transforming-growth-factor-beta and Weight-Loss

Wound-healing complications following body contouring for massive weight loss patients are significant, with rates exceeding 40 percent. To better understand aberrant healing in this population, the authors have performed a comparative analysis of the wound milieu literature for patient populations with similar complication rates.. PubMed and Ovid databases were reviewed from January of 1985 to January of 2009 for key terms, including wound healing, obesity, cancer, burn, transplant, and body contouring. Serum and wound levels of multiple factors, including matrix metalloproteinases (MMPs) and cytokines, were assessed.. Complication rates in body contouring surgery range from 31 to 66 percent. Sixty-five studies were reviewed, and wound-healing complication rates were identified for cancer (45.8 percent), burn (30.4 percent), posttransplant (36 percent), and obese (43 percent) populations. In these groups, matrix metalloproteinases and tissue inhibitors of metalloproteinase (TIMPs) help regulate wound repair. Matrix metalloproteinase levels were elevated in cancer (4-fold increase in MMP-2), burn (20- to 30-fold increase in MMP-9), transplant (1.4-fold increase in MMP-2), and obese/chronic (79-fold increase) populations. TIMPs were increased in cancer (1.9-fold increase in TIMP-2) and burn (1.4-fold increase in TIMP-1) patients but decreased in chronic wound (55-fold decrease in TIMP-1) populations. Alterations to these regulatory proteins lead to prolonged matrix degradation, up-regulation of inflammatory mediators, and decreased growth factors, delaying the wound-healing process.. Complications after body contouring surgery are likely multifactorial; however, molecular imbalances to the massive weight loss wound milieu may contribute to poor surgical outcomes. Examining wound regulatory proteins including transforming growth factor-beta, vascular endothelial growth factor, and matrix metalloproteinases could aid in understanding the healing difficulties observed clinically.

Topics: Bariatric Surgery; Biomarkers; Burns; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Neoplasms; Obesity; Organ Transplantation; Plastic Surgery Procedures; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Weight Loss; Wound Healing

There is now a large body of evidence that weight loss in older persons not only increases mortality, but also increases the incidence of hip fracture, functional deterioration and institutionalization. Weight loss is a central component of frailty. There is evidence that it is not only muscle, but also fat loss that leads to these deleterious effects. The reasons why fat loss can be harmful in older persons are reviewed. There are four major causes of weight loss in older persons viz. anorexia, sarcopenia, cachexia and dehydration. This review concentrates on the major causes of anorexia and sarcopenia. In particular, the emergence of new medications such as selective androgen receptor molecules, antimyostatin analogues, megestrol acetate (nanocrystal formulation), and ghrelin agonists are reviewed. The potential role of anabolic steroids is also discussed.

Topics: Adipose Tissue; Aged; Aged, 80 and over; Aging; Anabolic Agents; Anorexia; Appetite Stimulants; Feeding Behavior; Frail Elderly; Humans; Megestrol Acetate; Muscular Atrophy; Myostatin; Receptors, Androgen; Receptors, Ghrelin; Transforming Growth Factor beta; Weight Loss

Cachexia causes weight loss and increased mortality. It affects more than 5 million persons in the United States. Other causes of weight loss include anorexia, sarcopenia, and dehydration. The pathophysiology of cachexia is reviewed in this article. The major cause appears to be cytokine excess. Other potential mediators include testosterone and insulin-like growth factor I deficiency, excess myostatin, and excess glucocorticoids. Numerous diseases can result in cachexia, each by a slightly different mechanism. Both nutritional support and orexigenic agents play a role in the management of cachexia.

Topics: Aging; Anorexia; Arthritis, Rheumatoid; Cachexia; Chronic Disease; Cytokines; Glucocorticoids; HIV Wasting Syndrome; Humans; Insulin-Like Growth Factor I; Kidney Failure, Chronic; Myostatin; Neoplasms; Pulmonary Disease, Chronic Obstructive; Testosterone; Transforming Growth Factor beta; Weight Loss

The systemic administration of high doses of rHuTGF-beta 1 to rats produced a spectrum of lesions in multiple target tissues, including liver, bone, kidney, heart, thymus, pancreas, stomach, cecum, at the injection vein, and in skeletal muscle at the site of anesthetic injection. The majority of these lesions can be attributed to known biological activities of TGF-beta 1. High-dose dermal application resulted in local effects at the wound sites without systemic toxicity.

