Butyrate Attenuates Inflammation and Lipolysis Generated by the Interaction of Adipocytes and Macrophages

Abstract

Aim: Paracrine interaction between macrophages and adipocytes in obese visceral fat tissues is thought to be a trigger of chronic inflammation. The immunomodulatory effect of the short chain fatty acid, butyric acid, has been demonstrated. We hypothesize that sodium butyrate (butyrate) attenuates inflammatory responses and lipolysis generated by the interaction of macrophages and adipocytes. Methods: Using contact or transwell co-culture methods with differentiated 3T3-L1 adipocytes and RAW264.7 macrophages, we investigated the effects of butyrate on the production of tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), and the release of free glycerol, free fatty acids (FFAs) into the medium. We also examined the activity of nuclear factor-kappaB (NF-κB) and the phosphorylation of mitogen-activated protein kinases (MAPKs) in co-cultured macrophages, as well as lipase activity and expression in co-cultured adipocytes. Results: We found increased production of TNF-α, MCP-1, IL-6, and free glycerol, FFAs in the coculture medium, and butyrate significantly reduced them. Butyrate inhibited the phosphorylation of MAPKs, the activity of NF-κB in co-cultured macrophages, and suppressed lipase activity in co-cultured adipocytes. Lipase inhibitors significantly attenuated the production of TNF-α, MCP-1 and IL-6 in the co-culture medium as effectively as butyrate. Butyrate suppressed the protein production of adipose triglyceride lipase, hormone sensitive lipase, and fatty acid-binding protein 4 in co-cultured adipocytes. Pertussis toxin, which is known to block GPR41 completely, inhibited the antilipolysis effect of butyrate. Conclusion: Butyrate suppresses inflammatory responses generated by the interaction of adipocytes and macrophages through reduced lipolysis and inhibition of inflammatory signaling.

Fatty acid binding proteins

“…Paradoxically, pharmacological inhibition of fatty acid binding to FABP4 reversed NAFLD (5), while decreased FABP4 expression in adipocytes increased lipolysis (27). These studies reinforce previous studies showing that FABP4 has an important role in fatty acid storage, in the form of triacylglycerols.…”

“…In addition to its traditional role in trafficking of non-esterified fatty acids within cells, for example to and from PPAR and hormonesensitive lipase (HSL) (1)(21), FABP4 is now recognized as an adipokine secreted from adipocytes and macrophages (21). Increasing evidence exists for a link between lipid metabolism and inflammation, and FABP4 may mediate these effects, thus impacting on disease conditions such as metabolic syndrome, insulin resistance, NAFLD and atherosclerosis (22) Further support for the role of FABP4 as an adipokine has been provided by in vitro studies demonstrating that interaction between adipocytes and macrophages increases the secretion of FABP4 into culture medium (27), while serum levels of FABP4 have been directly correlated with levels of adiposity (29), metabolic syndrome, atherosclerosis (21) and the long-term prognosis of cardiovascular mortality (23). The expression of FABP4 has also been linked to the rupture of atherosclerotic plaques (30), production of pro-inflammatory leukotriene C 4 (31), IL6/VEGF expression (26), angiogenesis in endothelial cells (32), and increased adipogenic differentiation of primary osteoblasts (33).…”

The Pharmacology and Function of Receptors for Short-Chain Fatty Acids

“…Exogenous C2, C3, and C4 all inhibit lipolysis (Hong et al, 2005;Ge et al, 2008;Zaibi et al, 2010). Importantly this effect is PTX-sensitive (Ohira et al, 2013) and absent in FFA2 knockout mice . Reports suggest that FFA2 activation reduces insulin sensitivity in the adipocyte by G bgmediated inhibition of Akt phosphorylation downstream of the insulin receptor (Kimura et al, 2013).…”

“…C2 and C4 can inhibit tumor necrosis factor-a release (Säemann et al, 2000;Maslowski et al, 2009;Ohira et al, 2013), and C4 in particular can mediate a switch from a Th1 (which is exaggerated in Crohn's disease) to a Th2 profile of cytokine production (Säemann et al, 2000;Cavaglieri et al, 2003). Neither FFA2 nor FFA3 knockout mice recruit Th1 cells in a rectal inflammation model .…”

Seven-Day Caloric and Saturated Fat Restriction Increases Myocardial Dietary Fatty Acid Partitioning in Impaired Glucose-Tolerant Subjects

“…Bacterial fermentation of dietary fibers in the colon induces biosynthesis of short-chain fatty acids such as acetate, propionate, and butyrate (47). Butyrate decreases the synthesis of adipose TG lipase (48), which contributes to myocardial uptake and the oxidation of fatty acids (49). An increase in acetate production by the intestinal microbiota could induce an increase in the production of acetylCoA in myocardial cells, which in turn could induce an increase in malonyl-CoA, an allosteric inhibitor of carnitine palmitoyltransferase 1, the rate-limiting enzyme of b-oxidation (49).…”