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kopková,
Mikulá
Pura,
Miroslav Vl
ek,
ofia Rádiková,
Richard Imrich,
Barbara Ukropcová,
Mária Tajtáková,
Juraj Koka,
tefan Zórad,
Vítazoslav Belan,
Peter Va
uga,
Juraj Payer,
Juergen Eckel,
Iwar Klime and
Daniela Gaperíková
Institute of Experimental Endocrinology (J.U., A.P., M.S., M.V., Z.R., R.I., B.U., J.K., S.Z., I.K., D.G.), Slovak Academy of Sciences, 833 06 Bratislava, Slovakia; National Institute of Endocrinology and Diabetology (M.P., P.V.), 034 91 L’ubocha, Slovak Republic; The First Clinic of Internal Medicine (M.T.), P. J. afárik University, 041 80 Koice, Slovak Republic; Radiodiagnostic Clinic (V.B.) and The Fifth Clinic of Internal Medicine (J.P.), Comenius University School of Medicine, 811 08 Bratislava, Slovakia; and German Diabetes Center (J.E.), 40225 Düsseldorf, Germany
Address all correspondence and requests for reprints to: Jozef Ukropec, Ph.D., Diabetes Laboratory, Institute of Experimental Endocrinology, Centre of Excellence acknowledged by European Commission, Slovak Academy of Sciences, Vlárska 3, 833 06 Bratislava, Slovak Republic. E-mail: jozef.ukropec{at}savba.sk (http://www.endo.sav.sk/d-ldn.htm).
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Objective: The objective of the study was to test the hypothesis that GHD might change the spectrum of adipokines and thus influence the adipose tissue and the whole-body metabolic and inflammatory status leading to development of insulin resistance.
Design: This was a single-center observational study with a cross-sectional design.
Participants and Methods: Protein arrays were used to characterize adipokines expressed in the sc adipose tissue obtained from young GHD adults and compared with age-, gender-, and body mass index (BMI)-matched group of healthy individuals. All subjects underwent an oral glucose tolerance test, euglycemic hyperinsulinemic clamp, and magnetic resonance imaging examination.
Results: Presence of abdominal obesity, enlarged adipocytes, increased circulating high-sensitivity C-reactive protein, impaired glucose tolerance, and decreased insulin action were found in GHD. Changes in adipokine protein expression due to GHD were highly dependent on the obesity phenotype. Lean GHD individuals (BMI 
23 kg/m2) had decreased protein levels for stem cell factor and epithelial growth factor, indicating a possible defect in adipocyte differentiation and proliferation. Decrease of vascular endothelial growth factor, stromal cell-derived factor, angiopoietin-2, and brain-derived neurotrophic factor advocated for attenuated angiogenesis and neurogenesis. Presence of obesity (BMI 31 kg/m2) eliminated these inhibitory effects. However, adipose tissue expansion in GHD individuals was paralleled by an elevation of adipose tissue proinflammatory cytokines (IL-1β, interferon-
) and chemoattractants (interferon-inducible T cell 
-chemoattractant, monocyte chemotactic protein-2, monocyte chemotactic protein-3, eotaxin).
Conclusion: Our data demonstrate that GHD modulates adipokine and cytokine protein expression pattern, which might influence the adipose tissue growth and differentiation and predispose to tissue hypoxia, inflammation, and a defect in the whole-body insulin action.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Adipose tissue is a dynamic participant in endocrine physiology serving as the source of secreted adipokines and cytokines (14, 15). It is important to note that adipose tissue contains multiple cell types, including endothelial cells and macrophages, which have been associated with cytokine production (16). Many recent studies have now examined the role of adipokines such as adiponectin and TNF as the early possible predictors of cardiovascular events in obese and diabetics (17, 18). Mediators of the chronic inflammatory status have been implicated in the pathogenesis of metabolic diseases such as obesity and diabetes as well as atherosclerosis (12, 16, 17, 18, 19). Proinflammatory factors such as hsCRP and IL-6 are considered surrogate markers of future vascular and metabolic complications (19).