Topics: Animals; Cell Line; CHO Cells; Cricetinae; Female; Humans; Injections, Intradermal; Injections, Intravenous; Male; Organ Size; Rabbits; Rats; Recombinant Proteins; Skin; Transforming Growth Factor beta; Viscera; Weight Loss; Wound Healing

Surgical weight loss procedures like vertical sleeve gastrectomy (SG) are sufficient in resolving obesity comorbidities and are touted to reduce the burden of pro-inflammatory cytokines and augment the release of anti-inflammatory cytokines. Recent reports suggest a reduced improvement in weight resolution after SG in Black Americans (BA) versus White Americans (WA). The goal of this study was to determine if differences in immunoglobulin levels and general markers of inflammation after SG in Black Americans (BA) and White Americans (WA) may contribute to this differential resolution.. Personal information, anthropometric data, and plasma samples were collected from 58 participants (24 BA and 34 WA) before and 6 weeks after SG for the measurement of immunoglobulin A (IgA), IgG, IgM, C-reactive protein (CRP), and transforming growth factor (TGFβ). Logistic regression analysis was used to determine the relationship of measures of body size and weight and inflammatory markers.. Both IgG and CRP were significantly elevated in BA in comparison to WA prior to weight loss. Collectively, IgG, TGFβ, and CRP were all significantly reduced at six weeks following SG. CRP levels in BA were reduced to a similar extent as WA, but IgG levels were more dramatically reduced in BA than WA despite the overall higher starting concentration. No change was observed in IgA and IgM.. These data suggest that SG improves markers of immune function in both BA and WA. More diverse markers of immune health should be studied in future work.

Topics: Biomarkers; Black or African American; Cytokines; Gastrectomy; Humans; Immunoglobulin G; Immunoglobulin M; Obesity, Morbid; Transforming Growth Factor beta; Weight Loss; White

To investigate the effects of bariatric surgery on metabolic parameters, incretin hormone secretion, and duodenal and ileal mucosal gene expression.. Nine patients with type 2 diabetes mellitus (T2DM), chronic serum hyperglycemia for more than 2 years, and a body mass index (BMI) of 30-35 kg/m(2) underwent metabolic surgery sleeve gastrectomy with transit bipartition between May 2011 and December 2011. Blood samples were collected pre and 3, 6 and 12 mo postsurgery. Duodenal and ileal mucosa samples were collected pre- and 3 mo postsurgery. Pre- and postoperative blood samples were collected in the fasting state before ingestion of a standard meal (520 kcal) and again 30, 60, 90, and 120 min after the meal to determine hemoglobin A1c (HbA1c) levels and the lipid profile, which consisted of triglyceride and total cholesterol levels. Intestinal gene expression of p53 and transforming growth factor (TGF)-β was analyzed using quantitative reverse-transcription PCR. Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were quantified using the enzyme-linked immunoassay method and analyzed pre- and postoperatively. Student's t test or repeated measurements analysis of variance with Bonferroni corrections were performed as appropriate.. BMI values decreased by 15.7% within the initial 3 mo after surgery (31.29 ± 0.73 vs 26.398 ± 0.68, P < 0.05) and then stabilized at 22% at 6 mo postoperative, resulting in similar values 12 mo postoperatively (20-25 kg/m(2)). All of the patients experienced improved T2DM, with 7 patients (78%) achieving complete remission (HbA1c < 6.5%), and 2 patients (22%) achieving improved diabetes (HbA1c < 7.0% with or without the use of oral hypoglycemic agents). At 3 mo postoperatively, fasting plasma glucose had also decreased (59%) (269.55 ± 18.24 mg/dL vs 100.77 ± 3.13 mg/dL, P < 0.05) with no further significant changes at 6 or 12 mo postoperatively. In the first month postoperatively, there was a complete withdrawal of hypoglycemic medications in all patients, who were taking at least 2 hypoglycemic drugs preoperatively. GLP-1 levels significantly increased after surgery (149.96 ± 31.25 vs 220.23 ± 27.55) (P < 0.05), while GIP levels decreased but not significantly. p53 gene expression significantly increased in the duodenal mucosa (P < 0.05, 2.06 fold) whereas the tumor growth factor-β gene expression significantly increased (P < 0.05, 2.52 fold) in the ileal mucosa after surgery.. Metabolic surgery ameliorated diabetes in all of the patients, accompanied by increased anti-proliferative intestinal gene expression in non-excluded segments of the intestine.

