Citrulline production and protein homeostasis.

PURPOSE OF REVIEW: Protein homeostasis is crucial for maintaining cell functions. Citrulline, an endogenous amino acid, is considered as an efficient source of arginine at systemic and cellular level. Accumulating evidence, obtained from citrulline supplementation studies, suggest anabolic properties especially in malnourished rodents and human. Although these studies might suggest a key role for citrulline in protein homeostasis, the supraphysiological concentrations of citrulline do not allow to conclude on a physiological role. This review aimed to assess the role of endogenous citrulline production on protein homeostasis. RECENT FINDINGS: According to recent studies, endogenous citrulline, through its regulating effect on nitric oxide production, seems to play a key role in regulating endothelial and immune functions. We can assume that citrulline-dependent endothelial vasodilation could improve organ perfusion and thus amino acid and insulin supply. Furthermore, citrulline regulates immune cells and thus could regulate inflammation and indirectly protein metabolism. SUMMARY: Although we have currently no direct evidence of a regulating role of endogenous citrulline production on protein homeostasis, we can hypothesize that physiologically through its role in endothelial and immune function, citrulline could indirectly participate to protein homeostasis.

Lean Body Mass and Endocrine Status But Not Age Are Determinants of Resting Energy Expenditure in Patients with Non-Small Cell Lung Cancer.

BACKGROUND: Cancer and aging are both frequently associated with malnutrition, a factor of poor prognosis. In adult cancer patients, this may be related in part to impaired energy metabolism, with higher than predicted resting energy expenditure (REE) in about 50% of patients. We hypothesized that frequently impaired energy metabolism in elderly patients could potentiate cancer-associated hypermetabolism, further promoting risk of malnutrition. OBJECTIVE: To study the hypermetabolic response to cancer in a predominantly aged population and the potential underlying determinants. METHODS: This was a cross-sectional exploratory study in patients with non-small-cell lung cancer. REE was measured by indirect calorimetry. Body composition was determined from a single CT scan imaging at L3 level. Endocrine, inflammatory, nutritional and metabolic status were evaluated. RESULTS: Twenty-seven patients, of median age 68 years (range 32-81) completed the study. In this population, mean measured REE was 7.5% higher than calculated REE. Sex and weight accounted for about 51% of REE variations, whereas age accounted only for 4%. However, these parameters did not explain the REE-to-lean body mass (LBM) ratio variations, suggesting that they influenced REE only through their effect on LBM. Among the other parameters evaluated, only the thyroid-stimulating hormone and interleukin-6 plasma levels appeared to have an influence on REE. The study of the consequences of this increase in REE-to-LBM ratio showed a growing inability of patients to meet their energy needs but showed no effect on nutritional markers such as transthyretin. CONCLUSIONS: The results of this pilot study suggest that in our population, age was not an important factor of REE. The elevated energy metabolism was associated with patients' failure to increase their energy intakes sufficiently, which can contribute to the development of cachexia. CLINICAL TRIAL: This trial is registered at clinicaltrials.gov under NCT0314.

Oral arginine supplementation protects female mice from the onset of non-alcoholic steatohepatitis.

Dietary arginine (Arg) supplementation has been proposed to have positive effects on the development of liver diseases. In the present study, we investigate if an oral Arg supplementation in diet protects mice fed a fructose, fat and cholesterol enriched Western-style diet (WSD) from the development of non-alcoholic steatohepatitis (NASH). Female C57BL/6J mice were fed a liquid control diet or a liquid WSD ± Arg (2.49 g/kg body weight/day) for 6 weeks. Indices of liver injury, glucose metabolism and intestinal permeability were determined. While Arg supplementation had no effects on body weight gain, fasting blood glucose levels were significantly lower in WSD+Arg-fed mice than in C+Arg-fed animals. WSD-fed mice developed liver steatosis accompanied with inflammation, both being significantly attenuated in WSD+Arg-fed mice. These effects of Arg supplementation went along with a protection against WSD-induced decreased tight junction protein levels in the upper parts of the small intestine, increased levels of bacterial endotoxin in portal plasma as well as increased hepatic toll-like receptor-4 mRNA and 4-hydroxynonenal protein adduct levels. In conclusion, Arg supplementation may protect mice from the development of NASH.