Indications that adipokines and inflammatory cytokines play a significant role in pathologies also accompanying the adult GHD prompted us to investigate the adipose tissue adipokine and cytokine protein expression pattern in sc adipose tissue of GHD individuals using protein arrays. The aim was to identify major changes in adipose tissue adipokine and cytokine protein expression related to the GHD and accompanying metabolic and cardiovascular risk factors, both in the absence and in the presence of obesity.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Sixteen adult individuals (10 males and six females) with untreated GHD and 16 age-, gender-, and body mass index (BMI)-matched healthy controls, a total 32 individuals (16 pairs), were according to their BMI assigned to the lean (n = 18, BMI 23.1 ± 0.4 kg/m2) and mildly obese (n = 14, BMI 30.8 ± 0.9 kg/m2) subgroups. This matching enabled direct evaluation of the effects related to GHD, independent of obesity, age, and gender. Presence of GHD was diagnosed by a peak of GH response less than 3 µg/l during an insulin tolerance test as well as by measuring the circulating IGF-1 levels (Table 1
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In addition to GHD, all patients suffered from multiple pituitary deficiencies (>1), except for two subjects with isolated GHD of idiopathic and postoperative origin. Hormone replacement therapy with L-thyroxine (75–150 µg/d) and hydrocortisone (5–35 mg/d) was given where appropriate. Hypogonadism was treated in men with im (n = 6) or oral (n = 2) administration of testosterone esters and in women with oral estradiol (n = 1) or estroprogestinic combinations (n = 4). Two male and one female subject had normal gonadal function and three individuals were on desmopressin (60–300 µg/d) therapy. All other hormonal deficiencies were fully substituted for during the study period, and adequacy of the hormone replacement therapy was assessed periodically for at least 12 months (last examination < 2 months) before study entry by measuring the serum-free thyroid hormones, testosterone/estradiol, and urinary free cortisol levels (supplementary Table 1, published as supplemental data on The Endocrine Society’s Journals Online Web site at http://jcem.endojournals.org). None of the patients received GH and lipid-lowering treatment. Patients with malignant disease, diabetes mellitus, existing vascular disease, and uncontrolled hypertension were not eligible to enter this study.
The study was approved by the Ethics Committee of the Derer’s University Hospital, Slovak Health Care University in Bratislava, and conforms to the ethical guidelines of the 2000 Helsinki declaration. All patients and healthy control volunteers provided witnessed written informed consent before entry into the study.
Study design
This was a single-center observational study with a cross-sectional design. All subjects attended two visit assessments at the Clinical Research Facility of the Institute of Experimental Endocrinology. During the first visit, anthropometric measurements, fasted-state blood collections and the sc abdominal adipose tissue biopsy preceding an oral glucose tolerance test were performed. Two days later, insulin sensitivity was determined with aid of the euglycemic-hyperinsulinemic clamp (EHC) and quantification of the sc and visceral adipose tissue cross-sectional areas was determined by magnetic resonance imaging (MRI) at the Department of Radiology, Derer’s Hospital in Bratislava.
Methods
Height and weight were measured to calculate BMI (kilograms per meter–2). Waist circumference was measured at the midpoint between the lower border of the rib cage and the iliac crest and hip circumference at the level of the greater trochanters.
Abdominal fat distribution was evaluated by MRI using gradient sequence, repetition time of 34 msec, and echo time of 2.38/5.24 msec (Symphony 1.5 T spin echo; Siemens, Munich, Germany). Total abdominal as well as visceral and sc abdominal adipose tissue areas were evaluated from a single slice scan at the level between the L4 and L5 vertebral body using the image analysis freeware (ImageJ, National Institutes of Health, Bethesda, MD). Adipocyte size was assessed microscopically after their isolation by collagenase digestion as previously described (20). The cell diameter was determined using the PC-BAS TINA software (Raytest, Staubenhardt, Germany). Average diameter of at least 100 cells from each adipocyte suspension was calculated.
Oral glucose tolerance test
After an overnight fast, an indwelling catheter (Surflo-W, Terumo, Belgium) was placed into an antecubital vein for blood sampling. After 30 min rest, blood pressure was measured using Dinamap Vital Signs Monitor 845 XT (Critikon Inc., Tampa, FL). Blood samples were drawn before (0 min) and after (30, 60, 90, and 120 min) ingestion of 75 g glucose and used to determine the plasma glucose, insulin, and C-peptide levels.
