Lipid-mobilizing Factor Research Articles

Zinc-a2-Glycoprotein Acts as a Component of PNN to Protect Hippocampal Neurons from Apoptosis.

In the adult mouse brain, perineuronal net (PNN), a highly structured extracellular matrix, surrounds subsets of neurons. The AZGP1 gene encodes zinc-2-glycoprotein (ZAG) is a lipid-mobilizing factor. However, its expression and distribution in the adult brain have been controversial. Here, for the first time, we demonstrate that the secreted ZAG is localized to Wisteria floribunda agglutinin (WFA)-positive PNNs around parvalbumin (PV)-expressing interneurons in the hippocampus, cortex, and a number of other PNN-bearing neurons and co-localizes with aggrecan, one of the components of PNNs. Few ZAG-positive nets were seen in the area without WFA staining by chondroitinase ABC (ChABC) which degrades glycosaminoglycans (GAGs) from the chondroitin sulfate proteoglycans (CSPGs) in the PNN. Reanalysis of single-cell sequencing data revealed that ZAG mRNA was mainly expressed in oligodendrocyte lineages, specifically in olfactory sheathing cells. The ZAG receptor β3 adrenergic receptor (β3AR) is also selectively co-localized with PV interneurons and CA2 pyramidal neurons in the hippocampus. In addition, molecular docking provides valuable new insights on how GAGs interfere with ZAG and ZAG/β3AR complex. Finally, our results indicated that human recombinant ZAG could significantly inhibit serum derivation-induced cell apoptosis in HT22 cells. Our combined experimental and theoretical approach raises a unique hypothesis namely that ZAG may be a crucial functional attribute of PNNs in the brain to protect neuronal cell from apoptosis.

Expression and Function of Zinc-α2-Glycoprotein.

Zinc-α2-glycoprotein (ZAG), encoded by the AZGP1 gene, is a major histocompatibility complex I molecule and a lipid-mobilizing factor. ZAG has been demonstrated to promote lipid metabolism and glucose utilization, and to regulate insulin sensitivity. Apart from adipose tissue, skeletal muscle, liver, and kidney, ZAG also occurs in brain tissue, but its distribution in brain is debatable. Only a few studies have investigated ZAG in the brain. It has been found in the brains of patients with Krabbe disease and epilepsy, and in the cerebrospinal fluid of patients with Alzheimer disease, frontotemporal lobe dementia, and amyotrophic lateral sclerosis. Both ZAG protein and AZGP1 mRNA are decreased in epilepsy patients and animal models, while overexpression of ZAG suppresses seizure and epileptic discharges in animal models of epilepsy, but knowledge of the specific mechanism of ZAG in epilepsy is limited. In this review, we summarize the known roles and molecular mechanisms of ZAG in lipid metabolism and glucose metabolism, and in the regulation of insulin sensitivity, and discuss the possible mechanisms by which it suppresses epilepsy.

Serum levels of the adipokine zinc-alpha2-glycoprotein (ZAG) predict mortality in hemodialysis patients

Wasting has been associated with increased cardiovascular and all-cause mortality in chronic kidney disease (CKD). We investigated whether serum zinc-alpha2-glycoprotein (ZAG), a potent cachectic and lipid-mobilizing factor that is increased in patients with CKD, predicts clinical outcomes in patients on chronic hemodialysis. We quantified serum ZAG at baseline in a prospective cohort of 252 patients undergoing maintenance hemodialysis. Serum ZAG concentrations were inversely associated with serum albumin, creatinine, and triglycerides and, conversely, positively associated with age. Although ZAG is strongly linked to protein energy wasting (PEW) in patients with cancer, higher ZAG concentrations were not associated with PEW in our cohort. During a mean study follow-up of 954 days, 49 patients died and 62 patients experienced a cardiovascular event. Kaplan-Meier analysis revealed a significant correlation between serum ZAG concentrations and all-cause mortality and cardiovascular events. In separate multivariable Cox regression models, serum ZAG concentrations remained significantly associated with all-cause mortality and cardiovascular events after adjustment for demographic factors (age, sex, and dialysis vintage), metabolic parameters (serum albumin, prealbumin, triglycerides, cholesterol, normalized protein catabolic rate, and body mass index), and cardiovascular risk factors (diabetes, dyslipidemia, history of cardiovascular disease, smoking, and diuretic use as a proxy of residual renal function). Thus, serum ZAG appears to be a strong and independent predictor of mortality and cardiovascular events in patients with end-stage renal disease. Further studies are necessary to confirm this association and to elucidate the underlying mechanisms.

