Dietary citrate acutely induces insulin resistance and markers of liver inflammation in mice.

Abstract

Citrate is widely used as a food additive being part of virtually all processed foods. Although considered inert by most of the regulatory agencies in the world, plasma citrate has been proposed to play immunometabolic functions in multiple tissues through altering a plethora of cellular pathways. Here, we used a short-term alimentary intervention (24 hours) with standard chow supplemented with citrate in amount corresponding to that found in processed foods to evaluate its effects on glucose homeostasis and liver physiology in C57BL/6J mice. Animals supplemented with dietary citrate showed glucose intolerance and insulin resistance as revealed by glucose and insulin tolerance tests. Moreover, animals supplemented with citrate in their food displayed fed and fasted hyperinsulinemia and enhanced insulin secretion during an oral glucose tolerance test. Citrate treatment also amplified glucose-induced insulin secretion in vitro in INS1-E cells. Citrate supplemented animals had increased liver PKCα activity and altered phosphorylation at serine or threonine residues of components of insulin signaling including IRS-1, Akt, GSK-3 and FoxO1. Furthermore, citrate supplementation enhanced the hepatic expression of lipogenic genes suggesting increased de novo lipogenesis, a finding that was reproduced after citrate treatment of hepatic FAO cells. Finally, liver inflammation markers were higher in citrate supplemented animals. Overall, the results demonstrate that dietary citrate supplementation in mice causes hyperinsulinemia and insulin resistance both in vivo and in vitro, and therefore call for a note of caution on the use of citrate as a food additive given its potential role in metabolic dysregulation.

• Authors: Jessica Ristow Branco, Amanda Moreira Esteves, João Gabriel Bernardo Leandro, Thainá M Demaria, Vilma Godoi, André Marette, Helber da Maia Valença, Manuella Lanzetti, Marie-Line Peyot, Salah Farfari, Marc Prentki, Patricia Zancan, Mauro Sola-Penna
• Journal: The Journal of nutritional biochemistry (J Nutr Biochem) Vol. 98 Pg. 108834 (12 2021) ISSN: 1873-4847 [Electronic] United States
• PMID: 34371126 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Insulin
• Citric Acid
• Glycogen Synthase Kinase 3
• Glucose

Topics

• Animals
• Citric Acid (adverse effects, pharmacology)
• Diet
• Glucose (metabolism)
• Glucose Intolerance (metabolism)
• Glucose Tolerance Test (methods)
• Glycogen Synthase Kinase 3 (metabolism)
• Hepatocytes (metabolism)
• Homeostasis
• Hyperinsulinism (etiology)
• Inflammation (metabolism)
• Insulin (metabolism)
• Insulin Resistance
• Lipogenesis (drug effects)
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (etiology)