Whole-body insulin sensitivity
One-step hyperinsulinemic euglycemic clamp was carried out between 0800 and 1100 h after an overnight fast. Regular human insulin (Actrapid; Novo Nordisk, Copenhagen, Denmark) was infused in a primed-continuous fashion at the rate of 1 mU/kg–1·min–1 for 2–3 h. Blood glucose was determined every 5 min and maintained at euglycemia (5.0 mmol/liter) using a variable rate of 20% glucose infusion. The whole-body insulin sensitivity index (M value) was determined during the final 40 min of the clamp from the mean infusion rate of glucose required to maintain euglycemia per kilogram body weight per minute.
Protein array analysis of the sc adipose tissue
Aspiration needle biopsy of sc abdominal adipose tissue was taken in the basal fasted state prior the glucose load as described previously (21). The tissue sample was immediately cleaned up from contaminating blood and connective tissue, clamp frozen in liquid nitrogen, and stored at –70 C until further analyses.
Tissue lysates were prepared from 70–150 mg of powdered sc adipose tissue from all 32 subjects using cell lysis buffer (RayBiotech, Norcross, GA) with addition of the protease inhibitor cocktail (Complete; Roche, Switzerland). After 2 h lysis at 4 C and centrifugation at 10,000 x g for 15 min at 4 C, the protein content in the supernatant was measured using the Bio-Rad Protein Assay (Bio-Rad, Ivry-sur-Seine, France). Two hundred micrograms of proteins were used for analysis.
The predesigned protein arrays (RayBioHuman Cytokine Antibody Arrays C series 1000.1; RayBiotech, supplementary Table 2) were processed according to manufacturer instructions; the array sensitivity and reproducibility data are available (http://www.raybiotech.com/human_array_sensitivity.pdf). Signal intensity was quantified by densitometry with aid of the LumiImager using the LumiAnalyst software (Roche, Applied Science, Penzberg, Germany). The data were normalized to an internal positive control provided on each membrane. Relative expression levels (target gene signal/positive control signal) were used for the statistical evaluation.
Real-time PCR
Total RNA was isolated using the RNeasy lipid tissue minikit (QIAGEN, Hilden, Germany), DNase treatment was included. RNA quantity, purity, and integrity were determined. Gene expression was measured with aid of the real-time PCR using the predesigned TaqMan gene expression assays (Applied Biosystems, Foster City CA). This technique was used to determine expression of leptin, TNF, IL-6, CD68, CD14, plasminogen activator inhibitor (PAI)-1, and 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1). The 18S rRNA was used as an internal reference to calculate the relative expression of the aforementioned genes. Specific information about the predesigned TaqMan gene expression assays for all of these genes is available (http://www.appliedbiosystems.com).
The real-time PCR was performed using the RotorGene 2000 real-time cycler (Corbett Research, Sydney, Australia) as described previously (21).
Biochemical assays
Plasma glucose concentrations were measured using the glucose oxidase method (Hitachi 911, Tokyo, Japan). Serum IGF-I, free insulin, and C-peptide levels were determined with immunoradiometric assay (Immunotech, Roissy, France). Serum total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride levels were measured with enzymatic kits from Roche Diagnostics (Lewes, UK) using an autoanalyzer (Hitachi 911). Low-density lipoprotein (LDL) cholesterol concentration was calculated using the formula of Friedewald. hsCRP levels were measured by the immunoturbidimetric method (Randox, Antrum, UK).
Statistical analyses
All statistical analyses were performed using the SPSS software (SPSS Inc, Chicago, IL). The primary aim was to identify changes related to GHD in lean and obese subpopulations. Pair-wise comparisons between age-, gender-, and BMI-matched GHD and healthy individuals were made with the aid of a t test. All the GHD individuals were treated as one group due to the fact that no significant differences related to the age of onset, duration, or etiopathogenesis of GHD had been observed in any of the evaluated parameters. Differences among all four experimental groups were evaluated with ANOVA. Nonparametric methods were used where appropriate. Multiple regression analysis with waist circumference, IGF-I circulating concentration and hsCRP as independent variables representing the effects presented by phenotypes of obesity, GHD, and inflammation, respectively, was also performed. The data are reported as mean ± SEM with P < 0.05 indicating statistical significance.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Sixteen adults with untreated GHD and sixteen age-, gender-, and BMI-matched healthy controls were divided to lean and obese subgroups. Lean GHD males had bigger waist circumference than the corresponding controls, whereas this effect was not significant in obesity and was not found in females (Table 1
). MRI measurement revealed elevation in the content of the sc as well as visceral adipose tissue mass in lean but not obese GHD patients (Table 1 and Fig. 1).