Removal of Histidine residue from ZN- a-2- glycoprotein by Carboxypeptidase enzyme using Spectrofluorimetry and Maldi-tof-Mass Spectroscopy

The present invention relates, in general, to methods developed of diagnosing and monitoring to binding with Zn-a-2-glycoprotein in order to design rational drugs. Zinc-alpha-2-glycoprotein (ZAG) is a secreted protein that is present in most bodily fluids. It is interesting because of its ability to play many important functions in the human body, including fertilization and lipid mobilization. After the discovery of this molecule, during the last 5 decades, various studies have been documented on its structure and functions but still it is considered as a protein with an unknown function. Its expression is regulated by glucocorticoids. Due to its high sequence homology with lipid-mobilizing factor and high expression in cancer cachexia, it is considered as a novel adipokine. On the other hand, its X-ray crystal structure and folding structure is similar to MHC class I antigen-presenting molecule; hence ZAG may have a role in the expression of the immune response and providing defined binding-altered mutants for cellular signaling studies and potential medical application. Spectrofluorimetry and MALDI-TOF Mass Spectroscopy showed that ZAG binds DAUDA with Kdin the micro molar range. This study will examine removal of histidine residue from recombinant ZAG protein by enzymes through Spectrofluorimetry and MALDI-TOF Mass Spectroscopy.

Serum zinc is associated with plasma leptin and Cu–Zn SOD in elite male basketball athletes

This paper investigates the relationship between plasma trace element and plasma leptin, as well as percent fat mass, in 16 male basketball athletes. Blood samples were obtained before intensive training and 24h after intensive training to measure plasma zinc (Zn), copper (Cu), calcium (Ca), magnesium (Mg), iron (Fe), and leptin levels. High-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglyceride (TG), total and cholesterol (TC) levels were determined using commercially available kits for humans. Subjects presented similar values in terms of age (21.1±2.2 years old), body mass index (23.9±2.00kg/m2), percent body fat (14.40±1.52%), plasma hemoglobin (150.1±9.4g/L), plasma Zn (17.47±1.28μmol/l), plasma Cu (13.42±1.40μmol/L), plasma Ca (2.41±0.14mmol/L), and plasma Mg (0.96±0.02mmol/L). The correlation analysis between degree of plasma leptin and plasma element contents was performed using the SPSS 16.0 software. Plasma Zn correlated positively with plasma leptin (r=0.746, P<0.01), Cu–Zn SOD (r=0.827, P<0.01), and negatively with percent fat mass (r=–0.598, P<0.05) under no-training conditions. Meanwhile, plasma Cu, Ca, Mg, and Fe did not correlate with plasma leptin or percent fat mass (P>0.05). In conclusion, plasma Zn may be involved in the regulation of plasma leptin and may serve as a lipid-mobilizing factor in Chinese men's basketball athletes.

The American Pancreatic Association/Hirshberg Foundation Symposium Celebrating the 10th Anniversary of the Seed Grant Program

The Hirshberg Foundation for Pancreatic Cancer Research was founded by Agi Hirshberg in 1997, following her husband Ronald Hirshberg’s 8-month, 7-day battle with the disease. (http://www.pancreatic.org/). At the time, the Hirshberg family viewed pancreatic cancer as the ‘‘unknown enemy’’ (http:// www.pancreatic.org/site/c.htJYJ8MPIwE/b.8276835/k.66CB/ Agi_Hirshbergs_Story.htm). In the years since Ronald Hirshberg’s death, Agi Hirshberg has made it her mission to unmask the unknown for others facing the same enemy. When patients present with a new diagnosis of pancreatic cancer, most are already in an advanced stage of the disease. Pancreatic cancer is resistant to most chemotherapeutic agents and radiotherapy. These factors combine to make pancreatic cancer a highly lethal disease, and according to the National Cancer Institute (NCI) 2013 estimates, pancreatic cancer was diagnosed in approximately 45,220 US citizens, and some 38,460 died of the disease. 1 The Annual Report to the Nation on the Status of Cancer, 1975Y2009, shows that overall cancer death rates continued to decline in the United States among both men and women, among all major racial and ethnic groups, and for all of the many common cancer sites, including lung, colon and rectum, female breast, and prostate. However, this trend does not hold true for pancreatic cancer. The report demonstrates that death rates continued to increase during the latest time period (2000 through 2009) for pancreatic cancer. 2 Only about 23% of patients with cancer of the pancreas will still be living 1 year after diagnosis, and only about 4% will survive 5 years. Even for those diagnosed with pancreatic cancer that has not spread to other organs or systems, the overall 5-year survival rate approaches only 15%. The Hirshberg Foundation’s vision is to advance pancreatic cancer research and provide information, resources, and support to pancreatic cancer patients and their families. The mission of the Foundation is as follows: & To find a cure for pancreatic cancer in honor of Ron Hirshberg and the thousands of people who are diagnosed with this disease each year. & To create a premier Pancreatic Cancer Center where all needs of pancreatic cancer patients can be met in one location with the most advanced treatment options. & To be recognized as a patient support reference source for

