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J Zapf

Publications and source records attributed to J Zapf.

At least 19 recordsLinked to original sources
PubMed2002

IGF-I in human breast cancer: low differentiation stage is associated with decreased IGF-I content.

OBJECTIVE: Few investigations on the potential role of IGF-I in human breast cancer have used morphological criteria, and the data presented on the localisation of IGF-I are controversial. Moreover, little information exists on a potential correlation between local IGF-I and the grade of malignancy or prognostic factors. Therefore, we investigated the immunohistochemical localisation of IGF-I in specimens of human breast cancer tumours of the ductal type, graded as G1/G2 (well-/moderately differentiated, n=115) and G3 (poorly differentiated, n=28). METHODS: IGF-I immunoreactivity was quantified using a scaling from no (-) to numerous (+++) IGF-I-immunoreactive cells. From 29 of the G1/G2 and 17 of the G3 tumours IGF-I was also measured by RIA. Cytosolic oestrogen receptor (ER) and progesterone receptor (PR) levels, and S-phase fraction were established and related to the number of IGF-I-immunoreactive cells. RESULTS: IGF-I immunoreactivity occurred predominantly in ductal epithelial cells. Of G3 tumours, 57% exhibited IGF-I immunoreactivity as compared with 84% of G1/G2 tumours. Correspondingly, the amount of IGF-I measured by RIA was significantly lower in G3 tumours (6.9+/-0.9 ng/g wet weight) than in G1/G2 tumours (10.5+/-1.1 ng/g wet weight) (P=0.031). G1/G2 tumours exhibited a higher percentage of IGF-I-immunoreactive cells (16% -, 23% +, 41% ++, 20% +++) than G3 tumours (43% -, 37% +, 12% ++, 8% +++). When comparing the - with the +++ G1/G2 tumours, the frequency of IGF-I-immunoreactive cells was related significantly to the ER (P<0.016) and the PR (P<0.008) levels. In G1/G2 and G3 tumours, the ER and PR levels increased with the amount of IGF immunoreactivity while the S-phase fraction increased with decreasing IGF-I content. In 25% of the specimens, IGF-I immunoreactivity occurred in stromal cells, but there was no obvious difference between the different types of tumours. The survival of the G1/G2 tumour patients increased with increasing numbers of IGF-I-immunoreactive cells. CONCLUSIONS: It is concluded that IGF-I is associated with the more-differentiated type of epithelial cells and that increasing dedifferentiation goes along with decreased IGF-I content. Thus, the presence of IGF-I immunoreactivity in breast cancer epithelial cells indicates a lower degree of malignancy than the lack of IGF-I.

Adult↗
PubMed2001

Transferrin binds insulin-like growth factors and affects binding properties of insulin-like growth factor binding protein-3.

In the circulation, most of the insulin-like growth factors (IGFs) are bound to a ternary 150 kDa complex with IGF-binding protein (IGFBP)-3 and the acid labile subunit. In the current study, we identify transferrin (Tf) by mass spectrometry, and immunoprecipitation as a component of a major IGF-binding fraction separated from human plasma. IGF ligand blotting, cross-linkage experiments and surface plasmon resonance spectrometry have been used to demonstrate the capability of Tf to bind IGFs specifically. In combination with Tf, IGFBP-3 showed a 5-fold higher affinity for IGF-II than IGFBP-3 alone. The data suggest that Tf may play an important role in regulating IGF/IGFBP-3 functions.

Chromatography, Affinity↗
PubMed2001

Insulin-like growth factor (IGF) I down-regulates type 1 IGF receptor (IGF 1R) and reduces the IGF I response in A549 non-small-cell lung cancer and Saos-2/B-10 osteoblastic osteosarcoma cells.

