Aderville Cabassi

Metabolic consequences and vulnerability to diet-induced obesity in male mice under chronic social stress.

Social and psychological factors interact with genetic predisposition and dietary habit in determining obesity. However, relatively few pre-clinical studies address the role of psychosocial factors in metabolic disorders. Previous studies from our laboratory demonstrated in male mice: 1) opposite status-dependent effect on body weight gain under chronic psychosocial stress; 2) a reduction in body weight in individually housed (Ind) male mice. In the present study these observations were extended to provide a comprehensive characterization of the metabolic consequences of chronic psychosocial stress and individual housing in adult CD-1 male mice. Results confirmed that in mice fed standard diet, dominant (Dom) and Ind had a negative energy balance while subordinate (Sub) had a positive energy balance. Locomotor activity was depressed in Sub and enhanced in Dom. Hyperphagia emerged for Dom and Sub and hypophagia for Ind. Dom also showed a consistent decrease of visceral fat pads weight as well as increased norepinephrine concentration and smaller adipocytes diameter in the perigonadal fat pad. On the contrary, under high fat diet Sub and, surprisingly, Ind showed higher while Dom showed lower vulnerability to obesity associated with hyperphagia. In conclusion, we demonstrated that social status under chronic stress and individual housing deeply affect mice metabolic functions in different, sometime opposite, directions. Food intake, the hedonic response to palatable food as well as the locomotor activity and the sympathetic activation within the adipose fat pads all represent causal factors explaining the different metabolic alterations observed. Overall this study demonstrates that pre-clinical animal models offer a suitable tool for the investigation of the metabolic consequences of chronic stress exposure and associated psychopathologies.

Severe Hypomagnesemia During Long-term Treatment With a Proton Pump Inhibitor

Severe hypomagnesemia is a serious clinical ondition that can be complicated by lifehreatening arrhythmias (ventricular tachycardia, entricular fibrillation, and torsades de pointes) nd neurologic manifestations (neuromuscular yperexcitability, frank ataxia, confusion, deirium, and seizures). Moreover, hypokalemia nd hypocalcemia frequently are documented as ccompanying electrolyte disorders. Hypomagesemia is relatively common in hospitalized atients, particularly in intensive care units. eading causes of the acquired disorder are malbsorption, uncontrolled diabetes, chemotherapy, cute pancreatitis, drugs, and refeeding. Very few cases of severe hypomagnesemia elated to long-term use of proton pump inhibiors (PPIs) have been published to date, and he likely pathogenetic mechanisms are not fully lucidated. We report a case of severe symptomatic hypoagnesemia in a patient treated with PPIs for any years because of Barrett esophagus. The ifferential diagnosis and potential pathogenetic echanisms are discussed within a more general onceptual framework of the pathophysiology tate of serum magnesium homeostasis.

Alterations of intestinal barrier and microbiota in chronic kidney disease

Recent studies have highlighted the close relationship between the kidney and the gastrointestinal (GI) tract--frequently referred to as the kidney--gut axis--in patients with chronic kidney disease (CKD). In this regard, two important pathophysiological concepts have evolved: (i) production and accumulation of toxic end-products derived from increased bacterial fermentation of protein and other nitrogen-containing substances in the GI tract, (ii) translocation of endotoxins and live bacteria from gut lumen into the bloodstream, due to damage of the intestinal epithelial barrier and quantitative/qualitative alterations of the intestinal microbiota associated with the uraemic milieu. In both cases, these gut-centred alterations may have relevant systemic consequences in CKD patients, since they are able to trigger chronic inflammation, increase cardiovascular risk and worsen uraemic toxicity. The present review is thus focused on the kidney-gut axis in CKD, with special attention to the alterations of the intestinal barrier and the local microbiota (i.e. the collection of microorganisms living in a symbiotic coexistence with their host in the intestinal lumen) and their relationships to inflammation and uraemic toxicity in CKD. Moreover, we will summarize the most important clinical data suggesting the potential for nutritional modulation of gut-related inflammation and intestinal production of noxious by-products contributing to uraemic toxicity in CKD patients.