Systemic and local mechanisms leading to cachexia in cancer

Cachexia is a multifactorial syndrome of atrophy of skeletal muscle and adipose tissue, resulting in progressive loss of body weight associated with low quality of life and poor prognosis in cancer. Studies on experimental animal models and observations on patients have shown that the soluble factors secreted by tumor cells and tissues of the patient can participate in regulation of the wasting process. Cachexia is often accompanied by anorexia, which is caused by predominance of signals inhibiting appetite in the hypothalamus, such as release of proopiomelanocortin and anorexigenic action of proinflammatory cytokines (IL-1α, IL-1β, IL-6, TNF-α). Cachexia is also accompanied by extensive metabolic changes consisting of increase of resting energy expenditure and disturbance of carbohydrate, protein and lipid metabolism. Increased expression of protein uncoupling phosphorylation leads to increased thermogenesis in skeletal muscle. Tumor tissue hypoxia caused by its growth beyond blood vessels activates the transcription factor HIF-1, which results in increase in glycolysis, and leads to lactic acid accumulation and activation of the energy inefficient Cori cycle. Loss of fat tissue is caused by increase of lipolysis induced by lipid-mobilizing factor (LMF) and proinflammatory cytokines. Skeletal muscle wasting in cachexia is caused by a reduction of protein synthesis at the stage of initiation and elongation of translation and the simultaneous increase of protein degradation via ubiquitin-dependent and lysosomal pathways. The main mediators of skeletal muscle wasting in cancer are proteolysis-inducing factor (PIF), proinflammatory cytokines, and angiotensin II acting through increased levels of reactive oxygen species (ROS) and nuclear factor NF-κB activation, as well as glucocorticoid activated FOXO transcription factors and myostatin. Understanding of the complexity of the interaction of factors produced by the tumor and the patient's body may form the basis for the development of effective treatments for cachexia in cancer and other pathological conditions.

White adipose tissue overproduces the lipid-mobilizing factor zinc α2-glycoprotein in chronic kidney disease

Chronic kidney disease (CKD) is frequently associated with protein-energy wasting, a recognized strong predictive factor of mortality. Zinc α2-glycoprotein (ZAG) is a new adipokine involved in body weight control through its lipid-mobilizing activity. Here we tested whether the uremic environment in CKD could alter ZAG production by white adipose tissue and contribute to CKD-associated metabolic disturbances. Compared with normal plasma, uremic plasma induced a significant increase in ZAG synthesis (124%), was associated with a significant increase in basal lipolysis (31%), and significantly blunted lipogenesis (-53%) in 3T3-L1 adipocytes in vitro. In 5/6 nephrectomized rats and mice in vivo, there was a significant decrease in white adipose tissue accretion (-44% and -43%, respectively) and a significantly higher white adipose tissue content of ZAG protein than in sham-operated, pair-fed control animals (498% and 106%, respectively). Subcutaneous white adipose tissue biopsies from patients with end-stage renal disease exhibited a higher content of ZAG (573%) than age-matched controls. Thus, the ZAG content is increased in white adipose tissue from patients or animal models with CKD. Overproduction of ZAG in CKD could be a major contributor to metabolic disturbances associated with CKD.