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). GHD was associated with elevated LDL cholesterol and higher atherogenic index among the lean patients (Table 1).
All of the subjects in this study had normal fasting glucose levels. Nevertheless, four lean (n = 9) and four obese (n = 7) GHD patients but none of the control individuals had impaired glucose tolerance. In addition, euglycemic hyperinsulinemic clamp revealed lower insulin action in lean GHD patients, compared with lean controls. This effect was also concealed by obesity-related decrease in insulin action (Table 1). GHD in both lean and obese groups was associated with a 4- to 5-fold increase in the serum hsCRP level. It also should be noted that hsCRP concentration found in the obese group was more than twice as high as in the lean group (Table 1).
Taken together, individuals with untreated GHD had increased abdominal obesity and impaired insulin action and exhibited signs of systemic inflammation.
Adipose tissue phenotype in GHD
This work revealed that the sc abdominal adipose tissue of individuals with untreated GHD contains adipocytes with a very large diameter (Fig. 2). Presence of large adipocytes was found to be strongly associated with GHD irrespective of obesity (Fig. 2C). Increased adipocyte diameter was also paralleled by an increase in waist circumference (R2 = 0.14, P = 0.04) and elevation of inflammatory markers (hsCRP: R2 = 0.25, P = 0.005; IL-1β protein: R2 = 0.19, P = 0.017; CD14 mRNA: R2 = 0.16, P = 0.031). Negative associations with brain-derived neurotrophic factor (BDNF; R2 = 0.18, P = 0.018) and angiopoietin-2 (R2 = 0.19, P = 0.017) indicated the possibility of a defect in neurogenesis and angiogenesis in the large adipocyte-containing adipose tissue of GHD patients. Negative association between adipocyte diameter and insulin sensitivity index (R2 = 0.20, P = 0.013) and positive correlation with the 2-h plasma glucose (R2 = 0.19, P = 0.016) indicated that the elevated adipocyte size may contribute to the whole-body metabolic derangements in GHD.
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GHD was associated with decreased circulating IGF-I concentration (Table 1). However, it was not associated with changes in the adipose tissue-specific IGF-I protein level (Fig. 3A and supplementary Table 3). Expression of the major circulating isoform of IGF-binding protein (IGFBP)-3 in adipose tissue was lower in lean GHD patients, reaching the levels similar to those found in obese individuals (Fig. 3A and supplementary Table 3). The IGFBP2 protein was decreased in lean GHD patients, whereas locally active IGFBP1 was elevated in obese patients with GHD (Fig. 3A and supplementary Table 3). In addition, we observed coordinated lowering of the factors regulating growth and differentiation of adipocytes [epithelial growth factor (EGF), stem cell factor] as well as factors important for angiogenesis [vascular endothelial growth factor (VEGF), stromal cell-derived factor (SDF1), angiopoietin 2] and neurogenesis (BDNF) of the adipose tissue (Fig. 3A and supplementary Table 3). It has to be emphasized that this complex regulation was observed in lean individuals and not in obesity, in which the elevation of IGFBP1 and thrombopoietin and lowering of the neurotrophin-3 indicated some but much weaker effects of GHD on adipokines regulating tissue growth and differentiation (Fig. 3A and supplementary Table 3).
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In lean individuals, GHD was associated with a decreased adipose tissue protein content of IL-2R and that of macrophage inflammatory proteins-1d and -3d. The IL-1β was, in fact, the only proinflammatory protein that showed to be elevated in adipose tissue of lean GHD individuals (Fig. 3B and supplementary Table 3). Unlike in lean individuals, the adipose tissue of obese GHD patients expressed many proinflammatory markers. We observed coordinately elevated expression of interferon (IFN)- and IFN-inducible T cell -chemoattractant, granulocyte chemotactic protein-2, monocyte chemotactic protein (MCP)-2, MCP3, and eotaxin (Fig. 3B and supplementary Table 3).
