Combined Short-Chain Fatty Acids Induce an Anti-Inflammatory and Anti-Chemotactic Secretory Profile from 3T3-L1 Adipocytes in Normoxic and Hypoxic Environmental Conditions.

Short-chain fatty acids (SCFAs), acetate, propionate, and butyrate, are typically produced in a 3:1:1 ratio, respectively, via microbial fermentation of non-digestible carbohydrates, and to a lesser degree, from undigested protein. The effects of individual SCFAs on adipocyte function have been described; however, the effects of SCFAs in combination on adipocyte function remain unknown. Mature 3T3-L1 adipocytes were treated with a 1 mM total dose of acetate, propionate, and butyrate combined in a 3:1:1 ratio, respectively, for 24 h ± lipopolysaccharide (LPS, 10 ng/mL) under both normoxic and hypoxic (via the addition of 100 µM cobalt chloride) environmental conditions. In both normoxic and hypoxic LPS-stimulated conditions, SCFAs increased the secretion of adiponectin and reduced the secretion of resistin, interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1/C-C motif chemokine ligand (CCL)2, and RANTES/CCL5, in addition to reducing intracellular protein levels of activated (i.e., the ratio of phosphorylated-to-total) nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) p65 and signal transducer and activator of transcription 3 (STAT3) (p < 0.05). Additionally, SCFA treatment reduced leptin secretion only in LPS-stimulated normoxic environmental conditions compared to control (p < 0.05). In normoxic conditions, SCFA + LPS increased mRNA expression of genes involved in fat storage), fatty acid recycling, and lipolysis, whereas in hypoxic conditions, SCFA + LPS decreased mRNA expression of genes involved in fat storage and triglyceride synthesis (p < 0.05), indicating different effects of SCFAs on adipocyte metabolic function depending on hypoxia status. Collectively, combined SCFAs in a 3:1:1 ratio beneficially modify the adipocyte adipokine secretory profile under both normoxic and hypoxic environmental conditions.