Crosstalk in human brain between globoid cell leucodystrophy and zinc-alpha-2-glycoprotein (ZAG), a biomarker of lipid catabolism

Zinc-alpha-2-glycoprotein (ZAG) is a protein identified as a lipid-mobilizing factor participating in a lipid catabolism. In spite of intensive studies conducted during last five decades, the role of this protein in processes of neurodegeneration remains unclear. The aim of our study was to examine the presence of ZAG protein in the brain of patients with Krabbe's disease, which is considered as a psychosine lipidosis caused by a mutation of a known gene. We found intracellular and extracellular localization of ZAG in the brain of Krabbe's disease patients but in the brain of control age-matched patients, ZAG was not detected. Distribution of ZAG in the brain suggests that the influx of ZAG into the brain involved a blood-brain barrier mechanism and adenoreceptors localized on astrocytes and some neurons.

ZigZAGging through Fat Stores

When reading how in the 1950s and 1960s Burgi and Schmid (1) at Harvard purified and isolated from human blood plasma a glycoprotein by zinc precipitation, which is now best known as Zn2-glycoprotein (ZAG), one can only wonder about the complete and detailed biochemical approach and pure marvel of biochemistry at that time. In the present-day world of ZAG, this seminal paper deserves a status similar, for instance, to that of the work of Lowry and colleagues on protein determination (reviewed in Ref. 2). What Burgi and Schmid did not know, nor could they anticipate, was the role played by “their” glycoprotein in endocrinology and metabolism. At that time, discussions still concerned questions such as whether a cell could produce only one hormone or maybe more. Hormones came from designated glands such as the pituitary gland, the endocrine pancreas, or adrenals. Tissues and organs, such as the skin, heart, liver, and kidney, were only later revealed as sources of endocrine signals. Now, almost 50 yr later, production of multiple signals by a single cell type is the rule rather than the exception, and the notion that tissues other than the classical endocrine glands, tissue such as liver and adipose, are endocrine tissues is established. Because many signals in our body serve functions beyond the classical endocrine function, viz. as intracrines, autocrines, and paracrines, we should be alert to the possibility of finding signals in body fluids other than blood plasma and not be prejudiced with regards to function because of exotic appearances of as yet poorlydefined signal substances. Such a notion would certainly apply to adipose tissue as an endocrine tissue and the complex web of adipo(cyto)kines produced by fat and liver cells involved in regulation of our energy stores and communication between these stores, other peripheral tissues of mesenchymal origin such as bone, or the immune system, and the central nervous system (3, 4). Indeed, ZAG is a rather enigmatic and multidisciplinary protein; although well studied, we still do not know ZAG’s function(s) with any great certainty (3). It is a single-chain, glycosylated polypeptide of approximately 40 kDa, produced by a variety of tissues and found in various body fluids and in rather high total concentrations. Liver and adipose tissue are main sites of production. ZAG is a major histocompatibility complex (MHC) class I look-alike, although the peptide binding groove in ZAG is less peptide-specific than in MHC molecules and was shown to bind polyethylene glycol in its groove (3), in line with a derived wider functionality. Apparently, ZAG serves a role as receptor and as adipocytokine signal as well, and its promiscuity toward ligands may greatly add to the complexity of its presumed signal functions. The typical blood plasma concentration in normal subjects is 60 mg/liter (5), which translates, with an apparent molecular radius of 40 kDa, to 1.5 M. If all the ZAG in plasma was freely available for binding to receptors, then this would be a receptor with an unusually low affinity for an endocrine signal (mostly nanomolar affinities or lower still); seminal plasma concentrations may even exceed those in plasma 6-fold (6), leading to further questioning of the endocrine nature of ZAG. But what do we know about free levels in body fluids, ligand-dependent ZAGcomplexes, or receptor types? Reportedly, ZAG (then, tumor-derived lipid-mobilizing factor that proved to be very similar to ZAG) increases cAMP levels in adipocytes through interference with a 3-adrenoceptor based on pharmacological studies with specific agonists and antagonists (7, 8) and, although 250 times more ZAG was required to obtain similar stimulation as with 1 nM isoprenaline, still a “high-affinity” receptor was indicated in kinetic studies (Kd: 78 nM). The search for and identification of a ZAG-specific G protein-coupled receptor

Serum Zinc-α2-Glycoprotein Correlates with Adiposity, Triglycerides, and the Key Components of the Metabolic Syndrome in Chinese Subjects