Topics: Adult; Bariatric Surgery; Biomarkers; Biopsy; Blood Glucose; Body Mass Index; Cell Proliferation; Diabetes Mellitus, Type 2; Duodenum; Fasting; Female; Gastrectomy; Gastric Inhibitory Polypeptide; Gene Expression Regulation; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Ileum; Intestinal Mucosa; Male; Middle Aged; Obesity; Postprandial Period; Remission Induction; Time Factors; Transforming Growth Factor beta; Treatment Outcome; Tumor Suppressor Protein p53; Weight Loss

Transforming growth factor-β (TGF-β) overproduction and activation of the TGF-β pathway are associated with the development of brain injury following germinal matrix hemorrhage (GMH) in premature infants. We examined the effects of GMH on the level of TGF-β1 in a novel rat collagenase-induced GMH model and determined the effect of inhibition of the TGF receptor I.. In total, 92 seven-day old (P7) rats were used. Time-dependent effects of GMH on the level of TGF-β1 and TGF receptor I were evaluated by Western blot. A TGF receptor I inhibitor (SD208) was administered daily for 3 days, starting either 1 hour or 3 days after GMH induction. The effects of GMH and SD208 on the TGF-β pathway were evaluated by Western blot at day 3. The effects of GMH and SD208 on cognitive and motor function were also assessed. The effects of TGF receptor I inhibition by SD208 on GMH-induced brain injury and underlying molecular pathways were investigated by Western blot, immunofluorescence, and morphology studies 24 days after GMH.. GMH induced significant delay in development, caused impairment in both cognitive and motor functions, and resulted in brain atrophy in rat subjects. GMH also caused deposition of both vitronectin (an extracellular matrix protein) and glial fibrillary acidic protein in perilesion areas, associated with development of hydrocephalus. SD208 ameliorated GMH-induced developmental delay, improved cognitive and motor functions, and attenuated body weight loss. SD208 also decreased vitronectin and glial fibrillary acidic protein deposition and decreased GMH-induced brain injury.. Increased level of TGF-β1 and activation of the TGF-β pathway associate with the development of brain injury after GMH. SD208 inhibits GMH-induced activation of the TGF-β pathway and leads to an improved developmental profile, partial recovery of cognitive and motor functions, and attenuation of GMH-induced brain atrophy and hydrocephalus.

Topics: Adult; Animals; Atrophy; Blotting, Western; Brain Injuries; Cerebral Ventricles; Extracellular Matrix Proteins; Female; Glial Fibrillary Acidic Protein; Humans; Hydrocephalus; Immunohistochemistry; Intracranial Hemorrhages; Nervous System Diseases; Neurologic Examination; Pregnancy; Pteridines; Rats; Rats, Sprague-Dawley; Signal Transduction; Survival; Transforming Growth Factor beta; Vitronectin; Weight Loss

Selenium (Se) is an essential micronutrient that exerts its functions via selenoproteins. Little is known about the role of Se in inflammatory bowel disease (IBD). Epidemiological studies have inversely correlated nutritional Se status with IBD severity and colon cancer risk. Moreover, molecular studies have revealed that Se deficiency activates WNT signaling, a pathway essential to intestinal stem cell programs and pivotal to injury recovery processes in IBD that is also activated in inflammatory neoplastic transformation. In order to better understand the role of Se in epithelial injury and tumorigenesis resulting from inflammatory stimuli, we examined colonic phenotypes in Se-deficient or -sufficient mice in response to dextran sodium sulfate (DSS)-induced colitis, and azoxymethane (AOM) followed by cyclical administration of DSS, respectively. In response to DSS alone, Se-deficient mice demonstrated increased morbidity, weight loss, stool scores, and colonic injury with a concomitant increase in DNA damage and increases in inflammation-related cytokines. As there was an increase in DNA damage as well as expression of several EGF and TGF-β pathway genes in response to inflammatory injury, we sought to determine if tumorigenesis was altered in the setting of inflammatory carcinogenesis. Se-deficient mice subjected to AOM/DSS treatment to model colitis-associated cancer (CAC) had increased tumor number, though not size, as well as increased incidence of high grade dysplasia. This increase in tumor initiation was likely due to a general increase in colonic DNA damage, as increased 8-OHdG staining was seen in Se-deficient tumors and adjacent, non-tumor mucosa. Taken together, our results indicate that Se deficiency worsens experimental colitis and promotes tumor development and progression in inflammatory carcinogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Azoxymethane; Carcinogenesis; Colitis; Colonic Neoplasms; Deoxyguanosine; Dextran Sulfate; Diet; DNA Damage; Epidermal Growth Factor; Gene Expression Regulation; Inflammation; Mice; Mice, Inbred C57BL; Selenium; Signal Transduction; Transforming Growth Factor beta; Weight Loss

