Systemic bile acids induce insulin resistance in a TGR5-independent manner.

Syring KE, Cyphert TJ, Beck TC, Flynn CR, Mignemi NA, McGuinness OP
Am J Physiol Endocrinol Metab. 2019 316 (5): E782-E793

PMID: 30779633 · PMCID: PMC6732652 · DOI:10.1152/ajpendo.00362.2018

Bile acids are involved in the emulsification and absorption of dietary fats, as well as acting as signaling molecules. Recently, bile acid signaling through farnesoid X receptor and G protein-coupled bile acid receptor (TGR5) has been reported to elicit changes in not only bile acid synthesis but also metabolic processes, including the alteration of gluconeogenic gene expression and energy expenditure. A role for bile acids in glucose metabolism is also supported by a correlation between changes in the metabolic state of patients (i.e., obesity or postbariatric surgery) and altered serum bile acid levels. However, despite evidence for a role for bile acids during metabolically challenging settings, the direct effect of elevated bile acids on insulin action in the absence of metabolic disease has yet to be investigated. The present study examines the impact of acutely elevated plasma bile acid levels on insulin sensitivity using hyperinsulinemic-euglycemic clamps. In wild-type mice, elevated bile acids impair hepatic insulin sensitivity by blunting the insulin suppression of hepatic glucose production. The impaired hepatic insulin sensitivity could not be attributed to TGR5 signaling, as TGR5 knockout mice exhibited a similar inhibition of insulin suppression of hepatic glucose production. Canonical insulin signaling pathways, such as hepatic PKB (or Akt) activation, were not perturbed in these animals. Interestingly, bile acid infusion directly into the portal vein did not result in an impairment in hepatic insulin sensitivity. Overall, the data indicate that acute increases in circulating bile acids in lean mice impair hepatic insulin sensitivity via an indirect mechanism.

MeSH Terms (19)

Animals Bile Acids and Salts Cholagogues and Choleretics Cholic Acids Deoxycholic Acid Gene Expression Profiling Gluconeogenesis Glucose Clamp Technique Hepatocytes Hep G2 Cells Humans Insulin Resistance Liver Mice Mice, Knockout Obesity Primary Cell Culture Receptors, G-Protein-Coupled Taurocholic Acid

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