Zinc-alpha2-glycoprotein (ZAG) is a 40-kDa circulating glycoprotein secreted from the liver and adipose tissues. Animal studies have demonstrated the role of ZAG as a lipid-mobilizing factor involved in regulating lipid metabolism and adiposity. However, the clinical relevance of these findings remains to be established. This study aimed to address the relationship of serum ZAG levels with adiposity and cardiometabolic risk factors in humans. A total of 258 Chinese subjects [aged 55.1 +/- 12.5 yr; 120 males, 138 females; body mass index (BMI), 25.4 +/- 4.1 kg/m(2)] were randomly selected from the population-based Hong Kong Cardiovascular Risk Factor Prevalence Study, based on their BMI. Serum ZAG levels were determined with ELISA. The relationship between serum ZAG levels and cardiometabolic parameters was assessed. Serum ZAG levels were higher in men (P < 0.001 vs. women). Serum ZAG correlated positively with age, parameters of adiposity (waist circumference and BMI), fasting insulin, insulin resistance indices, serum triglycerides, adipocyte-fatty acid-binding protein, and C-reactive protein, and diastolic blood pressure (all P < 0.005, age- and sex-adjusted), and inversely with high-density lipoprotein-cholesterol levels (P = 0.008, age- and sex-adjusted). It was also elevated progressively with an increasing number of components of the metabolic syndrome (P for trend < 0.001). On multivariate analysis, serum ZAG was independently associated with male sex, the metabolic syndrome (or type 2 diabetes and serum triglycerides), and C-reactive protein (all P <or= 0.002). ZAG might be involved in the pathogenesis of obesity-related metabolic disorders in humans and thus warrants further investigation.

Zinc α2-Glycoprotein: A Multidisciplinary Protein

Zinc alpha 2-glycoprotein (ZAG) is a protein of interest because of its ability to play many important functions in the human body, including fertilization and lipid mobilization. After the discovery of this molecule, during the last 5 decades, various studies have been documented on its structure and functions, but still, it is considered as a protein with an unknown function. Its expression is regulated by glucocorticoids. Due to its high sequence homology with lipid-mobilizing factor and high expression in cancer cachexia, it is considered as a novel adipokine. On the other hand, structural organization and fold is similar to MHC class I antigen-presenting molecule; hence, ZAG may have a role in the expression of the immune response. The function of ZAG under physiologic and cancerous conditions remains mysterious but is considered as a tumor biomarker for various carcinomas. There are several unrelated functions that are attributed to ZAG, such as RNase activity, regulation of melanin production, hindering tumor proliferation, and transport of nephritic by-products. This article deals with the discussion of the major aspects of ZAG from its gene structure to function and metabolism.

Acute in vivo stimulatory effects of human pituitary lipid-mobilizing factor on plasma levels of glucagon and insulin in rabbits.

The lipid-mobilizing factor LMF is prepared from deep-frozen human pituitary glands by alkaline extraction, followed by acetone precipitation at pH 4.8, Sephadex gel filtration and DEAE-cellulose chromatography. In addition to its adipokinetic effect in rabbits, LMF also increased the plasma levels of glucagon and insulin in rabbits in doses of 15 to 100 micrograms. The LMF-induced increases in the plasma levels of glucagon were most pronounced in fasted rabbits, whereas the increases in the plasma levels of insulin were most pronounced in fed rabbits. Glucose infusions decreased the LMF-induced hyperglucagonaemia and increased the LMF-induced hyperinsulinaemia. Somatostatin did not inhibit the LMF-induced hyperglucagonaemia with statistical significance, but inhibited the LMF-induced hyperinsulinaemia. The plasma levels of glucose were slightly decreased by 20 and 40 micrograms LMF in fasted rabbits and were unchanged in fed rabbits. In fasted rabbits, LMF had a toxic effect and 100 micrograms LMF killed one rabbits. Human growth hormone (hGH), prepared from the pituitary glands after removal of LMF, also increased the plasma levels of glucagon and insulin in rabbits. It is possible that the observed effects of LMF and hGH were due to the presence of some biologically active substances from the pituitary gland. These postulated substances could be involved in the pituitary control of the endocrine pancreas, and work is in progress to isolate them from the LMF preparation.