The insulin-like growth factor type 1 receptor (IGF 1R) mediates the acute metabolic effects of IGF I as well as IGF I-stimulated cell proliferation and protection from apoptosis. IGF binding proteins (IGFBPs) can modulate these responses. We, therefore, investigated whether intrinsic IGFBPs interfere with IGF I-induced regulation of IGF 1R expression and with the biological response to IGF I in two human tumor cell lines, the non-small-cell lung cancer cell line A549 and the osteoblastic osteosarcoma cell line Saos-2/B-10. We compared the growth rates, IGFBP production, IGF I binding characteristics, IGF 1R protein and mRNA levels, and the acute IGF I response (stimulation of glycogen synthesis) after pretreatment of the cells in serum-free medium with or without added IGF I or medium supplemented with 5% fetal calf serum (FCS). In contrast to A549 cells, which produce IGF I and significant amounts of IGFBPs, survival and proliferation of Saos-2/B-10 cells, which do not produce IGF I or significant amounts of IGFBPs, depended on the addition of exogenous IGF I. IGF I increased the concentration of IGFBP-2 and -3 and decreased the concentration of IGFBP-4 in the medium of A549 cells. As compared to FCS, IGF I pretreatment in both cell lines decreased the number of specific IGF I binding sites, down-regulated total and membrane IGF 1R protein, and largely reduced or abolished the acute IGF I response without affecting IGF 1R mRNA levels. The data suggest that the IGF 1R protein of the two cell lines is translationally and/or posttranslationally down-regulated by its ligand in the presence and in the absence of locally produced IGFBPs and that the cell lines have retained this negative feedback to counteract IGF I stimulation.

Apoptosis↗
PubMed2001

Stabilizing insulin-like growth factor-I in poly(D,L-lactide-co-glycolide) microspheres.

This study aimed at developing a controlled drug delivery system for recombinant human insulin-like growth factor-I (IGF-I) for localized delivery in bone healing. IGF-I was microencapsulated into an end-group uncapped 14 kDa poly(D,L-lactide-co-glycolide) 50:50 (PLGA 50:50) by solvent extraction from a W(1)/O/W(2) dispersion. Prior to encapsulation, IGF-I was exposed to ultrasonication in a water/dichloromethane dispersion, and its stability tested in the presence and absence of various excipients in the W(1) phase. HPLC and RIA were used for the assessment of IGF-I stability. Microencapsulated IGF-I was tested again for its structural intactness and also for in vitro release from various formulations containing appropriate co-encapsulated excipients. A specific fat cell assay was used to determine the biological activity of released IGF-I. Moderate ultrasonic treatment of aqueous IGF-I/dichloromethane mixtures caused approx. 50% IGF-I degradation. However, IGF-I was fully protected when bovine serum albumin, succinylated gelatin or poly(ethyleneglycol) were added to the aqueous IGF-I. Co-encapsulation of these excipients protected efficiently the protein upon microencapsulation. IGF-I release from microsphere formulations was sustained for up to 13 days featuring a moderately pulsatile pattern, depending on the microsphere composition. Typically, the amounts of IGF-I released within the first 24 h (burst) and during the second release pulse were in the order of 20 and 40%, respectively, of the total dose. The biological activity of released IGF-I was confirmed at selected time-points by the fat cell assay. In conclusion, the developed microspheres proved to be suitable to release biologically intact IGF-I over up to 13 days, a time-period considered to be relevant to promote bone fracture healing.

Adipocytes↗
PubMed2001

Pregnancy-associated plasma protein-A (PAPP-A) in ovine, bovine, porcine, and equine ovarian follicles: involvement in IGF binding protein-4 proteolytic degradation and mRNA expression during follicular development.

IGF binding protein-4 (IGFBP-4) proteolytic degradation is a common feature of preovulatory follicles from human, ovine, bovine, porcine, and equine ovary. In all these species, the protease is a zinc-dependent metalloprotease and its ability to degrade IGFBP-4 is IGF dependent. The human intrafollicular IGFBP-4-degrading protease has recently been identified as pregnancy-associated plasma protein-A (PAPP-A). The aim of this study was to investigate whether PAPP-A is also involved in IGFBP-4 degradation in ovine, bovine, porcine, and equine preovulatory follicles and to study the expression of PAPP-A mRNA in bovine and porcine granulosa cells from different classes of follicles. Immunoneutralization and immunoprecipitation with polyclonal antibodies raised against human PAPP-A inhibited IGFBP-4 proteolytic degradation in preovulatory follicular fluid from the four species studied. As previously reported for the intrafollicular proteolytic activity degrading IGFBP-4, recombinant human PAPP-A generated in vitro 17- and 10-kDa IGFBP-4-proteolytic fragments. Recombinant PAPP-A activity was also shown to be IGF dependent and was inhibited by heparin-binding domain-containing peptides. In all mammalian species studied, the PAPP-A sequences showed high degree of identity. Moreover, the PAPP-A gene was localized on porcine chromosome 1 (1q29-1q213), in agreement with the localization of human PAPP-A gene on human chromosome 9q33.1. In bovine and porcine ovaries, real-time quantitative RT-PCR showed that PAPP-A mRNA expression in granulosa cells was maximal in fully differentiated follicles and was positively correlated with expression of P450 aromatase and LH receptor mRNAs. Overall, these data show that PAPP-A is responsible for IGFBP-4 degradation in ovine, bovine, porcine, and equine preovulatory follicles. The high expression of PAPP-A mRNA in granulosa cells from large, differentiated follicles suggest that it is a new functional marker of follicular development.

