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Oxytocin (OT) is a well-characterized neurotransmitter that participates in a wide range of physiological processes including the inhibition of food intake. The avian ortholog, mesotocin (MT), differs from OT by a single amino acid. Little is known regarding the function of OT in regulating energy balance in birds; thus, this study was designed to determine the effects of central OT injection on food intake and adipose tissue physiology in chicks. At 4-d post-hatch, broiler chicks were fasted for 3 h and injected intracerebroventricularly with 0 (vehicle), 0.63, 2.5, 5.0, or 10 nmol OT. Oxytocin decreased food and water intake during the entire 180-min observation period. The reduction in water intake was likely not prandial because chicks that were food restricted after OT injection also drank less. There was increased c-Fos immunoreactivity in several appetite-associated hypothalamic nuclei in OT-injected chicks at 1 h, including the arcuate (ARC), dorsomedial nucleus (DMN), lateral hypothalamus (LH), paraventricular nucleus (PVN), and ventromedial hypothalamus (VMH). OT treatment was associated with reduced hypothalamic corticotropin-releasing factor (CRF) mRNA and increased cloacal temperature at 1 h post-injection. We then investigated appetite- and adipose tissue–associated effects of OT in chicks from lines that have undergone long-term selection for either low (LWS) or high (HWS) juvenile body weight. Central injection of OT decreased food intake in both lines with the magnitude of response greater in the HWS than LWS chicks. Adipose tissue abundance of fatty acid–binding protein 4, monoglyceride lipase (MGLL), MT, and perilipin-1 mRNA was greater in LWS than HWS chicks. Lipoprotein lipase, MGLL, and MT mRNAs increased in response to OT injection in LWS but not HWS chicks. In conclusion, central injection of OT induced anorexia, reduced water intake, increased body temperature, and was associated with activation of the ARC, DMN, LH, PVN, and VMH in the hypothalamus. The effects on appetite and body temperature may involve CRF signaling in the hypothalamus and lipolysis in the adipose tissue, respectively. There were differences in the appetite, and adipose tissue response to OT in body weight–selected lines of chicks supports that MT plays a role in energy balance regulation in chickens.

Resistin is an adipocytokine that has been related to inflammation and insulin resistance. Following knee injury, elevated levels of resistin have been found in synovial fluid (SF) while very little is known about the role of resistin in osteoarthritis (OA). The aim of the present study was to investigate resistin levels in OA joints and to determine if it is associated with inflammatory and catabolic factors in the joints.SF, plasma, and cartilage samples were collected from 88 OA patients undergoing knee replacement surgery. Resistin levels were measured by enzyme-linked immunosorbent assay (ELISA) in SF, plasma, and cartilage culture media.Significant levels of resistin [0.75 (0.67) ng/mL; median (IQR)] were found in SF from OA patients. Resistin correlated positively with interleukin (IL)-6 (r = 0.39, p0.001) and with matrix metalloproteinases MMP-1 (r = 0.31, p = 0.004) and MMP-3 (r = 0.24, p = 0.024) in SF. Resistin was also released from cultured OA cartilage and it correlated with resistin levels in SF (r = 0.39, p0.001). In addition, resistin levels in plasma correlated positively with those in SF (r = 0.44, p0.001). There were no differences in SF or plasma resistin concentrations between females and males or between non-diabetic and diabetic patients, and resistin did not correlate with body mass index (BMI).Resistin is present in OA joints and is released from OA cartilage. Levels of resistin in SF are associated with inflammatory and catabolic factors, suggesting that resistin has a role to play in the pathogenesis of, and as a possible drug target in, OA.