Comparison of Animal Models for Head and Neck Cancer Cachexia

Despite its negative impact on cancer patients, there are few animal models of cancer cachexia. Our hypothesis was that different human cell lines would variably induce cachexia. Prospective animal study. We established two xenograft models in athymic mice and compared these with a cachexigenic cell line, the murine adenocarcinoma 16 (MAC16) cell line. Eight-week-old female, athymic mice were injected with human head and neck cell lines (JHU022, JHU012) and the MAC16 cell line. Body weight, food intake, body composition, leg weights, serum cytokines, and lipid mobilizing factor (LMF) were compared. Mean food intake for all groups was equivalent. Mean percent change in body weight after 18 days was 18%, 19%, 12%, and 3% for control, JHU012, JHU022, and MAC16 experimental groups, respectively. Both JHU022- and MAC16-injected mice showed wasting even when tumor burden was low. In contrast, mice injected with JHU012 developed larger tumors yet lacked evidence of cachexia. These mice demonstrated loss of lean body mass but not fat mass. Serum cytokine levels for interleukin (IL)-1 alpha and IL-1 beta were elevated in JHU022-bearing mice, whereas IL-1 alpha, IL-6, interferon (IFN)-gamma, and tumor necrosis factor alpha (TNF)-alpha were elevated in MAC16-bearing mice. LMF was present in both the JHU022 and JHU012 cell lines. The JHU022 cell line caused more severe cachexia than the JHU012 cells, suggesting these cell lines may be used to further study cancer cachexia. IL-1 alpha and IL-1 beta in the JHU022 model may be mediators of cachexia, whereas TNF-alpha, IFN-gamma, and IL-6 may be mediators in MAC16-induced cachexia.

Defining Cancer Cachexia in Head and Neck Squamous Cell Carcinoma

Cancer cachexia is a devastating and understudied illness in patients with head and neck squamous cell carcinoma (HNSCC). The primary objective was to identify clinical characteristics and serum levels of cytokines and cachexia-related factors in patients with HNSCC. The secondary objective was to detect the occurrence of cytokine and cachexia-related factor gene expression in HNSCC tumors. For the primary objective, cross-sectional data were obtained from prospectively recruited patients identified as cachexia cases and matching cachexia-free controls. For the secondary objective, a retrospective cohort design with matched controls was used. Clinical characteristics associated with cancer cachexia in HNSCC were T(4) status (P = 0.01), increased C-reactive protein (P = 0.01), and decreased hemoglobin (P < 0.01). Exploratory multiplex analysis of serum cytokine levels found increased interleukin (IL)-6 (P = 0.04). A highly sensitive ELISA confirmed the multiplex result for increased IL-6 in cachectic patients (P = 0.02). Quality of life was substantially reduced in patients with cachexia compared with noncachectic patients (P < 0.01). All tumors of HNSCC patients both with and without cachexia expressed RNA for each cytokine tested and the cachexia factor lipid-mobilizing factor. There were no statistically significant differences between the cytokine and cachexia factor RNA expression of cachectic and noncachectic patients (each P > 0.05). No tumors expressed the cachexia factor proteolysis-inducing factor. We have identified clinical characteristics and pathophysiologic mechanisms associated with cancer cachexia in a carefully defined population of patients with HNSCC. The data suggest that the acute-phase response and elevated IL-6 are associated with this complex disease state. We therefore hypothesize that IL-6 may represent an important therapeutic target for HNSCC patients with cancer cachexia.

Postnatal expression of zinc-α 2-glycoprotein in rat white and brown adipose tissue

Zinc-α 2-glycoprotein (ZAG), a lipid-mobilizing factor, is a novel adipokine which may act locally to influence adipose tissue metabolism. This study examined the ontogeny of ZAG expression in adipose tissue during postnatal development. White (subcutaneous, gonadal, and perirenal) and brown (interscapular) fat was collected from rats aged 1–32 days. ZAG mRNA was detected from day 1 in subcutaneous fat, which appears the key site of synthesis postnatally. ZAG was detected in perirenal (day 5) and in gonadal (day 7) fat when the tissue was sufficient for analysis. ZAG mRNA and protein levels fell significantly at weaning (day 21) and thereafter. ZAG was also detected in brown fat at day 1 but it fell significantly afterwards. The downregulated ZAG expression in white fat depots at weaning, when fat mass is expanded substantially, suggests that ZAG might be involved in the postnatal development of adipose tissue mass.