Amino Acid Sequence↗
PubMed2001

Molecular mechanism of action at estrogen receptor alpha of a new clinically relevant antiestrogen (GW7604) related to tamoxifen.

Tamoxifen is the endocrine treatment of choice for all stages of estrogen receptor (ER)-positive breast cancer, and it is the first drug approved to reduce the incidence of breast cancer in high-risk women. Unfortunately, tamoxifen also possesses some estrogen-like effects in the uterus that cause a modest increase in the risk of endometrial cancer. GW5638 is a tamoxifen derivative with a novel carboxylic acid side chain with no uterotropic activity in the rat (Willson et al., J Med Chem, 1994, 37:1550-1552). We have compared and contrasted the actions of 4-hydroxytamoxifen (4-OHT, the active metabolite of tamoxifen) with GW7604 [the presumed metabolite of GW5638 in breast (MCF-7) and endometrial (ECC-1) cell lines in vitro]. GW7604 did not cause the growth of ECC-1 cells at any concentration (10(-11)-10(-6) M), but 4-OHT was weakly estrogen-like at low concentrations (10(-11)-10(-10) M). Compounds (10(-7) M) blocked the growth promoting action of estradiol (10(-10) M) in both ECC-1 and MCF-7 cells. Western blotting was used to show that GW7604 and raloxifene did not affect ER levels significantly, compared with controls, in MCF-7 cells; whereas the pure antiestrogen ICI182,780 decreased ER levels (P < 0.05). An assay system was used that can classify compounds into tamoxifen-like, raloxifene-like, or pure antiestrogens. The assay depends on the activation of the transforming growth factor alpha (TGFalpha) gene in situ by wild-type or D351Y mutant ER stably transfected into MDA-MB-231 cells (MacGregor-Schafer et al., Cancer Res, 1999, 59:4308-4313). GW7604 inhibited both estradiol (10(-9) M) and 4-OHT (10(-8), 10(-7) M) induction of TGFalpha in a concentration related manner (10(-9)-10(-6) M). GW7604 and raloxifene stimulated TGFalpha with the D351Y ER. In contrast, ICI 182,780 (10(-6) M) did not initiate TGFalpha and blocked the induction of TGFalpha with GW7604, raloxifene, and 4-OHT in D351Y-transfected cells. Using computer-assisted molecular models of ER complexes, we found that the antiestrogenic side chain of 4-OHT weakly interacted with the surface amino acid 351 (aspartate), but the carboxylic acid of GW7604 caused a strong repulsion of aspartate 351. We propose that GW7604 is less estrogen-like than 4-OHT, because it disrupts the surface charge around aa351 required for coactivator docking in the 4-OHT:ER complex. This charge is restored in the D351Y ER, thus converting GW7604 from an antiestrogen to an estrogen-like molecule.

Carcinoma↗
PubMed2001

Effects of IGF-I and -II, IGF binding protein-3 (IGFBP-3), and transforming growth factor-beta (TGF-beta) on growth and apoptosis of human osteosarcoma Saos-2/B-10 cells: lack of IGF-independent IGFBP-3 effects.