In addition, lean GHD patients had elevated gene expression for several proinflammatory cytokines (IL-6, TNF) and markers of tissue macrophage infiltration (CD68, CD14) as well as leptin, 11-βHSD, and PAI-1 (Fig. 4 and supplementary Table 3).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Presence of abnormal body composition and increased abdominal obesity in GHD was firmly established earlier (7, 22). Results of our study confirmed that lean GHD individuals tended to have larger waist circumference and more abdominal adiposity with proportional increase in both sc and visceral adipose tissue.
GHD was not associated with any change in circulating levels of triglycerides and HDL cholesterol. This is not surprising because several other reports showed variable effects of GHD on the HDL cholesterol and triglyceride levels (8, 23). GHD, however, was associated with robustly elevated LDL cholesterol concentration and a higher atherogenic index. Interestingly, these effects were masked in obesity. Many previous reports indicated that GHD is associated with a proatherogenic lipid profile, characterized by increased total cholesterol, small dense LDL particles and triglycerides, but not consistently decreased HDL cholesterol (1, 3, 4, 5, 6, 7, 8).
All of the subjects in this study had normal fasting glucose levels. Nevertheless, approximately half of the GHD patients had impaired glucose tolerance. In addition, GHD individuals had decreased in vivo insulin action as measured by EHC. Interestingly, this effect was masked by obesity. Similar findings of the impaired insulin action in GHD as well as improvement of insulin action with GH treatment were reported earlier (5, 9, 10).
Interestingly, GHD in both lean and obese groups was associated with an approximately 4- to 5-fold increase in the serum hsCRP level, indicating the presence of the proinflammatory state as shown in a few very recent reports (11, 12, 13).
Consistent with some earlier reports (24, 25), sc adipose tissue of individuals with untreated GHD contained adipocytes with very large diameter. Obesity is known to induce enlargement of adipocytes, which is either the cause or consequence of major molecular and metabolic alterations affecting systemic metabolism (26, 27). However, we observed that obesity itself had only minor effect on adipocyte size when compared with GHD. In addition, we showed that presence of elevated adipocyte diameter in GHD individuals was paralleled by an increase in waist circumference and inflammatory markers such as circulating hsCRP and adipose tissue, IL-1β protein, or CD14 mRNA. These markers were negatively associated with the protein levels of neurogenic and angiogenic growth factors such as BDNF and angiopoietin-2, which indicates a possible association of the proinflammatory status with early defects in neurogenesis and angiogenesis. It is plausible to speculate that the above-described adipocyte phenotype may contribute to the metabolic derangements as similarly described in obesity (26, 27). The latter is supported by the finding of an association between the adipocyte diameter and in vivo insulin action.
It is important to note that the development of obesity depends on the coordinated interplay of adipocyte growth and differentiation with angiogenesis and neurogenesis. Evidence suggests that adipogenesis occurs throughout life, in both response to normal cell turnover and response to the need for additional fat mass stores that arises when caloric intake exceeds nutritional requirements (28). Our data indicate that GHD may, at least partially, inhibit the aforementioned developmental processes.
Data from in vivo and in vitro studies support the role for IGF-I in the adipocyte differentiation and proliferation, which is necessary for normal obesity progression (29, 30). Here we report decreased circulating and unchanged adipose tissue IGF-I concentration due to GHD. The activity of IGF-I is regulated by a family of IGFBPs (31). The major IGF transport function can be attributed to IGFBP3, the most abundant circulating IGFBP (32). Adipose tissue protein content of IGFBP3 was decreased in lean GHD individuals to levels observed in the adipose tissue of obese GHD patients, thus limiting the bioavailability of IGF-I in the adipose tissue (32). IGFBP2 protein, the principal IGFBP secreted by white preadipocytes during adipogenesis and the second most abundant IGFBP, was also found to be decreased in GHD (31). A recent report by Wheatcroft et al. (33) showed reduced susceptibility to age-related development of obesity and insulin resistance in IGFBP2 transgenic mice, which is perhaps due to impaired adipogenesis. On the other hand, locally active IGFBP1, which is known as a predictor of type 2 diabetes and cardiovascular disease (27, 28, 29), was elevated in obese patients with GHD when compared with obese controls.