The relation between the incidence of hypernatremia and mortality in patients with severe traumatic brain injury

IntroductionThe study was aimed at verifying whether the occurrence of hypernatremia during the intensive care unit (ICU) stay increases the risk of death in patients with severe traumatic brain injury (TBI). We performed a retrospective study on a prospectively collected database including all patients consecutively admitted over a 3-year period with a diagnosis of TBI (post-resuscitation Glasgow Coma Score ≤ 8) to a general/neurotrauma ICU of a university hospital, providing critical care services in a catchment area of about 1,200,000 inhabitants.MethodsDemographic, clinical, and ICU laboratory data were prospectively collected; serum sodium was assessed an average of three times per day. Hypernatremia was defined as two daily values of serum sodium above 145 mmol/l. The major outcome was death in the ICU after 14 days. Cox proportional-hazards regression models were used, with time-dependent variates designed to reflect exposure over time during the ICU stay: hypernatremia, desmopressin acetate (DDAVP) administration as a surrogate marker for the presence of central diabetes insipidus, and urinary output. The same models were adjusted for potential confounding factors.ResultsWe included in the study 130 TBI patients (mean age 52 years (standard deviation 23); males 74%; median Glasgow Coma Score 3 (range 3 to 8); mean Simplified Acute Physiology Score II 50 (standard deviation 15)); all were mechanically ventilated; 35 (26.9%) died within 14 days after ICU admission. Hypernatremia was detected in 51.5% of the patients and in 15.9% of the 1,103 patient-day ICU follow-up. In most instances hypernatremia was mild (mean 150 mmol/l, interquartile range 148 to 152). The occurrence of hypernatremia was highest (P = 0.003) in patients with suspected central diabetes insipidus (25/130, 19.2%), a condition that was associated with increased severity of brain injury and ICU mortality. After adjustment for the baseline risk, the incidence of hypernatremia over the course of the ICU stay was significantly related with increased mortality (hazard ratio 3.00 (95% confidence interval: 1.34 to 6.51; P = 0.003)). However, DDAVP use modified this relation (P = 0.06), hypernatremia providing no additional prognostic information in the instances of suspected central diabetes insipidus.ConclusionsMild hypernatremia is associated with an increased risk of death in patients with severe TBI. In a proportion of the patients the association between hypernatremia and death is accounted for by the presence of central diabetes insipidus.

Copeptin (CTproAVP), a new tool for understanding the role of vasopressin in pathophysiology

Abstract Arginine vasopressin (AVP) plays a key role in many physiologic and pathologic processes. The most important stimulus for AVP release is a change in plasma osmolality. AVP is also involved in the response and adaptation to stress. Reliable measurement of AVP is hindered by several factors. Over 90% of AVP is tightly bound to platelets, and its estimation is influenced by the number of platelets, incomplete removal of platelets or pre-analytical processing steps. Copeptin (CTproAVP), a 39-aminoacid glycopeptide, is a C-terminal part of the precursor pre-provasopressin (pre-proAVP). Activation of the AVP system stimulates CTproAVP secretion into the circulation from the posterior pituitary gland in equimolar amounts with AVP. Therefore CTproAVP directly reflects AVP concentration and can be used as a surrogate biomarker of AVP secretion. In many studies CTproAVP represents AVP levels and its behavior represents changes in plasma osmolality, stress and various disease states, and shows some of the various physiologic and pathophysiologic conditions associated with increased or decreased AVP. Increased CTproAVP concentration is described in several studies as a strong predictor of mortality in patients with chronic heart failure and acute heart failure. Autosomal polycystic kidney disease (ADPKD) patients have both central and nephrogenic defects in osmoregulation and CTproAVP balance. A possibility raised by these clinical observations is that CTproAVP may serve to identify patients who could benefit from an intervention aimed at countering AVP.

Characterization of a novel peripheral pro-lipolytic mechanism in mice: role of VGF-derived peptide TLQP-21.

