Citrulline reduces glyceroneogenesis and induces fatty acid release in visceral adipose tissue from overweight rats

Joffin, Nolwenn; Jaubert, Anne-Marie; Durant, Sylvie; Bastin, Jean; Bandt, Jean‐Pascal De; Cynober, Luc; Moinard, Christophe; Coumoul, Xavier; Forest, Claude; Noirez, Philippe

doi:10.1002/mnfr.201400507

Cited by 16 publications

(44 citation statements)

References 53 publications

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“…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 …”

Section: Introductionmentioning

confidence: 96%

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

Goron

Lamarche

Blanchet

et al. 2019

J cachexia sarcopenia muscle

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Background Animal studies and clinical data support the interest of citrulline as a promising therapeutic for sarcopenia. Citrulline is known to stimulate muscle protein synthesis, but how it affects energy metabolism to support the highly energy‐dependent protein synthesis machinery is poorly understood. Methods Here, we used myotubes derived from primary culture of mouse myoblasts to study the effect of citrulline on both energy metabolism and protein synthesis under different limiting conditions. Results When serum/amino acid deficiency or energy stress (mild uncoupling) were applied, citrulline stimulated muscle protein synthesis by +22% and +11%, respectively. Importantly, this increase was not associated with enhanced energy status (ATP/ADP ratio) or mitochondrial respiration. We further analysed the share of mitochondrial respiration and thus of generated ATP allocated to different metabolic pathways by using specific inhibitors. Our results indicate that addition of citrulline allocated an increased share of mitochondrially generated ATP to the protein synthesis machinery under conditions of both serum/amino acid deficiency (+28%) and energy stress (+21%). This reallocation was not because of reduced ATP supply to DNA synthesis or activities of sodium and calcium cycling ion pumps. Conclusions Under certain stress conditions, citrulline increases muscle protein synthesis by specifically reallocating mitochondrial fuel to the protein synthesis machinery. Because ATP/ADP ratios and thus Gibbs free energy of ATP hydrolysis remained globally constant, this reallocation may be linked to decreased activation energies of one or several ATP (and GTP)‐consuming reactions involved in muscle protein synthesis.

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Section: Introductionmentioning

confidence: 96%

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

Goron

Lamarche

Blanchet

et al. 2019

J cachexia sarcopenia muscle

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“…Brown adipocytes express the uncoupling protein 1 (UCP1), which uncouples the oxidative phosphorylation from ATP production; as a result, the energy dissipates in the form of heat . Studies that examined the effect of citrulline on lipolysis showed that treatment with citrulline was effective in increasing basal lipolysis, reducing glyceroneogenesis, increasing palmitate oxidation in WAT explants, and incrementing the expression of UCP1, PPAR and PGC1‐α in young rats …”

Section: Introductionmentioning

confidence: 99%

Potential roles of Citrulline and watermelon extract on metabolic and inflammatory variables in diabetes mellitus, current evidence and future directions: A systematic review

Azizi

Mahdavi

Vaghef-Mehrabany

et al. 2019

Clin Exp Pharma Physio

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Objective Diabetes mellitus is a prevalent endocrine disorder worldwide. Citrulline is an α‐amino acid, which is abundant in watermelon, and a precursor of arginine and nitric oxide. Decreased bioavailability of nitric oxide is associated with insulin resistance. The present systematic review focused on the existing evidence of citrulline and watermelon extract effects on metabolic and inflammatory parameters in diabetes mellitus. Methods A systematic search of the databases PubMed, Scopus, EMBASE, ProQuest and Google Scholar was conducted for relevant papers published from inception until October 2018. All clinical trials, animal and in vitro studies published in the English language that assessed the role of citrulline and watermelon extract on diabetes mellitus, were eligible. Studies providing inadequate information were excluded. Results Out of 1262 articles we found, only eight articles met the inclusion criteria for analysis. In three studies an increase in the synthesis of nitric oxide was reported with citrulline and watermelon extract supplementation. Four studies showed a significant reduction in blood glucose after supplementation with watermelon extract, and two studies reported a decrease in a number of inflammatory biomarkers following citrulline supplementation. Although citrulline intake caused a significant reduction in HOMA‐IR in one study, inconsistent results were revealed on the effects of citrulline and watermelon extract on insulin levels and lipid profile. Conclusion Citrulline and watermelon extract could improve nitric oxide synthesis, glycaemic status and inflammation in diabetes mellitus. However, further studies are required to shed light on the underlying mechanisms.

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“…By contrast, citrulline supplementation was shown to reduce visceral fat depots in old rats (Moinard et al ., ). Experiments on visceral adipose tissue explants from overweight rats showed that citrulline directly induced phosphorylation of hormone‐sensitive lipase and downregulated glyceroneogenesis, allowing an increased fatty acid release from the adipose tissue (Joffin et al ., ). Surprisingly, these effects were not observed in the present study because mice receiving citrulline alone did not show any reduction in fat mass in comparison with DIO mice.…”

Section: Discussionmentioning

confidence: 97%

“…In the present study, the metabolic adaptations induced in vivo by the combination of citrulline and atorvastatin were consistent with those observed on glucose homeostasis, visceral obesity and liver steatosis, when NO production was enhanced (Duplain et al ., ; Cook et al ., ; Schild et al ., ). Our observations on adipose tissue mass are also in agreement with those obtained in overweight rats (Joffin et al ., ). In that study, citrulline stimulated visceral adipose tissue lipolysis, and the effect was abolished by pretreatment of explants with l ‐NAME (Joffin et al ., ).…”

Section: Discussionmentioning

confidence: 97%

“…Our observations on adipose tissue mass are also in agreement with those obtained in overweight rats (Joffin et al ., ). In that study, citrulline stimulated visceral adipose tissue lipolysis, and the effect was abolished by pretreatment of explants with l ‐NAME (Joffin et al ., ). Furthermore, our observations on plasma amino acid concentrations showed that atorvastatin interferes with citrulline and arginine metabolism, thus corroborating a possible increase in NO production.…”

Section: Discussionmentioning

confidence: 97%

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

Capel

Chabrier

Pitois

et al. 2015

British J Pharmacology

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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

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Citrulline reduces glyceroneogenesis and induces fatty acid release in visceral adipose tissue from overweight rats

Cited by 16 publications

References 53 publications

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

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

Potential roles of Citrulline and watermelon extract on metabolic and inflammatory variables in diabetes mellitus, current evidence and future directions: A systematic review

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

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