Citrulline decreases hepatic endotoxin-induced injury in fructose-induced non-alcoholic liver disease: an ex vivo study in the isolated perfused rat liver.

Steatosis can sensitise the liver to various challenges and favour the development of non-alcoholic fatty liver disease (NAFLD). In this context, fructose feeding promotes endotoxin translocation from the gut, contributing to disease progression via an inflammatory process. Citrulline is protective against fructose-induced NAFLD; we hypothesised that this property might be related to its anti-inflammatory and antioxidative action against endotoxin-induced hepatic injuries. This hypothesis was evaluated in a model of perfused liver isolated from NAFLD rats. Male Sprague-Dawley rats (n 30) were fed either a standard rodent chow or a 60 % fructose diet alone, or supplemented with citrulline (1 g/kg per d) for 4 weeks. After an evaluation of their metabolic status, fasted rats received an intraperitoneal injection of lipopolysaccharide (LPS) (2·5 mg/kg). After 1 h, the livers were isolated and perfused for 1 h to study liver function and metabolism, inflammation and oxidative status. In vivo, citrulline significantly decreased dyslipidaemia induced by a high-fructose diet and insulin resistance. In the isolated perfused rat livers, endotoxaemia resulted in higher cytolysis (alanine aminotransferase release) and higher inflammation (Toll-like receptor 4) in livers of fructose-fed rats, and it was prevented by citrulline supplementation. Oxidative stress and antioxidative defences were similar in all three groups. Amino acid exchanges and metabolism (ammonia and urea release) were only slightly different between the three groups. In this context of mild steatosis, our results suggest that fructose-induced NAFLD leads to an increased hepatic sensitivity to LPS-induced inflammation. Citrulline-induced restriction of the inflammatory process may thus contribute to the prevention of NAFLD.

Oral citrulline supplementation protects female mice from the development of non-alcoholic fatty liver disease (NAFLD).

PURPOSE: Impairments of intestinal barrier function are discussed as risk factors for the development and progression of non-alcoholic fatty liver disease (NAFLD). Studies suggest an association between arginine/citrulline homeostasis and the development of liver damages. Here, the effect of an oral L-citrulline (Cit) supplement on the development of a Western-style diet (WSD)-induced NAFLD was determined in mice. METHODS: Female 6- to 8-week-old C57BL/6J mice were either pair-fed a liquid Western-style or control diet (C) ± 2.5 g/kg bodyweight Cit for 6 weeks (C + Cit or WSD + Cit). Indices of liver damage, glucose metabolism, intestinal barrier function and NO synthesis were measured. RESULTS: While bodyweight gain was similar between groups, markers of glucose metabolism like fasting blood glucose and HOMA index and markers of liver damage like hepatic triglyceride levels, number of neutrophils and plasminogen activator inhibitor-1 protein levels were significantly lower in WSD + Cit-fed mice when compared to WSD-fed mice only. Protein levels of the tight junction proteins occludin and zonula occludens-1 in duodenum were significantly lower in mice fed a WSD when compared to those fed a WSD + Cit (-~70 and -~60 %, respectively, P < 0.05), whereas portal endotoxin levels, concentration of 3-nitrotyrosine protein adducts in duodenum and toll-like receptor-4 mRNA expression in livers of WSD + Cit-fed mice were markedly lower than in WSD-fed mice (-~43 %, P = 0.056; -~80 and -~48 %, respectively, P < 0.05). CONCLUSION: Our data suggest that the protective effects of supplementing Cit on the development of NAFLD in mice are associated with a decreased translocation of endotoxin into the portal vein.

Hepatic steatosis: a role for citrulline.

PURPOSE OF REVIEW: The high worldwide prevalence of nonalcoholic fatty liver disease (NAFLD) makes it a major public health issue. Amino acids offer a promising approach for its prevention, and several experimental studies highlight the nutritional importance of citrulline in this setting. The purpose of this review is to discuss the potential interest of citrulline in the prevention and treatment of NAFLD. RECENT FINDINGS: Current findings shed light on the role of the gut-liver, adipose tissue-liver, and muscle-liver axes in NAFLD progression. Recent experimental studies have produced evidence for a role of citrulline in controlling the pathophysiological mechanisms involved in NAFLD through its action on these three axes. Data are needed to distinguish between direct and indirect effects of citrulline on the liver and between a specific effect and a nitrogen supply-related effect. SUMMARY: Good level of experimental evidence suggests that citrulline supply may be associated with an attenuation of NAFLD development, but further human studies are now needed to support these findings. This review may help define novel strategies to control fatty liver diseases.

