Increased Plasma Citrulline in Mice Marks Diet-Induced Obesity and May Predict the Development of the Metabolic Syndrome

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.

Citrulline and Nonessential Amino Acids Prevent Fructose-Induced Nonalcoholic Fatty Liver Disease in Rats

“…Finally, Cit may act on insulin resistance via its effects on Arg availability and nitric oxide synthesis, which plays a key role in the regulation of energy jn.nutrition.org metabolism (44). Fructose induced a decrease in plasma Arg, as observed in other models of insulin resistance in rats (45), and Cit prevented fructose-induced alterations in Arg metabolism, as shown by the normalization of plasma Arg-to-ornithine + Cit and Arg-to-Lys ratios and of plasma Cit, which is a marker of insulin resistance (12,22). In conclusion, both NEAAs and Cit exert beneficial effects on fructose-induced NAFLD.…”

“…Plasma Cit was higher in the F group than in the other 3 groups (P < 0.05). The ratio of Arg to ornithine + Cit, which can be considered as a marker of global Arg metabolism (22), tended to be lower in the F group than in the CNEAA group (P = 0.08) ( Figure 1A). In the FCit group, but not in the FNEAA group, this ratio tended to be higher than in the F group (P = 0.09).…”

Comment on Adam et al. Metformin Effect on Nontargeted Metabolite Profiles in Patients With Type 2 Diabetes and in Multiple Murine Tissues. Diabetes 2016;65:3776–3785

“…The liver does not play any significant role in these interorgan exchanges because liver citrulline is almost exclusively synthesized locally and channeled into the urea cycle. Intestinal citrulline synthesis is preserved in metabolic syndrome (3). Current data thus point to possible modifications in renal citrulline utilization.…”

“…Prasanthi Jegatheesan, 1 Jean-Pascal De Bandt, 2,3 and Luc Cynober 2,3 Diabetes 2017;66:e1-e2 | DOI: 10.2337/db16-1592…”

Quercetin decreases high-fat diet induced body weight gain and accumulation of hepatic and circulating lipids in mice

“…The homoeostasis model assessment-insulin resistance (HOMA-IR) was calculated using the following formula: fasting plasma insulin (mIU/l) 9 fasting glucose (mmol/l)/ 22.5. Taurine levels in serum and hepatic tissues were quantified as described (Sailer et al 2013) using the aTRAQ Ò reagent (aTRAQ TM Reagent Kit, ABSciex, Foster City, USA).…”