Oral thiopurines are effective and widely used in treatment of inflammatory bowel disease (IBD) in humans, although their use is limited due the development of adverse events. Here, we examine the efficacy and toxicity of oral treatment with 6-tioguanine (6-TG) and azathioprine (AZA) in a murine model of IBD.. We induced acute or chronic colitis in BALB/c mice by one or four cycles of 3% dextran sulphate sodium (DSS), respectively. Mice were treated by daily gavages of various dosages of 6-tioguanine, azathioprine, or by phosphate buffered saline (PBS) starting the first day of DSS or after two cycles of DSS, respectively. We monitored the efficacy and toxicity by measuring the weight change and serum alanine aminotransferase (ALT) activity and by disease severity and histology, at the end of the experiment. Moreover, we measured cytokine production after colon fragment cultivation by enzyme-linked immunoabsorbent assay and numbers of apoptotic cells in the spleen by flow cytometry.. 6-TG is effective in the treatment of acute DSS-induced colitis in a dose-dependent manner and 40 μg of 6-TG is significantly more effective in the treatment of acute colitis than both AZA and PBS. This effect is accompanied by decrease of IL-6 and IFN-γ production in colon. We did not observe histological abnormalities in liver samples from control (PBS) or 6-TG treated mice. However, liver samples from most mice treated with AZA showed mild, yet distinct signs of hepatotoxicity. In chronic colitis, all thiopurine derivatives improved colitis, 20 μg of 6-TG per dose was superior. High doses of 6-TG led to significant weight loss at the end of the therapy, but none of the thiopurine derivatives increased levels of serum ALT. Both thiopurine derivatives reduced the proportion of apoptotic T helper cells, but a high production of both IL-6 and TGF-β was observed only in colon of AZA-treated mice.. Use of 6-TG in the treatment of experimental colitis in mice appears superior to AZA administration and placebo. In contrast to 6-TG, the use of AZA resulted in histological liver abnormalities.

Topics: Acute Disease; Alanine Transaminase; Analysis of Variance; Animals; Apoptosis; Azathioprine; Chronic Disease; Colitis; Colon; Dextran Sulfate; Female; Interferon-gamma; Interleukin-6; Liver; Mice; Mice, Inbred BALB C; Models, Animal; T-Lymphocytes, Helper-Inducer; Thioguanine; Transforming Growth Factor beta; Weight Loss

Mycobacterium bovis Bacillus Calmette-Guérin (BCG), killed by extended freeze-drying (EFD), induces secretion of interleukin-10 and reduces lung inflammation in a mouse model of asthma. We investigated the effects of EFD BCG in mouse models of inflammatory bowel disease.. EFD BCG was administered subcutaneously to mice with colitis induced by dextran sodium sulfate (DSS), oxazolone, or adoptive transfer of CD4(+)CD45RB(high)Foxp3(-) T cells from C57Bl/6 Foxp3GFP mice to RAG2(-/-) mice.. EFD BCG, administered either before induction of DSS and oxazolone colitis or after development of acute or chronic DSS-induced colitis, reduced symptom scores, loss of body weight, and inflammation. Although transfer of CD4(+)CD45RB(high)Foxp3(-) cells induced colitis in RAG2(-/-) mice, administration of EFD BCG at the time of the transfer converted Foxp3(-) T cells to Foxp3(+) T cells and the mice did not develop colitis. EFD BCG protected mice from colitis via a mechanism that required expansion of T regulatory cells and production of interleukin-10 and transforming growth factor β. EFD BCG activated the retinoid X receptor (RXR)-α-peroxisome proliferator-activated receptor (PPAR)-γ heterodimer, blocked translocation of nuclear factor κB to the nucleus, and reduced colonic inflammation; it did not increase the number of colon tumors that formed in mice with chronic DSS-induced colitis.. EFD BCG controls severe colitis in mice by expanding T regulatory cell populations and PPAR-γ and might be developed to treat patients with inflammatory bowel disease.

Topics: Animals; BCG Vaccine; Colitis; Colon; Dextran Sulfate; Forkhead Transcription Factors; Freeze Drying; Interleukin-1; Interleukin-10; Interleukin-6; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mycobacterium bovis; NF-kappa B; Oxazolone; Peroxidase; PPAR gamma; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Weight Loss

Radiation therapy (RT) to the head and neck often results in damage to the vocal folds (VF) and surrounding structures. Characterization and treatment of these sequelae is limited, likely due to the lack of experimental models.. Larynges from rats exposed to 2 fractionation schedules (40 Gy total) were analyzed histologically. In vitro, reactive oxygen species (ROS) synthesis, and transcription of select genes associated with ROS, inflammation, and fibrosis were examined in VF fibroblasts after single-dose radiation.. Although radiation-induced histologic alterations are made to VF architecture, 1 fractionation schedule was accompanied by significant morbidity and mortality. In vitro, radiation increased ROS synthesis and inflammatory and profibrotic gene expression.. Our data suggest that hyperfractionated RT is more tolerable. Utilizing this model, RT-induced histologic aberrations are made to the VF mucosa. In addition, a relationship between radiation, ROS, and inflammatory and fibrotic gene expression was observed in vitro.