Accelerated fetal myocardial growth with altered cardiac function is a well-documented complication of human diabetic pregnancy, but its pathophysiology is still largely unknown. Our aim was to explore the mechanisms of fetal cardiac remodeling and cardiovascular hemodynamics in a rat model of maternal pregestational streptozotocin-induced hyperglycemia. The hyperglycemic group comprised 107 fetuses (10 dams) and the control group 219 fetuses (20 dams). Fetal cardiac function was assessed serially by Doppler ultrasonography. Fetal cardiac to thoracic area ratio, newborn heart weight, myocardial cell proliferative and apoptotic activities, and cardiac gene expression patterns were determined. Maternal hyperglycemia was associated with increased cardiac size, proliferative, apoptotic and mitotic activities, upregulation of genes encoding A- and B-type natriuretic peptides, myosin heavy chain types 2 and 3, uncoupling proteins 2 and 3, and the angiogenetic tumor necrosis factor receptor superfamily member 12A. The genes encoding Kv channel-interacting protein 2, a regulator of electrical cardiac phenotype, and the insulin-regulated glucose transporter 4 were downregulated. The heart rate was lower in fetuses of hyperglycemic dams. At 13–14 gestational days, 98% of fetuses of hyperglycemic dams had holosystolic atrioventricular valve regurgitation and decreased outflow mean velocity, indicating diminished cardiac output. Maternal hyperglycemia may lead to accelerated fetal myocardial growth by cardiomyocyte hyperplasia. In fetuses of hyperglycemic dams, expression of key genes that control and regulate cardiomyocyte electrophysiological properties, contractility, and metabolism are altered and may lead to major functional and clinical implications on the fetal heart.

Background: Maternal diabetes is associated with numerous adverse effects in fetal and neonatal organs, including the lungs. Objective: To investigate the effects of intrauterine hyperglycemia on neonatal lung biological signaling, we performed a microarray analysis in the lungs of four 14-day-old rat pups born to a hyperglycemic dam and in four age mate control pup lungs. Methods: Total RNA was isolated and cDNA was hybridized to the Illumina Sentrix® RatRef-12 BeadChip. A total of 22,000 genes were analyzed for expression profiles and functional gene clustering. Ten selected genes differentially expressed in microarray were additionally analyzed by the real-time polymerase chain reaction. Results: Two hundred twenty-seven genes were differentially expressed in neonatal rat lungs exposed to intrauterine hyperglycemia when compared to normoglycemic controls (fold change > 1.2, p < 0.001). Functional clustering analysis revealed increased expression in signaling pathways involved with extracellular matrix regulation. The most significantly downregulated functions were cell proliferation, extracellular region, cell adhesion and reactive oxygen species metabolism. Conclusion: We found significant hyperglycemia-induced gene expression alterations in neonatal rat pulmonary tissue which may interfere with lung growth and biological signaling pathways.

Obesity is an important risk factor for osteoarthritis (OA) in weight-bearing joints, but also in hand joints, pointing to an obesity-related metabolic factor that influences on the pathogenesis of OA. Leptin is an adipokine regulating energy balance, and it has recently been related also to arthritis and inflammation as a proinflammatory factor. In the present paper, the effects of leptin on human OA cartilage were studied. Leptin alone or in combination with IL-1 enhanced the expression of iNOS and COX-2, and production of NO,PGE2, IL-6, and IL-8. The results suggest that the effects of leptin are mediated through activation of transcription factor nuclear factorκB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway c-JunNH2-terminal kinase (JNK). Interestingly, inhibition of leptin-induced NO production with a selective iNOS inhibitor 1400 W inhibited also the production of IL-6, IL-8, andPGE2, and this was reversed by exogenously added NO-donor SNAP, suggesting that the effects of leptin on IL-6, IL-8, andPGE2production are dependent on NO. These findings support the idea of leptin as a factor enhancing the production of proinflammatory factors in OA cartilage and as an agent contributing to the obesity-associated increased risk for osteoarthritis.