Indications and contraindications for infusing specific amino acids (leucine, glutamine, arginine, citrulline, and taurine) in critical illness.

PURPOSE OF REVIEW: The review assesses the utility of supplementing parenteral or enteral nutrition of ICU patients with each of five specific amino acids that display pharmacological properties. Specifying indications implies also stating contraindications.Combined supplementation of amino acids with ω3-fatty acids and/or trace elements (immune-enhancing diets) will not be considered in this review because these mixtures do not allow the role of amino acids in the effect (positive or negative) of the mixture to be isolated, and so cannot show whether or not supplementation of a given amino acid is indicated. RECENT FINDINGS: After decades of unbridled use of glutamine (GLN) supplementation in critically ill patients, recent large trials have brought a note of caution, indicating for example that GLN should not be used in patients with multiple organ failure. Yet these large trials do not change the conclusions of recent meta-analyses. Arginine (ARG), as a single dietary supplement, is probably not harmful in critical illness, in particular in a situation of ARG deficiency syndrome with low nitric oxide production. Citrulline supplementation strongly improves microcirculation in animal models with gut injury, but clinical studies are lacking. Taurine has a potent protective effect against ischemic reperfusion injury. SUMMARY: Amino acid-based pharmaconutrition has displayed familiar 'big project' stages: enthusiasm (citrulline and taurine), doubt (GLN), hunt for the guilty (ARG), and backpedalling (leucine). Progress in this field is very slow, and sometimes gives way to retreat, as demonstrated by recent large trials on GLN supplementation.

Leucine and Mammalian Target of Rapamycin-Dependent Activation of Muscle Protein Synthesis in Aging.

The preservation or restoration of muscle mass is of prime importance for healthy aging. However, aging has been repeatedly shown to be associated with resistance of muscle to the anabolic effects of feeding. Leucine supplementation has been proposed as a possible strategy because of its regulatory role on protein homeostasis. Indeed, it acts independently of growth factors and leads to enhanced cap-dependent mRNA translation initiation and increased protein synthesis. Leucine acts as a signaling molecule directly at the muscle level via the activation of mammalian/mechanistic target of rapamycin complex 1 (mTORC1). However, in aged muscle, mTORC1 activation seems to be impaired, with decreased sensitivity and responsiveness of muscle protein synthesis to amino acids, whereas the phosphorylation state of several components of this signaling pathway appears to be higher in the basal state. This may stem from specific age-related impairment of muscle signaling and from decreased nutrient and growth factor delivery to the muscle. Whether aging per se affects mTORC1 signaling remains to be established, because aging is frequently associated with inadequate protein intake, decreased insulin sensitivity, inactivity, inflammatory processes, etc. Whatever its origin, this anabolic resistance to feeding can be mitigated by quantitative and qualitative manipulation of protein supply, such as leucine supplementation; however, there remains the question of possible adverse effects of long-term, high-dose leucine supplementation in terms of insulin resistance and tumorigenesis.

Preventive effects of citrulline on Western diet-induced non-alcoholic fatty liver disease in rats.