OBJECTIVE: Insulin-like growth factor binding protein-3 (IGFBP-3) inhibits cell growth. Previous reports have suggested the existence of plasma membrane IGFBP-3 receptors that could mediate direct, IGF-independent effects. Thus far, however, the only well-defined putative IGFBP-3 receptor is the type V transforming growth factor-beta (TGF-beta) receptor, a membrane glycoprotein that mediates TGF-beta-induced growth inhibition in selected cells. The aim of the study was to test whether IGFBP-3 and TGF-beta exert short-term effects in an osteosarcoma cell line that produces no IGF but contains type 1 IGF receptors. DESIGN: DNA synthesis and apoptosis in Saos-2/B-10 cells were measured in response to IGF-I, IGF-II, IGFBP-3 and TGF-beta2, and to type 1 IGF receptor ligands with poor affinity for IGFBP-3 ([QAYL]-IGF-I and insulin). RESULTS: IGF-I and IGF-II stimulated thymidine incorporation into DNA and suppressed apoptosis in a dose-dependent manner with maximal effects at 1 and 3 nM respectively. TGF-beta2 slightly increased thymidine incorporation into DNA but had no effect on apoptosis. IGFBP-3 had no effect by itself. Whereas it blocked the above effects of 1 nmol/l IGF-I, it did not block those of 1 nmol/l [QAYL]-IGF-I or 100 nmol/l insulin. CONCLUSIONS: IGFBP-3 does not affect DNA synthesis or apoptosis in an IGF-independent manner in IGF-responsive osteosarcoma cells. It therefore appears to act essentially by sequestration of IGF.

Apoptosis↗
PubMed2000

Phex cDNA cloning from rat bone and studies on phex mRNA expression: tissue-specificity, age-dependency, and regulation by insulin-like growth factor (IGF) I in vivo.

Phosphate regulating gene with homology to endopeptidases on the X chromosome (Phex) inactivating mutations cause X-linked hypophosphatemia (XLH). The disorder is characterized by decreased renal phosphate (Pi) reabsorption in both humans and mice, in the latter shown to be due to a reduction in mRNA and protein of type II sodium-dependent phosphate cotransporter (NadPi-II). To gain insight into the physiological role of Phex, we cloned the rat cDNA and examined tissue-specific and age-dependent mRNA expression. The rat full-length cDNA (2247 nucleotides) shares 96 and 90% identity with the mouse and human cDNA, respectively. We found 6.6 kb Phex transcripts in calvarial bone and lungs, and a weaker signal in liver of newborn rats. In adult animals, Phex mRNA signals were weaker in bone and lungs and absent in liver. Phex mRNA expression in bones and NadPi-I and -II cotransporter mRNA expression in kidney were also determined in hypophysectomized rats. These rats, which lack GH and IGF I, stop growing and exhibit decreased serum Pi levels. Treatment during 6 days with IGF I stimulated growth and increased serum Pi. Phex and NadPi-II cotransporter mRNA levels were higher in IGF I than in vehicle-treated animals, while mRNA expression of NadPi-I, 1alpha-hydroxylase and 24-hydroxylase and serum levels of calcitriol remained unaffected. Age-dependency of Phex expression suggests a role for Phex in Pi retention during growth. Moreover, our findings indicate that an increase in Phex expression in bones under the influence of IGF I may contribute to increased serum Pi by enhancing renal phosphate reabsorption. Because IGF I treatment increased NadPi-II mRNA expression and serum Pi, IGF I appears to act at least partially at pretranslational levels to increase NadPi-II mediated renal Pi retention in growing rats.

Aging↗
PubMed2000

A transient interaction between two phosphorelay proteins trapped in a crystal lattice reveals the mechanism of molecular recognition and phosphotransfer in signal transduction.

BACKGROUND: Spo0F and Spo0B specifically exchange a phosphoryl group in a central step of the phosphorelay signal transduction system that controls sporulation in Bacilli. Spo0F belongs to the superfamily of response regulator proteins and is one of 34 such proteins in Bacillus subtilis. Spo0B is structurally similar to the phosphohistidine domain of histidine kinases, such as EnvZ, and exchanges a phosphoryl group between His30 and Asp54 on Spo0F. Information at the molecular level on the interaction between response regulators and phosphohistidine domains is necessary to develop a rationale for how phospho-signaling fidelity is maintained in two-component systems. RESULTS: Structural analysis of a co-crystal of the Spo0F response regulator interacting with the Spo0B phosphotransferase of the phosphorelay signal transduction system of B. subtilis was carried out using X-ray crystallographic techniques. The association of the two molecules brings the catalytic residues from both proteins into precise alignment for phosphoryltransfer. Upon complex formation, the Spo0B conformation remains unchanged. Spo0F also retains the overall conformation; however, two loops around the active site show significant deviations. CONCLUSIONS: The Spo0F-Spo0B interaction appears to be a prototype for response regulator-histidine kinase interactions. The primary contact surface between these two proteins is formed by hydrophobic regions in both proteins. The Spo0F residues making up the hydrophobic patch are very similar in all response regulators suggesting that the binding is initiated through the same residues in all interacting response regulator-kinase pairs. The bulk of the interactions outside this patch are through nonconserved residues. Recognition specificity is proposed to arise from interactions of the nonconserved residues, especially the hypervariable residues of the beta4-alpha4 loop.