Further evidence of coordinated down-regulation of factors responsible for the growth and differentiation of adipose tissue was found in lean GHD individuals. It was indicated by the concomitant decrease of the protein expression for the following: 1) adipocyte differentiation factors (IGFBPs and EGF); 2) factors regulating angiogenesis (VEGF, SDF1, angiopoietin 2); and 3) factors important in neurogenesis (BDNF). It has been recently shown that expression of many of the aforementioned factors is regulated by the hypoxia inducible factor (HIF)-1. Hypoxia enhances the IGFBP1 gene expression in liver (34). Activation of EGF receptor signaling increases HIF-1 protein synthesis under normoxic conditions, which results in the resistance to apoptosis (35). HIF-1 increases gene expression of VEGF, which stimulates new blood vessel formation (36). In addition, SDF1 gene expression is also dependent on HIF-1 in direct proportion to reduced oxygen tension (37). We observed that complex down-regulation of factors related to normal adipose tissue development was largely masked by the presence of obesity. It is conceivable to speculate that hypoxia present in the adipose tissue with extremely enlarged adipocytes (38) might stimulate these pathways and break through the barrier represented by GHD to enable adipose tissue expansion. Nevertheless, we assume that these defects could possibly contribute to the proinflammatory status of adipose tissue from obese GHD patients.
To support this notion, we clearly showed that the adipose tissue of obese GHD patients expressed many proinflammatory markers. This is, to the best of our knowledge, the first report indicating that adipose tissue of GHD individuals contains elevated levels of proinflammatory factors such as IL-1β, IFN-, and IFN-inducible T cell -chemoattractant as well as granulocyte chemotactic protein-2, MCP2, MCP3, and eotaxin, thus suggesting a large infiltration of adipose tissue from obese GHD patients with immunocompetent cells.
This notion was further supported by an observation of the elevated expression of genes encoding several proinflammatory factors (IL-6, TNF, PAI-1, leptin) and markers of tissue macrophage infiltration (CD68, CD14), which might be predictive of the proinflammatory status of the adipose tissue from GHD individuals.
Our results indicate that GHD seems to jeopardize normal adipose tissue growth and development by specific modulation of adipokines and cytokines expression, leading to the development of the large adipocyte phenotype associated with inflammation and metabolic incompetence of adipose tissue. This might contribute to the whole-body metabolic derangements found in GHD patients. Finally, it is conceivable to hypothesize that some of these defects might be normalized by GH therapy. However, further research is necessary to conclusively prove the positive effects of GH replacement therapy to adults on the adipose tissue health, which is necessary for the whole-body metabolic and cardiovascular well-being.
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Acknowledgments |
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Footnotes |
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Current address for J.K.: Obesity and Diabetes Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ.
Part of this work has been previously presented in a form of abstract at the 67th Annual Meeting of the American Diabetes Association, Chicago, IL, June 22–26, 2007, and the 9th European Congress of Endocrinology, Budapest, Hungary, April 28 to May 2, 2007.
Disclosure Statement: The authors have nothing to disclose.
First Published Online March 11, 2008
Abbreviations: BDNF, Brain-derived neurothropic factor; BMI, body mass index; EGF, epidermal growth factor; EHC, euglycemic-hyperinsulinemic clamp; GHD, GH deficiency; HDL, high-density lipoprotein; HIF, hypoxia inducible factor; hsCRP, high-sensitivity C-reactive protein; 11β-HSD, 11β-hydroxysteroid dehydrogenase; IGFBP, IGF binding protein; IFN, interferon; LDL, low-density lipoprotein; MCP, monocyte chemoattractant protein; MRI, magnetic resonance imaging; PAI, plasminogen activator inhibitor; SAT, sc adipose tissue; SDF1, stromal cell-derived factor 1; VAT, visceral adipose tissue; VEGF, vascular endothelial growth factor.
Received September 28, 2007.
Accepted March 3, 2008.
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References |
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system in obese subjects. Int J Obes Relat Metab Disord 23:355–360[CrossRef][Medline] signal pathways increases resistance to apoptosis by up-regulating survivin gene expression. J Biol Chem 281:25903–25914 pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest 117:1616–1626[CrossRef][Medline]
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