A Western diet induces insulin resistance, liver steatosis (non-alcoholic fatty liver disease (NAFLD)) and intestinal dysbiosis, leading to increased gut permeability and bacterial translocation, thus contributing to the progression of NAFLD to non-alcoholic steatohepatitis. In the present study, we sought, in a model of Western diet-induced NAFLD, to determine whether citrulline (Cit), an amino acid that regulates protein and energy metabolism, could decrease Western diet-induced liver injuries, as well as the mechanisms involved. Sprague-Dawley rats were fed a high-fat diet (45 %) and fructose (30 %) in drinking water or a control diet associated with water (group C) for 8 weeks. The high-fat, high-fructose diet (Western diet) was fed either alone (group WD) or with Cit (1 g/kg per d) (group WDC) or an isonitrogenous amount of non-essential amino acids (group WDA). We evaluated nutritional and metabolic status, liver function, intestinal barrier function, gut microbiota and splanchnic inflammatory status. Cit led to a lower level of hepatic TAG restricted to microvesicular lipid droplets and to a lower mRNA expression of CCAAT-enhancer-binding protein homologous protein, a marker of endoplasmic reticulum stress, of pro-inflammatory cytokines Il6 (P<0·05) and Tnfα, and of toll-like receptor 4 (Tlr4) (P<0·05). Cit also improved plasma TAG and insulin levels. In the colon, it decreased inflammation (Tnfα and Tlr4 expressions) and increased claudin-1 protein expression. This was associated with higher levels of Bacteroides/Prevotella compared with rats fed the Western diet alone. Cit improves Western diet-induced liver injuries via decreased lipid deposition, increased insulin sensitivity, lower inflammatory process and preserved antioxidant status. This may be related in part to its protective effects at the gut level.

Oral Glutamine Supplementation Protects Female Mice from Nonalcoholic Steatohepatitis.

BACKGROUND: Genetic factors, a diet rich in fat and sugar, and an impaired intestinal barrier function are critical in the development of nonalcoholic steatohepatitis (NASH). The nonessential amino acid glutamine (Gln) has been suggested to have protective effects on intestinal barrier function but also against the development of liver diseases of various etiologies. OBJECTIVE: The effect of oral Gln supplementation on the development of Western-style diet (WSD)-induced NASH in mice was assessed. METHODS: Female 6- to 8-wk-old C57BL/6J mice were pair-fed a control (C) diet or a WSD alone or supplemented with 2.1 g l-Gln/kg body weight for 6 wk (C+Gln or WSD+Gln). Indexes of liver damage, lipid peroxidation, and glucose metabolism and endotoxin concentrations were measured. RESULTS: Although Gln supplementation had no effect on the loss of the tight junction protein occludin, the increased portal endotoxin and fasting glucose concentrations found in WSD-fed mice, markers of liver damage (e.g., nonalcoholic fatty liver disease activity score and number of neutrophils in the liver) were significantly lower in the WSD+Gln group than in the WSD group (~47% and ~60% less, respectively; P < 0.05). Concentrations of inducible nitric oxide synthase (iNOS) protein and 3-nitrotyrosin protein adducts were significantly higher in livers of WSD-fed mice than in all other groups (~8.6- and ~1.9-fold higher, respectively, compared with the C group; P < 0.05) but did not differ between WSD+Gln-, C-, and C+Gln-fed mice. Hepatic tumor necrosis factor α and plasminogen activator inhibitor 1 concentrations were significantly higher in WSD-fed mice (~1.6- and ~1.8-fold higher, respectively; P < 0.05) but not in WSD+Gln-fed mice compared with C mice. CONCLUSION: Our data suggest that the protective effects of oral Gln supplementation on the development of WSD-induced NASH in mice are associated with protection against the induction of iNOS and lipid peroxidation in the liver.

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

BACKGROUND: Fructose induces nonalcoholic fatty liver disease (NAFLD). Citrulline (Cit) may exert a beneficial effect on steatosis. OBJECTIVE: We compared the effects of Cit and an isonitrogenous mixture of nonessential amino acids (NEAAs) on fructose-induced NAFLD. METHODS: Twenty-two male Sprague Dawley rats were randomly assigned into 4 groups (n = 4-6) to receive for 8 wk a 60% fructose diet, either alone or supplemented with Cit (1 g · kg(-1) · d(-1)), or an isonitrogenous amount of NEAAs, or the same NEAA-supplemented diet with starch and maltodextrin instead of fructose (controls). Nutritional and metabolic status, liver function, and expression of genes of hepatic lipid metabolism were determined. RESULTS: Compared with controls, fructose led to NAFLD with significantly higher visceral fat mass (128%), lower lean body mass (-7%), insulin resistance (135%), increased plasma triglycerides (TGs; 67%), and altered plasma amino acid concentrations with decreased Arg bioavailability (-27%). This was corrected by both NEAA and Cit supplementation. Fructose caused a 2-fold increase in the gene expression of fatty acid synthase (Fas) and 70% and 90% decreases in that of carnitine palmitoyl-transferase 1a and microsomal TG transfer protein via a nearly 10-fold higher gene expression of sterol regulatory element-binding protein-1c (Srebp1c) and carbohydrate-responsive element-binding protein (Chrebp), and a 90% lower gene expression of peroxisome proliferator-activated receptor α (Ppara). NEAA or Cit supplementation led to a Ppara gene expression similar to controls and decreased those of Srebp1c and Chrebp in the liver by 50-60%. Only Cit led to Fas gene expression and Arg bioavailability similar to controls. CONCLUSION: In our rat model, Cit and NEAAs effectively prevented fructose-induced NAFLD. On the basis of literature data and our findings, we propose that NEAAs may exert their effects specifically on the liver, whereas Cit presumably acts at both the hepatic and whole-body level, in part via improved peripheral Arg metabolism.