The peptides encoded by the VGF gene are gaining biomedical interest and are increasingly being scrutinized as biomarkers for human disease. An endocrine/neuromodulatory role for VGF peptides has been suggested but never demonstrated. Furthermore, no study has demonstrated so far the existence of a receptor-mediated mechanism for any VGF peptide. In the present study, we provide a comprehensive in vitro, ex vivo and in vivo identification of a novel pro-lipolytic pathway mediated by the TLQP-21 peptide. We show for the first time that VGF-immunoreactivity is present within sympathetic fibres in the WAT (white adipose tissue) but not in the adipocytes. Furthermore, we identified a saturable receptor-binding activity for the TLQP-21 peptide. The maximum binding capacity for TLQP-21 was higher in the WAT as compared with other tissues, and selectively up-regulated in the adipose tissue of obese mice. TLQP-21 increases lipolysis in murine adipocytes via a mechanism encompassing the activation of noradrenaline/β-adrenergic receptors pathways and dose-dependently decreases adipocytes diameters in two models of obesity. In conclusion, we demonstrated a novel and previously uncharacterized peripheral lipolytic pathway encompassing the VGF peptide TLQP-21. Targeting the sympathetic nerve-adipocytes interaction might prove to be a novel approach for the treatment of obesity-associated metabolic complications.

Serum adipokine zinc α2-glycoprotein and lipolysis in cachectic and noncachectic heart failure patients: relationship with neurohormonal and inflammatory biomarkers

Chronic heart failure is often complicated by the development of cachexia with the loss of fat mass. Zinc α2-glycoprotein (ZAG) is a serum adipokine with lipolytic effects in cancer cachexia. We evaluated in patients with advanced heart failure with (CxHF) or without cachexia (nCxHF) the relationship of ZAG with circulating free fatty acid (FFA), as an index of lipolysis, and with other neurohormonal and inflammatory biomarkers. Two groups, nCxHF (n = 46) and CxHF (n = 18), the latter having a documented, involuntary, edema-free loss of body weight of at least 7.5% in the previous 6 months, underwent plasma determination of FFA, ZAG, norepinephrine (NE), tumor necrosis factor-α, and natriuretic peptide levels (atrial natriuretic, B-type natriuretic peptide). The patients were compared with age-matched healthy controls (CTR) (n = 21). Zinc α2-glycoprotein, atrial natriuretic peptide, B-type natriuretic peptide, and tumor necrosis factor-α circulating levels were similarly greater in CxHF and nCxHF than in CTR. Free fatty acid and NE were higher in CxHF than in nCxHF. A positive correlation between FFA and NE was found in both CxHF (r = 0.73, P < .01) and nCxHF (r = 0.48, P < .01) but only in CxHF between ZAG and FFA (r = 0.54, P = .02) and between ZAG and NE (r = 0.70, P < .01). No correlations between natriuretic peptides and ZAG were found. Serum ZAG levels are increased in advanced heart failure patients compared with CTR, without differences between CxHF and nCxHF. Only in CxHF, ZAG levels are directly correlated to circulating levels of FFA and NE, suggesting a close interaction of ZAG with sympathetic-mediated lipolysis.

Norepinephrine Reuptake Is Impaired in Skeletal Muscle of Hypertensive Rats In Vivo