Bacillus subtilis↗
PubMed2000

[Spectrum of effectiveness of insulin-like growth factors (IGF)].

The insulin-like growth factors (IGF) I and II mediate endocrine and auto-/paracrine effects of growth hormone (GH) on cell growth, cell differentiation and tissue repair. Despite their insulin-like actions in vitro, they do not play a significant role in the acute regulation of substrate metabolism, as compared to insulin and growth hormone. In contrast, administration of IGF I in vivo causes a broad spectrum of effects: it increases insulin sensitivity, improves the lipid profile, supports protein anabolism, enhances kidney function and bone turnover, and exerts beneficial effects on the cardiovascular system. Understanding of the mechanisms underlying these effects provides the basis for potential therapeutic use of IGF I.

Cell Differentiation↗
PubMed2000

Insulin-like growth factor (IGF)-binding protein-4 proteolytic degradation in bovine, equine, and porcine preovulatory follicles: regulation by IGFs and heparin-binding domain-containing peptides.

We recently showed that insulin-like growth factor-binding protein-4 (IGFBP-4) proteolytic degradation in ovine preovulatory ovarian follicles is IGF-dependent and regulated by the heparin-binding domain (HBD) from IGFBP-3 and from connective tissue growth factor (CTGF), heparan/heparin-interacting protein (HIP), and vitronectin. The present study investigated regulation of IGFBP-4 proteolytic degradation in porcine, bovine, and equine ovarian preovulatory follicles. Follicular fluid from such preovulatory follicles contains proteolytic activity, degrading exogenous IGFBP-4. An excess of IGF-I enhanced IGFBP-4 degradation. In contrast, IGFBP-2 or -3 or monoclonal antibodies against IGF-I or -II dose-dependently inhibited IGFBP-4 degradation, and IGF-I or -II reversed this inhibition in a dose-dependent manner. Heparin-binding peptides derived from the C-terminal domain of IGFBP-3 or -5 inhibited IGFBP-4 degradation. Other heparin-binding peptides derived from CTGF, HIP, and vitronectin also inhibited IGFBP-4 degradation, except in porcine follicles. Finally, IGFBP-3 that was mutated in its HBD was less effective at inhibiting IGFBP-4 degradation. Thus, in bovine, porcine, and equine preovulatory follicles, IGFBP-4 proteolytic degradation both depends on IGFs and is inhibited by peptides containing HBD. Overall, these results suggest that during terminal development of follicles to the preovulatory stage in domestic animal species, the increase in IGF bioavailability might enhance IGFBP-4 degradation. In contrast, in atretic follicles, the decrease in IGF bioavailability, resulting partly from the increase in IGFBP-2 (sow, heifer, mare) and IGFBP-5 (heifer) expression would participate in the decrease of IGFBP-4 degradation. In bovine atretic follicles, IGFBP-5 would also strengthen the inhibition of IGFBP-4 degradation by direct interaction of its HBD with the protease. The involvement of other HBD-containing proteins in the modulation of intrafollicular proteases degrading IGFBP-4 remains to be investigated.

Animals↗
PubMed2000

A central domain binding site in insulin-like growth factor binding protein-5 for the acid-labile subunit.