Topics: Alopecia; Animals; Dehydration; Dose Fractionation, Radiation; Erythema; Fibrosis; Heme Oxygenase-1; Hypertrophy; In Vitro Techniques; Laryngeal Mucosa; Male; Matrix Metalloproteinase 1; Models, Animal; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA, Messenger; Skin Ulcer; Transforming Growth Factor beta; Vocal Cords; Weight Loss

Plasma transforming growth factor (TGF)-beta levels are high in the advanced stages of acute (wasting) pre-pubescent deficits of protein and energy. Consequently, this potently anti-inflammatory cytokine may help to sustain the depression of inflammatory immune competence in acute malnutrition. Our objective was to determine if plasma TGF-beta levels rise during the early stages of acute malnutrition and, secondarily, to confirm the elevation reported previously in advanced weight loss. In two experiments, male and female C57BL/6J mice, initially 19 d old, consumed ad libitum a complete purified diet (group C), or in restricted daily quantities (group R) or had free access to an isoenergetic low-protein diet (group LP). TGF-beta bioactivity in platelet-poor plasma was determined via inhibition of Mv1Lu mink lung cell proliferation after 3 d (Expt 1, early stage) or 14 d (Expt 2, advanced stage) of dietary intervention. At 3 d, mean plasma TGF-beta bioactivities were 802 (C), 2952 (R) and 4678 (LP) pg/ml, and after 14 d mean bioactivities were 1786 (C), 5360 (R) and 5735 (LP) pg/ml. At both time points, the malnourished groups differed from age-matched controls (P

Topics: Animals; Disease Models, Animal; Female; Immunocompetence; Inflammation; Male; Mice; Mice, Inbred C57BL; Protein-Energy Malnutrition; Transforming Growth Factor beta; Weaning; Weight Loss

Topics: Bariatric Surgery; Biomarkers; Burns; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Neoplasms; Obesity; Organ Transplantation; Plastic Surgery Procedures; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Weight Loss; Wound Healing

Anorexia and weight loss are part of the wasting syndrome of late-stage cancer, are a major cause of morbidity and mortality in cancer, and are thought to be cytokine mediated. Macrophage inhibitory cytokine-1 (MIC-1) is produced by many cancers. Examination of sera from individuals with advanced prostate cancer showed a direct relationship between MIC-1 abundance and cancer-associated weight loss. In mice with xenografted prostate tumors, elevated MIC-1 levels were also associated with marked weight, fat and lean tissue loss that was mediated by decreased food intake and was reversed by administration of antibody to MIC-1. Additionally, normal mice given systemic MIC-1 and transgenic mice overexpressing MIC-1 showed hypophagia and reduced body weight. MIC-1 mediates its effects by central mechanisms that implicate the hypothalamic transforming growth factor-beta receptor II, extracellular signal-regulated kinases 1 and 2, signal transducer and activator of transcription-3, neuropeptide Y and pro-opiomelanocortin. Thus, MIC-1 is a newly defined central regulator of appetite and a potential target for the treatment of both cancer anorexia and weight loss, as well as of obesity.

Topics: Animals; Anorexia; Antibodies; Cell Line, Tumor; Cytokines; Growth Differentiation Factor 15; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Mice, Transgenic; Multigene Family; Prostatic Neoplasms; Transforming Growth Factor beta; Weight Loss

Obesity is associated with insulin resistance in skeletal muscle; accordingly, weight loss dramatically improves insulin action. We sought to identify molecular remodeling of muscle commensurate with weight loss that could explain improvements in insulin action. Muscle from morbidly obese women was studied before and after gastric bypass surgery. Gastric bypass surgery significantly reduced body mass by approximately 45% and improved insulin action. We then assessed mRNA profiles using a stringent statistical analysis (statistical concordance with three probe set algorithms), with validation in a cross-sectional study of lean (n = 8) vs. morbidly obese (n = 8) muscle. Growth factor receptor-bound protein 14 (GRB14), glycerol-3-phosphate dehydrogenase 1 (GPD1), and growth differentiation factor 8 (GDF8; myostatin) significantly decreased approximately 2.4-, 2.2-, and 2.4-fold, respectively, after weight loss (gastric bypass). Increased expression of these transcripts was associated with increased obesity in the cross-sectional group (lean vs. morbidly obese muscle). Each transcript was validated by real-time quantitative RT-PCR assays in both study groups. Using Ingenuity Pathway Analysis, we show that all three transcripts are involved in the same regulatory network including AKT1, IGF1, TNF, PPARG, and INS. These results suggest that GRB14, GPD1, and GDF8 are weight loss-responsive genes in skeletal muscle and that the observed transcriptional modulation of these would be expected to improve insulin signaling, decrease triglyceride synthesis, and increase muscle mass, respectively, with weight loss. Thus our data provide a possible regulatory pathway involved in the development of insulin resistance in the morbidly obese state, and improvement of insulin resistance with weight loss.