In vitro anti-inflammatory effects of citrulline on peritoneal macrophages in Zucker diabetic fatty rats.

In type 2 diabetes (T2D) macrophage dysfunction increases susceptibility to infection and mortality. This may result from the associated decreased plasma concentration of arginine, an amino acid that plays an important role in immunity. In vitro, increasing arginine availability leads to an improvement in macrophage function; however, arginine supplementation in diabetic obese patients may be detrimental. The aim of the present study was to assess in vitro whether citrulline, an arginine precursor, could replace arginine in the regulation of macrophage function under a condition of diabetes and obesity. Peritoneal macrophages from diabetic obese or lean rats were incubated for 6 h in an arginine-free medium, in the presence of increasing citrulline concentrations (0·1, 0·5, 1 or 2 mmol/l). Cytokine and NO production was determined. Peritoneal macrophages from either lean or diabetic obese rats produced NO, and at higher levels in the cells from lean rats. In diabetic obese rats, TNF-α production decreased with increasing citrulline concentrations, but was higher than that in the cells from lean rats. In contrast, IL-6 production increased with increasing citrulline concentrations. The present experiment shows that citrulline is effectively used for NO production and regulates cytokine production in macrophages from diabetic obese rats. This effect warrants in vivo evaluation in T2D-related inflammation.

Effect of oral taurine on morbidity and mortality in elderly hip fracture patients: a randomized trial.

Hip fracture patients represent a large part of the elderly surgical population and face severe postoperative morbidity and excessive mortality compared to adult surgical hip fracture patients. Low antioxidant status and taurine deficiency is common in the elderly, and may negatively affect postoperative outcome. We hypothesized that taurine, an antioxidant, could improve clinical outcome in the elderly hip fracture patient. A double blind randomized, placebo controlled, clinical trial was conducted on elderly hip fracture patients. Supplementation started after admission and before surgery up to the sixth postoperative day. Markers of oxidative status were measured during hospitalization, and postoperative outcome was monitored for one year after surgery. Taurine supplementation did not improve in-hospital morbidity, medical comorbidities during the first year, or mortality during the first year. Taurine supplementation lowered postoperative oxidative stress, as shown by lower urinary 8-hydroxy-2-deoxyguanosine levels (Generalized estimating equations (GEE) analysis average difference over time; regression coefficient (Beta): -0.54; 95% CI: -1.08--0.01; p = 0.04), blunted plasma malondialdehyde response (Beta: 1.58; 95% CI: 0.00-3.15; p = 0.05) and a trend towards lower lactate to pyruvate ratio (Beta: -1.10; 95% CI: -2.33-0.12; p = 0.08). We concluded that peri-operative taurine supplementation attenuated postoperative oxidative stress in elderly hip fracture patients, but did not improve postoperative morbidity and mortality.

Glutamine in the intensive care unit.

PURPOSE OF REVIEW: To analyze the recent literature (2011-2013) on glutamine supplementation of parenteral and enteral nutrition in critically ill patients. Potential confounding factors that may explain conflicting results are suggested. RECENT FINDINGS: Some recent, prospective, multicenter trials and two small trials yielded conflicting results that weigh heavily in the conclusions of a recent meta-analysis. Heterogeneity of the patients enrolled (especially in terms of injury severity, age, and basal nutritional status) and difficulties in identifying patients truly in need of glutamine supplementation may explain the discrepancies. SUMMARY: Glutamine supplementation has been recognized as beneficial in acutely injured patients. However, recent conflicting results in either 'real-life conditions' or very severe situations suggest that its indications need to be more precisely determined.

