Increased plasma citrulline in mice marks diet-induced obesity and may predict the development of the metabolic syndrome

Sailer, Manuela, Dahlhoff, Christoph, Giesbertz, Pieter, Eidens, Mena K, de Wit, Nicole, Rubio-Aliaga, Isabel, Boekschoten, Mark V, Müller, Michael and Daniel, Hannelore (2013) Increased plasma citrulline in mice marks diet-induced obesity and may predict the development of the metabolic syndrome. PLoS One, 8 (5). ISSN 1932-6203

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Abstract

In humans, plasma amino acid concentrations of branched-chain amino acids (BCAA) and aromatic amino acids (AAA) increase in states of obesity, insulin resistance and diabetes. We here assessed whether these putative biomarkers can also be identified in two different obesity and diabetic mouse models. C57BL/6 mice with diet-induced obesity (DIO) mimic the metabolic impairments of obesity in humans characterized by hyperglycemia, hyperinsulinemia and hepatic triglyceride accumulation. Mice treated with streptozotocin (STZ) to induce insulin deficiency were used as a type 1 diabetes model. Plasma amino acid profiling of two high fat (HF) feeding trials revealed that citrulline and ornithine concentrations are elevated in obese mice, while systemic arginine bioavailability (ratio of plasma arginine to ornithine + citrulline) is reduced. In skeletal muscle, HF feeding induced a reduction of arginine levels while citrulline levels were elevated. However, arginine or citrulline remained unchanged in their key metabolic organs, intestine and kidney. Moreover, the intestinal conversion of labeled arginine to ornithine and citrulline in vitro remained unaffected by HF feeding excluding the intestine as prime site of these alterations. In liver, citrulline is mainly derived from ornithine in the urea cycle and DIO mice displayed reduced hepatic ornithine levels. Since both amino acids share an antiport mechanism for mitochondrial import and export, elevated plasma citrulline may indicate impaired hepatic amino acid handling in DIO mice. In the insulin deficient mice, plasma citrulline and ornithine levels also increased and additionally these animals displayed elevated BCAA and AAA levels like insulin resistant and diabetic patients. Therefore, type 1 diabetic mice but not DIO mice show the "diabetic fingerprint" of plasma amino acid changes observed in humans. Additionally, citrulline may serve as an early indicator of the obesity-dependent metabolic impairments.

Item Type: Article
Additional Information: © 2013 Sailer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Uncontrolled Keywords: amino acids, aromatic,animals,citrulline,diet, high-fat,insulin,intestine, small,kidney,male,metabolic syndrome x,mice,mice, inbred c57bl,muscle, skeletal,obesity,ornithine
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 10 Jun 2014 20:32
Last Modified: 14 Sep 2020 07:03
URI: https://ueaeprints.uea.ac.uk/id/eprint/47635
DOI: 10.1371/journal.pone.0063950

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