Combining citrulline with atorvastatin preserves glucose homeostasis in a murine model of diet‐induced obesity

Abstract

BACKGROUND AND PURPOSENO is a crucial regulator of energy and lipid metabolism, whose homeostasis is compromised during obesity. Combination of citrulline and atorvastatin potentiated NO production in vitro. Here we have assessed the effects of this combination in mice with diet-induced obesity (DIO). EXPERIMENTAL APPROACHC57BL/6J male mice were given a standard diet (control) or a high fat-high sucrose diet (DIO) for 8 weeks. DIO mice were then treated with DIO alone, DIO with citrulline, DIO with atorvastatin or DIO with citrulline and atorvastatin (DIOcit-stat) for 3 weeks. Thereafter, body composition, glucose tolerance, insulin sensitivity and liver fat metabolism were measured. KEY RESULTSDIOcit-stat mice showed lower body weight, fat mass and epididymal fat depots compared with other DIO groups. Unlike other DIO groups, glucose tolerance and insulin sensitivity of DIOcit-stat, along with blood glucose and insulin concentrations in response to feeding, were restored to control values. Refeeding-induced changes in liver lipogenic activity were also reduced in DIOcit-stat mice compared with those of DIO animals. This was associated with decreased gene expression of the transcription factor SREBP-1, liver X receptor α, ChREBP and of target lipogenic enzymes in the liver of DIOcit-stat mice compared with those of other DIO groups. CONCLUSIONS AND IMPLICATIONSThe citrulline-atorvastatin combination prevented fat mass accumulation and maintained glucose homeostasis in DIO mice. Furthermore, it potentiated inhibition of hepatic de novo lipogenesis activity. This combination has potential for preservation of glucose homeostasis in patients receiving statin therapy. AbbreviationsACC1 and Acc1, acetyl-CoA carboxylase 1; AMPKα, AMP-activated protein kinase α; ChREBP and Chrebp, carbohydrate-responsive element-binding protein; FAS and Fasn, fatty acid synthase; GPAM and Gpam, glycerol-3-phosphate acyltransferase; LXRα and Lxrα, liver X receptor α; RQ, respiratory quotient; SCD1 and Scd1, stearoyl-Coenzyme A desaturase 1; SREBP-1 and Srebf1, sterol regulatory element-binding transcription factor 1; VCO 2 , carbon dioxide production; VO 2 , oxygen consumption BJP British Journal of Pharmacology

Short‑term use of atorvastatin affects glucose homeostasis and suppresses the expression of LDL receptors in the pancreas of mice

“…A total of 16 ApoE-deficient mice were additionally divided into two groups and received a high-fat diet in addition to the treatment described above. As previously suggested by Capel et al ( 8 ), a 10 mg dose of atorvastatin has been repeatedly demonstrated to be effective on lipid metabolism in mice, and the relevant literature is listed in Table I ( 8 – 17 ). All mice were individually housed in plastic cages (30×20×13 cm) throughout the extent of the present study and maintained on a 12/12 h light/dark cycle (light off at noon) at constant temperature (22°C) with 10–15 hly cycles of fresh air and relative humidity (60±10%).…”

Citrulline decreases hepatic endotoxin-induced injury in fructose-induced non-alcoholic liver disease: anex vivostudy in the isolated perfused rat liver

“…Some of these studies showed a direct effect of Cit on adipocytes via a NO-dependent process, and on muscle cells through PI3K/MAPK/4E-BP1 signalling ( 13 , 26 ) . Cit supplementation is also associated with improved insulin sensitivity ( 27 ) and endothelial function ( 28 ) . Interestingly, in the experiments of the present study, Cit supplementation was found to be associated with higher plasma Arg, a trend toward normalisation of the Arg:Orn+Cit ratio – a marker of global Arg availability for NO synthesis ( 23 ) – and with a higher Arg:Lys ratio – a marker of Arg entry into the cells ( 22 ) .…”

Citrulline stimulates muscle protein synthesis, by reallocating ATP consumption to muscle protein synthesis

“…CIT ingestion by healthy aged rats increased muscle mitochondrial density and TFAM (a mitochondrial transcription factor) expression . CIT supplementation also increased energy expenditure in obese mice and, as a malate salt, improved phosphocreatine regeneration after exercise in humans . Moreover, CIT has been shown to affect lipid metabolism …”