Topics: Adaptor Proteins, Signal Transducing; Adult; Biopsy, Needle; Body Mass Index; Cross-Sectional Studies; Cytokines; Female; Gastric Bypass; Gene Expression Profiling; Glycerol-3-Phosphate Dehydrogenase (NAD+); Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Longitudinal Studies; Middle Aged; Models, Biological; Myostatin; Obesity, Morbid; Postoperative Period; Quadriceps Muscle; RNA, Messenger; Transcription, Genetic; Transforming Growth Factor beta; Weight Loss

Myostatin is a member of transforming growth factor-beta superfamily that plays an important inhibitory role during muscle development; in fact mutations of myostatin gene result in a hypermuscular phenotype. Moreover myostatin-deficient mice have a significant reduction in fat depots and a depression of adipogenesis. Little is known about myostatin function in muscle growth regulation in humans and in particular during caloric restriction. In the present work we quantified by real-time RT-PCR myostatin expression in muscle biopsies of a group of morbidly obese patients before and after weight loss obtained by biliopancreatic diversion (BPD). The patients reduced body weight by 38.9%, mostly due to fat-mass loss, showing also a significant reduction in the 24-hour EE as assessed by the respiratory chamber. Myostatin mRNA levels result clearly decreased after weight loss, suggesting a role in counteracting the progressive decline of muscle mass after BPD. Myostatin may provide therefore another mechanistic explanation for the control of energy partitioning between protein and fat, working against muscle wasting. Our data suggest that myostatin might represent an important regulator of skeletal muscle size also in conditions of food restriction in obese subjects.

Topics: Body Composition; Diet, Reducing; Energy Metabolism; Gene Expression; Humans; Muscle, Skeletal; Myostatin; Nitrogen; Obesity; Transforming Growth Factor beta; Weight Loss

Insulin is a major post-prandial muscle-anabolic hormone. A substantial loss of skeletal muscle mass occurs in insulin-deprived diabetes and is reversed by insulin treatment. Myostatin is a negative regulator of muscle mass upregulated in several chronic catabolic conditions. Whether myostatin expression is altered in insulin-deprived diabetes is unknown. In spite of opposite effects on muscle mass the potential role of basal circulating insulin in the regulation of myostatin expression is also undetermined.. We measured (Northern Blot) myostatin transcript levels in muscle groups with different fiber composition in streptozotocin-diabetic male rats receiving one of the following treatments for eight weeks: (1) control (C); (2) diabetes without treatment (DM); (3) diabetes with once-daily slow-acting insulin treatment (INS).. INS normalized plasma insulin and prevented weight reduction observed in DM. In fast-twitch gastrocnemius muscle myostatin transcript levels were unchanged (P>0.4) in both DM and INS compared to C. Myostatin transcripts were not measurable in any group in slow-twitch soleus muscle.. Muscle-specific myostatin expression is not increased under catabolic conditions in insulin-deprived diabetes. Insulin treatment also does not change myostatin transcript levels. The data provide the first assessment of potential interplay between insulin and myostatin and they do not support a major role of circulating insulin in the in vivo regulation of myostatin gene expression. A role of myostatin in muscle catabolism in chronic insulin-deprived diabetes is also not indicated by the current results.

