Tributyrin attenuates obesity-associated inflammation and insulin resistance in high-fat-fed mice

Abstract

-The aim of this study was to investigate whether treatment with tributyrin (Tb; a butyrate prodrug) results in protection against diet-induced obesity and associated insulin resistance. C57BL/6 male mice fed a standard chow or high-fat diet were treated with Tb (2 g/kg body wt, 10 wk) and evaluated for glucose homeostasis, plasma lipid profile, and inflammatory status. Tb protected mice against obesity and obesityassociated insulin resistance and dyslipidemia without food consumption being affected. Tb attenuated the production of TNF␣ and IL-1␤ by peritoneal macrophages and their expression in adipose tissue. Furthermore, in the adipose tissue, Tb reduced the expression of MCP-1 and infiltration by leukocytes and restored the production of adiponectin. These effects were associated with a partial reversion of hepatic steatosis, reduction in liver and skeletal muscle content of phosphorylated JNK, and an improvement in muscle insulin-stimulated glucose uptake and Akt signaling. Although part of the beneficial effects of Tb are likely to be secondary to the reduction in body weight, we also found direct protective actions of butyrate reducing TNF␣ production after LPS injection and in vitro by LPS-or palmitic acid-stimulated macrophages and attenuating lipolysis in vitro and in vivo. The results, reported herein, suggest that Tb may be useful for the treatment and prevention of obesity-related metabolic disorders.butyrate; macrophages; diabetes; cytokines; white adipose tissue THE CHRONIC LOW-GRADE INFLAMMATION associated with obesity plays a central role as a link between excessive fat accumulation and the development of pathologies (20). In obesity, adipose tissue is markedly infiltrated by proinflammatory macrophages and other leukocytes that secrete proinflammatory cytokines and chemokines (20,41,50). The overproduction of these inflammatory mediators together with changes in adipokine production and nonesterified fatty acid (NEFA) levels leads to the development of insulin resistance. In addition to adipose tissue, several organs, including the liver (1) and hypothalamus (28), develop a proinflammatory profile in response to the excessive nutrient supply. This systemic inflammatory state is associated with the activation of intracellular signaling pathways such as JUN NH 2 -terminal kinase (JNK) and IB kinase-␤ (IKK␤) that in turn phosphorylate serine residues in the insulin receptor substrate, inhibiting tyrosine phosphorylation and the interaction with phosphatidylinositol-3 kinase (19,21).In accord with an important role of inflammation in the development of obesity-associated diseases, whole body deletion of intracellular kinases activated upon inflammation, namely JNK (18) and IKK␤ (1), and pharmacological treatment with anti-inflammatory agents such as -3 fatty acids and salsalate, a salicylate derivate, were demonstrated to protect mice from the deleterious effects of high-fat feeding and obesity on insulin sensitivity (16,32).Butyrate is a short-chain fatty acid (SCFA) produced during fermentation o...

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

“…A low concentration of butyrate was reported to inhibit the proliferation of T-lymphocytes, and to induce apoptosis in activated T-lymphocytes, but not primary macrophages 41) . In the adipose tissue of obese mice, butyrate decreased infiltration by leukocytes 24) . Therefore, butyrate might contribute to the attenuation of inflammation in obese adipose tissues via the induction of T-cell apoptosis.…”

“…For instance, Gao et al reported improved insulin resistance by long-term ingestion of sodium butyrate in obese mice 23) . Vinolo et al also reported that oral administration of tributyrin improved obesity-associated inflammation in mice fed a high-fat diet 24) ; however, the effect of butyrate on the mutual inflammatory response in adipocytes and macrophages has not yet been elucidated.…”

Gut Bacteria Products Prevent AKI Induced by Ischemia-Reperfusion

“…15 SCFA treatment has ameliorated colitis, airway disease, and metabolic syndrome in diet-induced obese mice. [16][17][18] So far, researchers suggested that SCFAs may operate in two manners: by binding G-protein membrane receptors (GPR41 and GPR43), 19,20 or by entering cells directly through transporter channels in the cellular membrane and working as histone deacetylase (HDAC) inhibitors. Thus, they could act by modulating epigenetic processes.…”

DNA Methylation Changes Induced by a High-Fat Diet and Fish Oil Supplementation in the Skeletal Muscle of Mice

“…table 1S; for all online suppl. material, see www.karger.com/doi/10.1159/000381777) [31,32]. For both diets, the lard:soybean oil ratio was 9:1.…”