Like insulin-like growth factor binding protein-3 (IGFBP-3), IGFBP-5 forms a ternary complex with insulin-like growth factor (IGF)-I or IGF-II, and the acid-labile subunit (ALS). The study of IGFBP-5/IGFBP-6 chimeric proteins with amino-terminal and middle domain swaps, has revealed the existence of a site in the middle domain of IGFBP-5, that binds to ALS in the absence of the IGFBP-5 carboxy-terminal domain. An IGFBP-6 chimeric protein containing the central domain of IGFBP-5 complexed efficiently with ALS, and a carboxy-terminally truncated IGFBP-5 mutant, IGFBP-5'(1-169), also bound to ALS in the presence of IGFs, although with much less potency than full length rhIGFBP-5. In contrast to the latter, IGFBP-5(1-169) preferentially formed ternary complexes with IGF-II rather than IGF-I. These results indicate that a site which binds ALS exists in IGFBP-5 mutants which lack the IGFBP-5 carboxy-terminal domain.

Binding Sites↗
PubMed2000

Effect of growth hormone and insulin-like growth factor I (IGF-I) on the expression of IGF-I messenger ribonucleic acid and peptide in rat tibial growth plate and articular chondrocytes in vivo.

Conflicting data exist as to whether insulin-like growth factor I (IGF-I) messenger RNA (mRNA) and peptide are expressed within chondrocytes. This question is pertinent to the mode of GH action on longitudinal bone growth. We have, therefore, investigated this issue in normal rats and in hypophysectomized rats treated for 24 h with GH or IGF-I using in situ hybridization and immunohistochemistry. Serum IGF-I, body weight, and tibial growth plate, but not articular cartilage, height increased with both treatments. Both IGF-I mRNA and IGF-I immunoreactivity occurred in all chondrocyte layers of growth plate and articular cartilage. The percentage of cells with IGF-I mRNA correlated well with IGF-I immunoreactivity under all experimental conditions. In normal rats, IGF-I expression was highest in the upper hypertrophic zone in growth plate (68-71%) and articular cartilage (32-34%). Hypophysectomy, GH, or IGF-I did not significantly affect this percentage. In the stem cell and proliferative and lower hypertrophic zones of growth plate, hypophysectomy dramatically reduced the percentage of labeled chondrocytes, and GH restored it. IGF-I increased IGF-I mRNA and immunoreactivity only in the proliferative zone. In articular cartilage, both remained unchanged under all experimental conditions. Together with our previous finding that GH infusion of hypophysectomized rats enhances chondrocyte maturation at all differentiation stages, the present results are compatible with the idea that IGF-I produced by all chondrocyte layers under the influence of GH mediates chondrocyte maturation and thus longitudinal bone growth in an autocrine/paracrine manner.

Animals↗
PubMed1999

Mitogenic and antiapoptotic effects of insulin-like growth factor binding protein-6 in the human osteoblastic osteosarcoma cell line Saos-2/B-10.

Insulin-like growth factor (IGF) I is a potent mitogen for human osteosarcoma cells such as the Saos-2/B-10 cell line. IGF binding proteins (IGFBPs) prevent stimulation of DNA synthesis by IGFs. In contrast to recombinant human (rh) IGFBP-2, -3, -4, and -5, 10-100 nM rhIGFBP-6 stimulated [(3)H]thymidine incorporation into DNA and multiplication of Saos-2/B-10 cells. Upon withdrawal of serum, 30 nM IGFBP-6 also decreased apoptosis (within 4 h) and increased protein content and sodium-dependent phosphate uptake (within 24 h), but less potently than IGF I. (125)I-labeled rhIGFBP-6 did not bind to the cells, and cold IGFBP-6 did not affect (125)I-labeled IGF I binding. Production of IGF I, IGF II, and IGFBP-6 by the cells or significant degradation of rhIGFBP-6 could not be detected within 24 h of incubation. Thus, among the rhIGFBPs tested, rhIGFBP-6 is unique in stimulating osteosarcoma cell growth. Furthermore, it has an antiapoptotic effect.

Alkaline Phosphatase↗
PubMed1999

Hepatic and pulmonary metastases from a meningeal hemangiopericytoma and severe hypoglycemia due to abnormal secretion of insulin-like growth factor: a case report.

A 42-year-old woman was hospitalized for severe hypoglycemic coma. She had a voluminous hepatic metastasis and multiple small lung metastases from a meningeal hemangiopericytoma initially operated on 11 years earlier. High blood levels of an abnormal form of insulin-like growth factor type 2 (IGF II) associated with low blood levels of insulin, growth hormone, IGF I, and IGF BP3 were observed. After surgical resection of the liver and pulmonary metastases, serum glucose levels and hormonal abnormalities returned to normal.