Topics: Animals; Blotting, Northern; Diabetes Mellitus, Experimental; Gene Expression Regulation; Hypoglycemic Agents; Insulin; Male; Muscle, Skeletal; Myostatin; Random Allocation; Rats; Rats, Wistar; Streptozocin; Transforming Growth Factor beta; Weight Loss

To investigate the tissue factor (TF) pathway in clinical obesity and associated metabolic syndrome.. Thirty-seven morbidly obese patients (4 men; BMI, 48 +/- 7 kg/m(2); range, 42 to 53 kg/m(2)), undergoing elective gastroplasty for the induction of weight loss, were examined for hemostatic, metabolic, and inflammatory parameters at baseline and 14 +/- 5 months postoperatively.. Weight loss significantly reduced circulating plasma TF (314 +/- 181 vs. 235 +/- 113 pg/mL, p = 0.04), coagulation factor VII (130 +/- 22% vs. 113 +/- 19%, p = 0.023), and prothrombin fragment F1.2 (2.4 +/- 3.4 vs. 1.14 +/- 1.1 nM, p = 0.04) and normalized glucose metabolism in 50% of obese patients preoperatively classified as diabetic or of impaired glucose tolerance. The postoperative decrease in plasma TF correlated with the decrease of F1.2 (r = 0.56; p = 0.005), a marker of in vivo thrombin formation. In subgroup analysis stratified by preoperative glucose tolerance, baseline circulating TF (402.6 +/- 141.6 vs. 176.2 +/- 58.2, p < 0.001) and TF decrease after gastroplasty (DeltaTF: 164.7 +/- 51.4 vs. -81 +/- 31 pg/mL, p = 0.02) were significantly higher in obese patients with impaired glucose tolerance than in patients with normal glucose tolerance.. Procoagulant TF is significantly reduced with weight loss and may contribute to a reduction in cardiovascular risk associated with obesity.

Topics: Adult; Blood Glucose; Body Mass Index; C-Reactive Protein; Factor VII; Female; Gastroplasty; Glycated Hemoglobin; Humans; Insulin; Interleukin-6; Leptin; Lipoproteins; Longitudinal Studies; Male; Obesity, Morbid; Prospective Studies; Prothrombin Time; Statistics, Nonparametric; Thromboplastin; Transforming Growth Factor beta; Weight Loss

Transforming growth factor-beta1 (TGF-beta1) has been demonstrated to be overexpressed in hypertension. Leptin, an adipocyte product, has been shown to play a role in obesity-related hypertension and in vitro studies demonstrated a biologic interaction between leptin and TGF-beta1. Thus, we evaluate a possible in vivo association between TGF-beta1, body mass index (BMI), and leptin circulating levels in hypertensive subjects.. Blood samples for fasting leptin and TGF-beta1, were evaluated in 29 overweight, 46 obese, and 29 nonobese hypertensive patients before and after a 12-week calorie-restricted diet. Monocyte cultures were used for in vitro experiments.. Transforming growth factor-beta1 was significantly elevated in hypertensive obese patients (n = 46) as compared with TGF-beta1 levels of hypertensive patients with normal BMI (n = 29) (8. 9 +/- 3 ng/mL v 4.4 +/- 2; P < .001). The circulating levels of TGF-beta1 were associated with BMI and leptin levels in an univariate analysis (r = 0.59, P < .0001; r = 0.62, P < .0001, respectively) and these associations were still present after stepwise multivariate analysis. Weight loss of 10% produced a parallel decrease in TGF-beta1 (from 8.9 +/- 3 ng/mL to 5.3 +/- 2.8 ng/mL; P < .01) and leptin levels (from 30 +/- 24 ng/mL to 17 +/- 14; P < .05). In vitro experiments showed that leptin is able to induce a dose-dependent increase in TGF-beta1 production and mRNA expression in human monocyte cultures.. Our data indicate that TGF-beta1 levels are positively associated with BMI and leptin levels in hypertensive patients and suggest that adipose tissue may be an important determinant of TGF-beta1 levels possibly by a leptin-dependent pathway.

Topics: Adult; Blood Pressure; Body Mass Index; Female; Gene Expression; Humans; Hypertension; In Vitro Techniques; Leptin; Male; Middle Aged; Obesity; Regression Analysis; RNA, Messenger; Transforming Growth Factor beta; Weight Loss

Experimental autoimmune myasthenia gravis (EAMG) is an animal model for human myasthenia gravis (MG), characterized by an autoaggressive T-cell-dependent antibody-mediated immune response directed against the acetylcholine receptor (AChR) of the neuromuscular junction. Dendritic cells (DC) are unique antigen-presenting cells which control T- and B-cell functions and induce immunity or tolerance. Here, we demonstrate that DC exposed to TGF-beta1 in vitro mediate protection against EAMG. Freshly prepared DC from spleen of healthy rats were exposed to TGF-beta1 in vitro for 48 h, and administered subcutaneously to Lewis rats (2 x 10(6)DC/rat) on day 5 post immunization with AChR in Freund's complete adjuvant. Control EAMG rats were injected in parallel with untreated DC (naive DC) or PBS. Lewis rats receiving TGF-beta1-exposed DC developed very mild symptoms of EAMG without loss of body weight compared with control EAMG rats receiving naive DC or PBS. This effect of TGF-beta1-exposed DC was associated with augmented spontaneous and AChR-induced proliferation, IFN-gamma and NO production, and decreased levels of anti-AChR antibody-secreting cells. Autologous DC exposed in vitro to TGF-beta1 could represent a new opportunity for DC-based immunotherapy of antibody-mediated autoimmune diseases.