Nutritional Support in Cancer

The management of cancer patients is frequently complicated by the occurrence of cachexia, a complex syndrome characterized by marked depletion of body weight, associated with profound alterations of both nutritional status and metabolic homeostasis. Progressive wasting of skeletal muscle mass and adipose tissue is a typical feature of cancer cachexia. This syndrome has a large impact on morbidity and mortality, and significantly affects patients quality of life. On this line, understanding the pathogenic mechanisms of cachexia is of crucial importance to define targeted therapeutic strategies. Many studies have addressed the relevance of nutritional interventions in cancer hosts. In particular, it has been shown that malnutrition in cancer patients can be delayed when nutritional supplementation is adopted early in the course of the disease. The preservation of a good nutritional status, in particular when it is achieved concurrently with specific antineoplastic treatment, will prevent or at least delay the onset of overt cachexia, allowing the use of more aggressive therapeutic regimens. This paper will review the relevant literature, focusing on those options that have shown more promising for the clinical practice. Keywords: cancer-related anorexia, Malignant tumors, metabolism, HDL-cholesterol levels, Lipid-Mobilizing Factor

Immunocompetent murine model of cancer cachexia for head and neck squamous cell carcinoma

Muscle wasting and weight loss were observed when carcinomas were induced in a murine model of head and neck squamous cell carcinomas. Our hypothesis was C3H/HeN mice would develop evidence of cachexia when injected with tumor cells Age- and weight-matched female mice were injected with SCCF/VII cells. Daily food intake and weights were measured. Body composition and analysis of circulating cytokines was performed. At the completion of experiments, hind legs were weighed. Muscle atrophy was detected using analysis for muscle ring finger 1 (MuRF1). The tumor-derived lipid mobilizing factor (LMF) was measured. Despite increased food intake, tumor-bearing mice lost weight and experienced reduced hind leg weights. Interleukin-1beta (IL-1beta) was increased and MuRF1 was present in tumor-bearing mice but not controls. LMF was present in SCCF/VII cells. In this immunocompetent murine model, we demonstrated the development of cancer cachexia in mice inoculated with SCCF cells, which express LMF. There was increased serum IL-1beta, weight loss, and muscle wasting and atrophy in tumor-bearing mice.

Plasma Zinc, Copper, Leptin, and Body Composition Are Associated in Elite Female Judo Athletes

This study evaluated levels of plasma zinc, copper, and leptin, body composition, and their relationship in nine elite female judo athletes under two different training conditions. Body composition and biochemical measurements (hematological indexes, plasma zinc, plasma copper, and plasma leptin) were analyzed 24 h after intense training and following a 5-d period without training (no-training). Plasma leptin and plasma zinc increased with no-training. Plasma zinc correlated negatively with percent fat mass (r= -0.62; r=0.05) and positively with plasma leptin (r=0.83; p=0.002) in the no-training condition. Plasma copper did not change during the study and correlated positively with plasma leptin (r=0.66; p=0.05) and with percent fat mass (r=0.80; p=0.007) after training. Percent fat mass was associated negatively with plasma zinc (r=-0.62; p=0.05) in the no-training condition. Moreover, percent fat mass was negatively associated with the Zn/Cu plasma ratio under both training conditions (r< -0.78, p< 0.001). These results are consistent with the possible function of zinc as a lipid-mobilizing factor and of copper as a limiting factor in energy metabolism.

Zn-α2-glycoprotein, an MHC Class I-Related Glycoprotein Regulator of Adipose Tissues: Modification or Abrogation of Ligand Binding by Site-Directed Mutagenesis

Zn-alpha(2)-glycoprotein (ZAG) is a soluble lipid-mobilizing factor associated with cancer cachexia and is a novel adipokine. Its X-ray crystal structure reveals a poly(ethylene glycol) molecule, presumably substituting for a higher affinity natural ligand, occupying an apolar groove between its alpha(1) and alpha(2) domain helices that corresponds to the peptide binding groove in class I MHC proteins. We previously provided evidence that the groove is a binding site for hydrophobic ligands that may relate to the protein's signaling function and that the natural ligands are probably (polyunsaturated) fatty acid-like. Using fluorescence-based binding assays and site-directed mutagenesis, we now demonstrate formally that the groove is indeed the binding site for hydrophobic ligands. We also identify amino acid positions that are involved in ligand binding and those that control the shape and exposure to solvent of the binding site itself. Some of the mutants showed minimal effects on their binding potential, one showed enhanced binding, and several were completely nonbinding. Particularly notable is Arg-73, which projects into one end of the binding groove and is the sole charged amino acid adjacent to the ligand. Replacing this amino acid with alanine abolished ligand binding and closed the groove to solvent. Arg-73 may therefore have an unexpected dual role in binding site access and anchor for an amphiphilic ligand. These data add weight to the distinctiveness of ZAG among MHC class I-like proteins in addition to providing defined binding-altered mutants for cellular signaling studies and potential medical applications.