Since maternal diabetes may affect fetal development and the umbilical cord provides an extension of the fetal vasculature, we decided to investigate cords' biological responses to maternal diabetic milieu.Using microarray analysis, we determined the gene expression profiles in the umbilical cords of six neonates born to type 1 diabetic mothers and in six control cords. Umbilical cord tissue was collected immediately after elective cesarean section. Expression data were confirmed by real-time polymerase chain reaction (11 genes). Additionally, the same umbilical cords were analyzed histologically.Two hundred eighty six genes were differentially expressed in the umbilical cords from diabetic pregnancies compared to the controls (fold change ±1.5 and P 0.01). Maternal diabetes had a major effect on the expression of genes involved in vascular development (Bone morphogenetic protein 4, Delta-like 1, and Notch homolog 4), vessel wall integrity (Collagen type VIII alpha 1, Myocyte enhancer factor 2C, and Matrix metalloproteinase 2), and vascular function (Natriuretic peptide precursor B, Endothelin 1, Endothelin receptor B, Cyclooxygenase 1, and Phosphodiesterase 5A). Maternal diabetes was associated with thicker umbilical vein intima-media layers and larger umbilical vein and artery intima-media areas compared to the controls.Maternal diabetic environment seems to alter umbilical cord expression of genes involved in the regulation of vascular development and function with simultaneous umbilical vessel muscle layer thickening. These alterations suggest vascular phenotypic modifications, which in turn may lead to long-term vascular consequences in various tissues in infants of diabetic mothers.

Maternal diabetes is associated with increased risk for abnormal fetal organogenesis, but its effects on the developing lungs are still insufficiently known. To determine the effect of maternal hyperglycemia on postnatal lung development, we studied lung structural and cellular changes in newborn rats exposed to intrauterine hyperglycemia. We induced hyperglycemia in Sprague-Dawley rats with i.p. streptozotocin before pregnancy and allowed the hyperglycemic and control dams deliver at term. Lungs were obtained on postnatal day (d) 0, d7, and d14 and analyzed for lung weight and morphology, as well as cellular apoptosis (TUNEL staining) and proliferation (PCNA staining). Quantitative micro-CT analysis of the lung vasculature was additionally performed at d14. At birth, maternal hyperglycemia resulted in decreased relative lung weight, thinner alveolar septa and increased cellular apoptosis and proliferation, when compared to controls. At 1 and 2 weeks of age pulmonary cell apoptosis and alveolar chord length remained unchanged, but cell proliferation and number of secondary crests were increased in the hyperglycemia-exposed neonatal lungs in comparison with the controls. Density of small arterioles on histological examination and the structure of pulmonary arterial vasculature in micro-CT analysis of the neonatal lungs were not influenced by maternal hyperglycemia. Our results suggest, that maternal hyperglycemia is related to developmental structural alterations in postnatal rat lungs. These early changes may reflect aberrant maturational adaptation in response to the hyperglycemic fetal environment.

Introduction Adiponectin is an adipokine that regulates energy metabolism and insulin sensitivity, but recent studies have pointed also to a role in inflammation and arthritis. The purpose of the present study was to investigate the association and effects of adiponectin on inflammation and cartilage destruction in osteoarthritis (OA). Methods Cartilage and blood samples were collected from 35 male OA patients undergoing total knee replacement surgery. Preoperative radiographs were evaluated using Ahlbäck classification criteria for knee OA. Circulating concentrations of adiponectin and biomarkers of OA, that is, cartilage oligomeric matrix protein (COMP) and matrix metalloproteinase 3 (MMP-3), were measured. Cartilage samples obtained at the time of surgery were cultured ex vivo, and the levels of adiponectin, nitric oxide (NO), IL-6, MMP-1 and MMP-3 were determined in the culture media. In addition, the effects of adiponectin on the production of NO, IL-6, MMP-1 and MMP-3 were studied in cartilage and in primary chondrocyte cultures. Results Plasma adiponectin levels and adiponectin released from OA cartilage were higher in patients with the radiologically most severe OA (Ahlbäck grades 4 and 5) than in patients with less severe disease (Ahlbäck grades 1 to 3). Plasma adiponectin concentrations correlated positively with biomarkers of OA, that is, COMP (r = 0.55, P = 0.001) and MMP-3 (r = 0.34, P = 0.046). Adiponectin was released by OA cartilage ex vivo, and it correlated positively with production of NO (r = 0.43, P = 0.012), IL-6 (r = 0.42, P = 0.018) and MMP-3 (r = 0.34, P = 0.051). Furthermore, adiponectin enhanced production of NO, IL-6, MMP-1 and MMP-3 in OA cartilage and in primary chondrocytes in vitro in a mitogen-activated protein kinase (MAPK)-dependent manner. Conclusions The findings of this study show that adiponectin is associated with, and possibly mediates, cartilage destruction in OA.