Topics: Animals; Antigen Presentation; Autoantigens; Autoimmune Diseases; Cell Differentiation; Dendritic Cells; Female; Humans; Immunotherapy; Injections, Subcutaneous; Myasthenia Gravis, Autoimmune, Experimental; Rats; Rats, Inbred Lew; Receptors, Cholinergic; Recombinant Proteins; Transforming Growth Factor beta; Transforming Growth Factor beta1; Weight Loss

Mice and cattle with genetic deficiencies in myostatin exhibit dramatic increases in skeletal muscle mass, suggesting that myostatin normally suppresses muscle growth. Whether this increased muscling results from prenatal or postnatal lack of myostatin activity is unknown. Here we show that myostatin circulates in the blood of adult mice in a latent form that can be activated by acid treatment. Systemic overexpression of myostatin in adult mice was found to induce profound muscle and fat loss analogous to that seen in human cachexia syndromes. These data indicate that myostatin acts systemically in adult animals and may be a useful pharmacologic target in clinical settings such as cachexia, where muscle growth is desired.

Topics: 3T3 Cells; Activins; Adipose Tissue; Animals; Body Weight; Cachexia; CHO Cells; Cricetinae; Eating; Female; Follistatin; Liver; Mice; Mice, Nude; Muscle Fibers, Skeletal; Muscle, Skeletal; Myostatin; Organ Size; Peptide Fragments; Recombinant Proteins; Transforming Growth Factor beta; Wasting Syndrome; Weight Loss

During chemo- and radiation therapy, the balance between epithelial cell proliferation, differentiation, and cell death at the villus tip is disrupted by premature death of dividing epithelial cells. This will subsequently lead to the onset of mucosal barrier injury in the whole gastrointestinal tract. Up till now there is no validated method to treat side effects occurring due to therapy. An approach to manage this side effect might be to reversibly arrest growth of epithelial stem cells during therapy using Transforming Growth Factor-beta2. A Transforming Growth Factor-beta2 enriched fraction prepared from bovine milk was shown to protect small intestinal epithelial cells against cell cycle specific chemotherapeutic agents by arresting the cells in G1-phase. Secondly, in a rat model for induced small intestinal damage, oral supplementation of rats exposed to methotrexate with the Transforming Growth Factor-beta2 enriched fraction significantly reduced the chemotherapy-associated weight loss and ileal villus atrophy by reducing cell proliferation in the normal stem cell population. Thus oral supplementation with a bovine milk fraction enriched for Transforming Growth Factor-beta2 attenuated the side effects of chemotherapy in the small intestine in rats.

Topics: Administration, Oral; Animals; Antimetabolites, Antineoplastic; Atrophy; Cell Cycle; Cell Death; Disease Models, Animal; Epithelial Cells; Female; Immunosuppressive Agents; Intestine, Small; Methotrexate; Rats; Transforming Growth Factor beta; Transforming Growth Factor beta2; Weight Loss

Mucositis is a common, dose-limiting complication in patients receiving cancer chemotherapy, which derives from damage to the epithelial cell layer. We have shown that transforming growth factor-beta 3 (TGF-beta 3) negatively regulates epithelial cell proliferation and reduces the incidence of oral mucositis. Here, we report the findings of a large study examining the effects of TGF-beta 3 administration in a hamster model on oral epithelial cell cycling in vivo, on oral mucositis, on weight retention and on survival. Topical application of TGF-beta 3 to the buccal mucosa significantly reduced basal cell proliferation, as measured by proliferating cell nuclear antigen (PCNA) immunohistochemistry and DNA ploidy. Administration of topical TGF-beta 3 prior to chemotherapy with 5-fluorouracil (5-FU) significantly reduced the severity of mucositis with respect to time, reduced chemotherapy-associated weight loss and increased survival.

Topics: Administration, Topical; Animals; Antimetabolites, Antineoplastic; Biomarkers; Cell Division; Cricetinae; Fluorouracil; Injections, Subcutaneous; Mouth Mucosa; Proliferating Cell Nuclear Antigen; Severity of Illness Index; Stomatitis; Survival Rate; Transforming Growth Factor beta; Weight Loss