Certain forms of experimental hypertension are characterized by organ-specific alterations of catecholaminergic pathways. The purpose of this study was to evaluate, in the same awake and freely moving normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) before and after the development of arterial hypertension, the norepinephrine (NE) turnover and, in particular, the neuronal NE reuptake activity that ends its effects once released from nerve terminals, in subcutaneous adipose tissue and in skeletal muscle, whose sympathetic efferents are respectively independent or dependent from baroreflexes. Plasma and tissue interstitial NE and 3,4-dihydroxyphenylethylene glycol (DHPG), its major deaminated metabolite, were measured before and after blockade of NE reuptake by tissue perfusion of desipramine through microdialysis probes. Arterial pressure and plasma NE in SHR were similar to those in WKY at 5 weeks of age but increased at 16 weeks of age. In contrast, plasma DHPG was already higher in young SHR. Basal interstitial NE and DHPG were increased in both tissues of young and old SHR compared with age-matched WKY. Desipramine induced a higher rise of interstitial NE in SHR of both ages, with a lesser increase in the skeletal muscle of old compared with young SHR. These results indicate an increased NE turnover in prehypertensive and hypertensive SHR in both baroreflex-dependent and -independent tissues, not shown by plasma NE levels in young SHR. In the skeletal muscle, where sympathetic efferents are baroreflex dependent, the reduced interstitial NE reuptake contributes to the higher availability of interstitial NE for postsynaptic effects in old SHR.

Psychosocial stress induces hyperphagia and exacerbates diet-induced insulin resistance and the manifestations of the Metabolic Syndrome.

Stress and hypercaloric food are recognized risk factors for obesity, Metabolic Syndrome (MetS) and Type 2 Diabetes (T2D). Given the complexity of these metabolic processes and the unavailability of animal models, there is poor understanding of their underlying mechanisms. We established a model of chronic psychosocial stress in which subordinate mice are vulnerable to weight gain while dominant mice are resilient. Subordinate mice fed a standard diet showed marked hyperphagia, high leptin, low adiponectin, and dyslipidemia. Despite these molecular signatures of MetS and T2D, subordinate mice fed a standard diet were still euglycemic. We hypothesized that stress predisposes subordinate mice to develop T2D when synergizing with other risk factors. High fat diet aggravated dyslipidemia and the MetS thus causing a pre-diabetes-like state in subordinate mice. Contrary to subordinates, dominant mice were fully protected from stress-induced metabolic disorders when fed both a standard- and a high fat-diet. Dominant mice showed a hyperphagic response that was similar to subordinate but, unlike subordinates, showed a significant increase in VO2, VCO2, and respiratory exchange ratio when compared to control mice. Overall, we demonstrated a robust stress- and social status-dependent effect on the development of MetS and T2D and provided insights on the physiological mechanisms. Our results are reminiscent of the effect of the individual socioeconomic status on human health and provide an animal model to study the underlying molecular mechanisms.

Specific nutritional problems in acute kidney injury, treated with non-dialysis and dialytic modalities

Patients who develop AKI, especially in the intensive care unit (ICU), are at risk of protein–energy malnutrition, which is a major negative prognostic factor in this clinical condition. Despite the lack of evidence from controlled trials of its effect on outcome, nutritional support by the enteral (preferentially) and/or parenteral route appears clinically indicated in most cases of ICU-acquired AKI, independently of the actual nutritional status of the patient, in order to prevent deterioration in the nutritional state with all its known complications. Extrapolating from data in other conditions, it seems intrinsically unlikely that starvation of a catabolic patient is more beneficial than appropriate nutritional support by an expert team with the skills to avoid the potential complications of the enteral and parenteral nutrition methodologies. By the same token, it is ethically impossible to conduct a trial in which the control group undergoes prolonged starvation. The primary goals of nutritional support in AKI, which represents a well-known inflammatory and pro-oxidative condition, are the same as those for other critically ill patients with normal renal function, i.e. to ensure the delivery of adequate nutrition, to prevent protein–energy wasting with its attendant metabolic complications, to promote wound healing and tissue repair, to support immune system function, to accelerate recovery and to reduce mortality. Patients with AKI on RRT should receive a basic intake of at least 1.5 g/kg/day of protein with an additional 0.2 g/kg/day to compensate for amino acid/protein loss during RRT, especially when daily treatments and/or high efficiecy modalities are used. Energy intake should consist of no more than 30 kcal non-protein calories or 1.3 × BEE (Basal Energy Expenditure) calculated by the Harris–Benedict equation, with ∼30–35% from lipid, as lipid emulsions. For nutritional support, the enteral route is preferred, although it often needs to be supplemented through the parenteral route in order to meet nutritional requirements.