Effects of a diabetes-specific enteral nutrition on nutritional and immune status of diabetic, obese, and endotoxemic rats: interest of a graded arginine supply.

OBJECTIVE: Obese and type 2 diabetic patients present metabolic disturbance-related alterations in nonspecific immunity, to which the decrease in their plasma arginine contributes. Although diabetes-specific formulas have been developed, they have never been tested in the context of an acute infectious situation as can be seen in intensive care unit patients. Our aim was to investigate the effects of a diabetes-specific diet enriched or not with arginine in a model of infectious stress in a diabetes and obesity situation. As a large intake of arginine may be deleterious, this amino acid was given in graded fashion. DESIGN: Randomized, controlled experimental study. SETTING: University research laboratory. SUBJECTS: Zucker diabetic fatty rats. INTERVENTIONS: Gastrostomized Zucker diabetic fatty rats were submitted to intraperitoneal lipopolysaccharide administration and fed for 7 days with either a diabetes-specific enteral nutrition without (G group, n=7) or with graded arginine supply (1-5 g/kg/day) (GA group, n=7) or a standard enteral nutrition (HP group, n=10). MEASUREMENTS AND MAIN RESULTS: Survival rate was better in G and GA groups than in the HP group. On day 7, plasma insulin to glucose ratio tended to be lower in the same G and GA groups. Macrophage tumor necrosis factor-α (G: 5.0±1.1 ng/2×106 cells·hr⁻¹; GA: 3.7±0.8 ng/2×106 cells·hr⁻¹; and HP: 1.7±0.6 ng/2×106 cells·hr⁻¹; p<.05 G vs. HP) and nitric oxide (G: 4.5±1.1 ng/2×106 cells·hr⁻¹; GA: 5.1±1.0 ng/2×106 cells·hr⁻¹; and HP: 1.0±0.5 nmol/2×106 cells·hr⁻¹; p<.05 G and GA vs. HP) productions were higher in the G and GA groups compared to the HP group. Macrophages from the G and GA groups exhibited increased arginine consumption. CONCLUSIONS: In diabetic obese and endotoxemic rats, a diabetes-specific formula leads to a lower mortality, a decreased insulin resistance, and an improvement in peritoneal macrophage function. Arginine supplementation has no additional effect. These data support the use of such disease-specific diets in critically ill diabetic and obese patients.

Chemically Defined Formulas, Symbiotics and Cow's Milk Protein Allergy.

Cow's milk protein (CMP) allergy (CMPA) is the earliest and most common food allergy in children [...].

Branched-Chain Amino Acids and Insulin Resistance, from Protein Supply to Diet-Induced Obesity.

For more than a decade, there has been a wide debate about the branched-chain amino acids (BCAA) leucine, valine, and isoleucine, with, on the one hand, the supporters of their anabolic effects and, on the other hand, those who suspect them of promoting insulin resistance. Indeed, the role of leucine in the postprandial activation of protein synthesis has been clearly established, even though supplementation studies aimed at taking advantage of this property are rather disappointing. Furthermore, there is ample evidence of an association between the elevation of their plasma concentrations and insulin resistance or the risk of developing type 2 diabetes, although there are many confounding factors, starting with the level of animal protein consumption. After a summary of their metabolism and anabolic properties, we analyze in this review the factors likely to increase the plasma concentrations of BCAAs, including insulin-resistance. After an analysis of supplementation or restriction studies in search of a direct role of BCAAs in insulin resistance, we discuss an indirect role through some of their metabolites: branched-chain keto acids, C3 and C5 acylcarnitines, and hydroxyisobutyrate. Overall, given the importance of insulin in the metabolism of these amino acids, it is very likely that small alterations in insulin sensitivity are responsible for a reduction in their catabolism long before the onset of impaired glucose tolerance.

Intestinal microbiota in inflammation and insulin resistance: relevance to humans.

