Pregnancy-Associated Plasma Protein (PAPP)-A2 in Physiology and Disease.

The growth hormone (GH)/insulin-like growth factor (IGF) axis plays fundamental roles during development, maturation, and aging. Members of this axis, composed of various ligands, receptors, and binding proteins, are regulated in a tissue- and time-specific manner that requires precise control that is not completely understood. Some of the most recent advances in understanding the implications of this axis in human growth are derived from the identifications of new mutations in the gene encoding the pregnancy-associated plasma protein PAPP-A2 protease that liberates IGFs from their carrier proteins in a selective manner to allow binding to the IGF receptor 1. The identification of three nonrelated families with mutations in the PAPP-A2 gene has shed light on how this protease affects human physiology. This review summarizes our understanding of the implications of PAPP-A2 in growth physiology, obtained from studies in genetically modified animal models and the PAPP-A2 deficient patients known to date.

Cerebral Insulin Bolus Revokes the Changes in Hepatic Lipid Metabolism Induced by Chronic Central Leptin Infusion.

Central actions of leptin and insulin on hepatic lipid metabolism can be opposing and the mechanism underlying this phenomenon remains unclear. Both hormones can modulate the central somatostatinergic system that has an inhibitory effect on growth hormone (GH) expression, which plays an important role in hepatic metabolism. Using a model of chronic central leptin infusion, we evaluated whether an increase in central leptin bioavailability modifies the serum lipid pattern through changes in hepatic lipid metabolism in male rats in response to an increase in central insulin and the possible involvement of the GH axis in these effects. We found a rise in serum GH in leptin plus insulin-treated rats, due to an increase in pituitary GH mRNA levels associated with lower hypothalamic somatostatin and pituitary somatostatin receptor-2 mRNA levels. An augment in hepatic lipolysis and a reduction in serum levels of non-esterified fatty acids (NEFA) and triglycerides were found in leptin-treated rats. These rats experienced a rise in lipogenic-related factors and normalization of serum levels of NEFA and triglycerides after insulin treatment. These results suggest that an increase in insulin in leptin-treated rats can act on the hepatic lipid metabolism through activation of the GH axis.

Hypothalamic GHR-SIRT1 Axis in Fasting.

Many aspects of physiological functions are controlled by the hypothalamus, a brain region that connects the neuroendocrine system to whole-body metabolism. Growth hormone (GH) and the GH receptor (GHR) are expressed in hypothalamic regions known to participate in the regulation of feeding and whole-body energy homeostasis. Sirtuin 1 (SIRT1) is the most conserved mamma-lian nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase that plays a key role in controlling life span and sensing nutrient availability in the hypothalamus in response to caloric restriction. However, the interaction between GHR signaling and SIRT1 in the hypothal-amus is not established. In the arcuate nucleus (ARC) of the hypothalamus, the anorexigenic proopiomelanocortin (POMC)-expressing neurons and the orexigenic agouti-related protein (AgRP)-expressing neurons are the major regulators of feeding and energy expenditure. We show that in the ARC, the majority of GHR-expressing neurons also express SIRT1 and respond to fasting by upregulating SIRT1 expression. Accordingly, hypothalamic upregulation of SIRT1 in response to fasting is blunted in animals with GHR deletion in the AgRP neurons (AgRPEYFPΔGHR). Our data thus reveal a novel interaction between GH and SIRT1 in responses to fasting.

Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits.

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.

Study on the growth hormone axis in aged patients with congestive heart failure / 中华老年医学杂志

Objective To observe the changes of growth hormone axis(GH axis) and to study the mechanism of acquired growth hormone resistance in aged patients with congestive heart failure (CHF). Methods Ninety-five patients with congestive heart failure were divided into three groups (Grade Ⅱ , n = 28; Grade Ⅲ , n = 36;and Grade Ⅳ , n = 31) according to New York Heart Association criterion. Another 30 healthy people were used as controls. The concentrations of plasma GH , insulin growth factor 1 (IGF-1) and insulin growth factor binding protein 3 (IGFBP-3) were measured by radioimmunoassay, and growth hormone sensitivity was assessed by log(IGF-1 /GH). Results Plasma concentration of GHC[(5. 83 ? 1. 41) mlU/L vs (1. 56 ? 0. 97) mlU/L were higher in grade Ⅳ group than those in normal subjects ( P