Little is known about leptin's interaction with other circulating proteins which could be important for its biological effects. Sephadex G-100 gel filtration elution profiles of 125I-leptin-serum complex demonstrated 125I-leptin eluting in significant proportion associated with macromolecules. The 125I-leptin binding to circulating macromolecules was specific, reversible, and displaceable with unlabeled leptin (ED50: 0.73 +/- 0.09 nM, mean +/- SEM, n = 3). Several putative leptin binding proteins were detected by leptin-affinity chromatography of which either 80- or 100-kD proteins could be the soluble leptin receptor as approximately 10% of the bound 125I-leptin was immunoprecipitable with leptin receptor antibodies. Significantly higher (P 0.05) decrease was observed in bound leptin in either group. These studies suggest that in obese individuals the majority of leptin circulates in free form, presumably bioactive protein, and thus obese subjects are resistant to free leptin. In lean subjects with relatively low adipose tissue, the majority of circulating leptin is in the bound form and thus may not be available to brain receptors for its inhibitory effects on food intake both under normal and food deprivation states.

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Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting.

Insulin-like growth factor binding proteins (IGFBPs) have been shown to serve as carrier proteins for the insulin-like growth factors (IGFs) and to modulate their biologic effects. Since extracellular matrix (ECM) has been shown to be a reservoir for IGF-I and IGF-II, we examined the ECM of cultured human fetal fibroblasts and found that IGFBP-5 was incorporated intact into ECM, while mostly inert proteolytic fragments were found in the medium. In contrast, two other forms of IGFBP that are secreted by these cells were either present in ECM in minimal amounts (IGFBP-3) or not detected (IGFBP-4). Likewise, when purified IGFBPs were incubated with ECM, IGFBP-5 bound preferentially. IGFBP-5 was found to bind to types III and IV collagen, laminin, and fibronectin. Increasing salt concentrations inhibited the binding of IGFBP-5 to ECM and accelerated the release of IGFBP-5 from ECM, suggesting an ionic basis for this interaction. ECM-associated IGFBP-5 had a sevenfold decrease in affinity for IGF-I compared to IGFBP-5 in solution. Furthermore, when IGFBP-5 was present in cell culture substrata, it potentiated the growth stimulatory effects of IGF-I on fibroblasts. When IGFBP-5 was present only in the medium, it was degraded to a 22-kD fragment and had no effect on IGF-I-stimulated growth. We conclude that IGFBP-5 is present in fibroblast ECM, where it is protected from degradation and can potentiate the biologic actions of IGF-I. These findings provide a molecular explanation for the association of the IGF's with the extracellular matrix, and suggest that the binding of the IGF's to matrix, via IGFBP-5, may be important in mediating the cellular growth response to these growth factors.

/pdf/extracellular-matrix-contains-insulin-like-growth-factor-1fqp9hl2mr.pdf

Extracellular matrix contains insulin-like growth factor binding protein-5 : potentiation of the effects of IGF-I

INTRODUCTION 147 EPIDERMAL GROWTH FACTOR (EGF) 148 Background and General Physiological Function 148 Milk Concentration and Sources 149 Effects on the Neonate 151 INSULIN, RELAX]N, AND INSULIN-LIKE GROWTH FACTOR-I AND -ll ....... 154 Background ~ General Physiological Function 154 l~.sulin 154 R¢laxin 156 IGF.I., IGF.II., AND IGF-BINDING PROTEINS 157 OTHER PEFrIDE GROWTH FACTORS IN MILK 159 CONCLUDING REMARKS 160

/pdf/growth-factors-in-milk-as-mediators-of-infant-development-3dips7capw.pdf

Growth Factors in Milk as Mediators of Infant Development

Reduction of postnatal morbidity and mortality of mammalian neonates poses a significant challenge to agricultural and medical sciences. Because nutritional insufficiency and diarrhea represent major stressors, an understanding of factors mediating postnatal growth and development of the gastrointestinal tract is essential. This review explores the role that milkborne growth factors may play in stimulating functional development of the neonatal intestine, with emphasis on the porcine, bovine, and ovine species. Studies reporting milk concentrations and intestinal effects are reviewed, with emphasis on epidermal growth factor, insulin, and the insulin-like growth factors. Collectively, these studies suggest that milkborne growth factors may provide important regulatory signals to the neonatal intestine under both normal and pathophysiological states.

Intestinal effects of milkborne growth factors in neonates of agricultural importance.

Hormones, mammary growth, and lactation: a 41-year perspective

Insulin-like growth factor binding proteins (IGFBPs) are soluble proteins present in in extracellular fluids. They have high affinity for IGF-I and -II. Blood concentrations are controlled by nutrition and by hormones in a manner that in most, but not all, instances correlates with plasma concentrations of IGF-I or -II. IGF binding proteins are secreted by a range of cell types in a manner that may serve to modulate the functions of the growth factors in a pericellular environment. IGF binding proteins cxan modify IGF interaction with the type I receptor and may thereby alter IGF signal transduction through this transmembrane signalling unit. Binding proteins may also act as inhibitors or potentiators of biological responsiveness and thereby directly cell type specific responses.

Clemmons Dr

Papers

Insulin-like growth factor binding proteins: roles in regulating IGF physiology.