PURPOSE OF REVIEW: The gut microbiota is a very complex ecosystem which interacts extensively with the host, influencing multiple metabolic and physiological functions. Several diseases have been shown to be associated with specific alterations in gut microbiota. It is more and more underscored as playing a major role in the development of insulin resistance and inflammation associated with excess weight gain. RECENT FINDINGS: Recent studies in obese patients have shown perturbations in gut microbiota with a weight gain-associated increase in the Firmicutes/Bacteroidetes ratio ameliorated by various attempts at inducing weight loss. SUMMARY: Intestinal microbiota may contribute to the development of inflammation and insulin resistance by two main mechanisms. First, gut microbiota might facilitate energy harvest from the gut leading via perturbation in energy homeostasis to fat deposition and increased adipokine production and plasma free fatty acid levels both contributing to insulin resistance and inflammation. Alternatively, it can initiate an inflammatory process either originating from the intestine or generated at the peripheral level via endotoxin leakage into the blood from the intestine, both leading secondarily to insulin resistance.

A central role for polyamines in microtubule assembly in cells.

Owing to preferential electrostatic adsorption of multivalent cations on highly anionic surfaces, natural multivalent polyamines and especially quadrivalent spermine can be considered as potential regulators of the complex dynamical properties of anionic MTs (microtubules). Indeed, the C-terminal tails of tubulin display many negative residues in a row which should enable the formation of a correlated liquid-like phase of multivalent counterions on its surface. Although it is known that polyamine counterions promote MT assembly in vitro, little is known about the relevance of this interaction in vivo. In the present study, we have explored the relationship between polyamine levels and MT assembly in HeLa and epithelial NRK (normal rat kidney) cells using DFMO (alpha-difluoromethylornithine), an irreversible inhibitor of ornithine decarboxylase, and APCHA [N-(3-aminopropyl)-N-cyclohexylamine], a spermine synthase inhibitor. Under conditions of intracellular polyamine depletion, the MT network is clearly disrupted and the MT mass decreases. Addition of spermine to polyamine-depleted cells reverses this phenotype and rapidly promotes the extensions of the MT network. Finally, we show that polyamine levels modulate the coating of MTs with MAP4 (MT-associated protein 4), an MT-stabilizing protein, and the spatial distribution of EB1 (end-binding protein 1), an MT plus-end-binding protein. In addition, polyamines favour the formation of gap junctions in NRK cells, a process which requires MT extensions at the cell periphery. The present study provides a basis for a better understanding of the role played by polyamines in MT assembly and establishes polyamine metabolism as a potential cellular target for modulating MT functions.

Obesity, Nutrients and the Immune System in the Era of COVID-19.

The past year has shown that obesity is a risk factor for severe complications of SARS-CoV-2 infection. Excess fat mass during obesity is known to be a risk factor for chronic diseases but also for severe infections and infectious complications. We have focused here on the elements responsible for this particular susceptibility to infections and more specifically to COVID-19. Excess fat is, in itself, responsible for alterations of the immune system by disrupting the production and function of immune cells. Indeed, hypertrophic adipocytes produce more pro-inflammatory adipokines (including cytokines). The increase in their apoptosis induces a release of pro-inflammatory compounds into the circulation and a recruitment of pro-inflammatory macrophages into the adipose tissue. A chronic systemic inflammatory state is then observed. In addition, diet, apart from its role in the development of adipose tissue, can also affect the immune system, with excess simple sugars and saturated fats exerting pro-inflammatory effects. This inflammation, the adipokines released by the adipocytes, and the infiltration of lipids into the lymphoid organs affects the production of immune cells and, directly, the functions of these cells. The alteration of the immune system increases the risk of infection as well as complications, including secondary bacterial infections and septic states, and increases infection-related mortality. During COVID-19, the chronic inflammatory state promotes the cytokine shock, characteristic of severe forms, caused in particular by excessive activation of the NLRP3 inflammasome. Furthermore, in obese subjects, the already present endothelial dysfunction will render endothelial inflammation (endotheliitis) due to viral infiltration all the more severe. Added to this is a state of hypercoagulability and a decrease in respiratory capacity, leading to a risk of severe COVID-19 with cardiovascular complications, acute respiratory distress syndrome, and disseminated intravascular coagulation, which can lead to multiple organ failure and even death.