glucose uptake (80). These effects were mediated via reduced phosphorylation of PKB, a key player in insulin signal transduction (80). Altogether, because microbially produced isobutyrate reaches the systemic circulation, these data indicate that increases in isobutyrate‐producing bacteria may be associated with improved metabolic outcomes in this model.…”

Nutritional interest of dietary fiber and prebiotics in obesity: Lessons from the MyNewGut consortium

“…In obesity, there is also a decrease in BCFA content in the serum [95] and adipose tissue biopsies [96]. These changes might have physiological relevance since the in vitro exposure of adipocytes to two BCFA (isobutyric acid and isovaleric acid) influences adipocyte lipid and glucose metabolism [97]. Thus, the significance of the reduction of BCFA observed after the intake of AXOS or AX-rich WBE awaits to be investigated.…”

The Microbiota and Epigenetic Regulation of T Helper 17/Regulatory T Cells: In Search of a Balanced Immune System

“…This in turn leads to the activation of the mammalian target of rapamycin (mTOR), a critical kinase involved in T-cell differentiation, and can facilitate T effector or Treg differentiation (121, 132). In addition, both butyrate and propionate have been reported to inhibit de novo fatty acid synthesis though the deactivation of acetyl-CoA carboxylase 1 (133), a process known to limit Th17 cell differentiation and promote Treg development (134). GPCRs, some of which act as receptors for various SCFAs including acetate, butyrate, propionate, or for niacin, have been linked to the regulation of inflammation in various diseases (135), and GPCR signaling plays a critical role in the regulation of Th17 cell and Treg development (131).…”