Adult↗
PubMed1999

Leptin is suppressed during infusion of recombinant human insulin-like growth factor I (rhIGF I) in normal rats.

To examine whether insulin-like growth factor I (IGF I) or growth hormone (GH) influences leptin in vivo we measured leptin mRNA in epididymal fat pads and serum leptin of normal rats infused subcutaneously for 6 days with recombinant human (rh)IGF I (1 mg/day), rhGH (200 mU/day), or vehicle. In addition, we determined fat pad weight and food consumption as well as IGF I, insulin, glucose, non-esterified fatty acid (NEFA), glycerol, beta-hydroxybutyrate and triglyceride (TG) serum concentrations. Food intake was identical during all three treatments. RhIGF I but not rhGH raised IGF I serum concentrations, reduced fat pad weight (60.3 +/- 7.4% of control rats, p = 0.019), and suppressed leptin mRNA (38.8 +/- 11.9% of control rats, p = 0.002), serum leptin (51.6 +/- 10.5% of control rats, p = 0.0028) and serum triglycerides (39.3 +/- 8.0% of control rats, p = 2.6 x 10(-6)). Both rhIGF I and rhGH reduced non-esterified fatty acids (NEFA) (p = 0.00001 and 0.0007, respectively), whereas serum glycerol, beta-OH butyrate and glucose concentrations remained unchanged. Serum insulin concentrations during rhIGF I were lower than during rhGH infusion and correlated with leptin mRNA (r = 0.589, p = 0.016) and fat pad weight (r = 0.643, p = 0.007). Reduction of adipose tissue mass and suppression of leptin by IGF I appear to be due to reduced circulating insulin leading to enhanced fat mobilization and NEFA oxidation as well as to increased gluconeogenesis from glycerol. In contrast, decreased NEFA concentrations during rhGH in the presence of unchanged fat pad weight, serum glycerol and triglycerides might result from more efficient re-esterification of released fatty acids within the triglyceride-fatty acid cycle. The results also show that exogenously infused IGF I and GH act on lipid metabolism by different mechanisms and suggest an IGF-independent, probably direct, metabolic effect of GH. Finally, in agreement with previous studies in GH-infused hypophysectomized rats, it appears unlikely that GH regulates leptin in the rat.

3-Hydroxybutyric Acid↗
PubMed1999

Insulin-like growth factor-I lowers fasting and postprandial triglyceride levels without affecting chylomicron clearance in healthy men.

OBJECTIVES: To study whether IGF-I treatment alters the postprandial lipid and lipoprotein metabolism. DESIGN: Randomized, crossover study. SETTING: University Hospital, Zürich, Switzerland. SUBJECTS: Seven young healthy male subjects (aged 27+/-4 years, body mass index (BMI) 21.8+/-1.7 kg m(-2)). INTERVENTIONS: Each subject was studied two times at 2-week intervals, treated with saline 0.9% (S) and IGF-I (8 microg kg(-1) h(-1)) by a continuous subcutaneous infusion. 60 h after the start of treatment a vitamin A loading test was performed after an overnight 12-h fast. MAIN OUTCOME MEASURES: Glucose, insulin, total and free IGF-I, FFA, triglycerides and retinyl palmitate, total cholesterol, HDL and LDL cholesterol, lipoprotein (a) and apolipoprotein B were measured in serum before and after the fatty meal. RESULTS: Total IGF-I levels rose from 29.0+/-3.3 nmol L(-1) to 113.3+/-9.0 nmol L(-1) (P<0.02) and free IGF-I from 0.24+/-0.05 to 1.08+/-0.28 nmol L(-1) (P<0.02) during IGF-I treatment. IGF-I administration reduced insulin concentrations by 50% (P<0.02), as assessed by the area under the curve. Serum triglyceride levels were significantly lower at baseline and after the fat load during IGF-I treatment (P<0.02), whereas the retinyl palmitate concentrations in chylomicron and nonchylomicron lipoprotein fractions were similar during both treatment periods. CONCLUSIONS: IGF-I treatment reduces the triglyceride levels most probably by decreasing insulin secretion and the production of VLDL particles, and possibly by increasing their turnover. IGF-I treatment has no significant effect on the metabolism of intestine-derived triglyceride-rich lipoproteins after a high fat meal in healthy young men.

Adult↗