Central and peripheral administration of human relaxin-2 to adult male rats inhibits food intake.

AIM: Relaxin is a polypeptide hormone involved in pregnancy and lactation. It is mainly secreted by the corpus luteum and placenta, but is expressed in a number of other tissues, including heart and brain. Within the brain, relaxin is expressed in the olfactory and limbic systems, the cortex and the hypothalamic arcuate nucleus (ARC). Its cognate receptor, relaxin family peptide receptor 1 (RXFP1), is also widely expressed in the brain, including the hypothalamic ARC and paraventricular nucleus (PVN), areas important in appetite regulation. The aim of this study was to investigate whether relaxin influences food intake through central hypothalamic circuits. METHODS: The human form of relaxin, human relaxin-2 (H2) was administered centrally and peripherally to male Wistar rats and food intake measured. Behaviour was also assessed. RESULTS: Intracerebroventricular (ICV) administration of H2 significantly decreased 1-h food intake in the early dark phase [2.95 ± 0.45 g (saline) vs. 0.95 ± 0.18 g (180 pmol H2), p < 0.001]. ICV administration of H2 decreased feeding behaviour and increased grooming and headdown behaviour. Intraparaventricular injections of H2 significantly decreased 1-h food intake in the early dark phase [3.13 ± 0.35 g (saline) vs. 1.35 ± 0.33 g (18 pmol H2), p < 0.01, 1.61 ± 0.31 g (180 pmol H2), p < 0.05 and 1.23 ± 0.32 g (540 pmol H2), p < 0.001]. Intraperitoneal (IP) administration of H2 significantly decreased 1-h food intake in the early dark phase [4.63 ± 0.46 g (vehicle) vs. 3.08 ± 0.15 g (66 nmol H2), p < 0.01, 3.00 ± 0.17 g (200 nmol H2), p < 0.01 and 2.26 ± 0.36 g (660 nmol H2), p < 0.001]. CONCLUSIONS: Central and peripheral administration of H2 reduces the food intake in rats. This effect may be mediated via the PVN and/or other brain regions.

The effect of a 12-week low glycaemic index diet on heart disease risk factors and 24 h glycaemic response in healthy middle-aged volunteers at risk of heart disease: a pilot study.

OBJECTIVE: To compare the effects of two energy-restricted healthy diets, one with a low GI and one with a high GI, on heart disease risk factors and weight loss in subjects at risk of heart disease. DESIGN: A 12-week randomized parallel study of low and high GI, healthy eating diets was carried out. SETTING: The study was carried out at the Hammersmith Hospital. SUBJECTS: Eighteen subjects were recruited by advertisement and randomized to one of the two diets. Fourteen completed the study but one was excluded from the final analysis. METHODS: At randomization, subjects were advised to follow the intervention diet for 12 weeks. Before randomization and on completion of the study, anthropometrics, fasting cholesterol and glucose blood tests and 24-h glucose measurements were taken using a continuous glucose monitoring system (CGMS). Statistical analysis was carried out using non-parametric tests. Median (IQR) are presented. RESULTS: A significantly different dietary GI was achieved in the low GI (median: 51.3 (IQR: 51.0-52.0) compared to the high GI (59.3 (59.2-64.0) (P=0.032) group. By week 12, both groups reduced their energy intake by: low GI group: (-)167 ((-)312-(-)123) kcal/day (P=0018) vs high GI group: (-)596 ((-)625-(-)516) (P=0.018) kcal/day, the difference between the groups being significant (P=0.010). However, only the low GI group lost weight ((-)4.0 ((-)4.4-(-)2.4) kg (P=0.018) whereas the high GI group did not significantly change in weight ((-)1.5 ((-)3.6-0.8) kg (P=0.463). By week 12, the low GI group also had a significantly lower 24-h area under the curve (AUC) (7556 (7315-8434) vs 8841 (8424-8846) mmol-h/l (P=0.045) and overnight AUC (2429 (2423-2714) vs 3000 (2805-3072) mmol-h/l (P=0.006) glucose as measured by CGMS. There were no differences in the other heart disease risk factors assessed. CONCLUSIONS: This pilot study provides some evidence that consuming a low GI diet in addition to weight loss and healthy eating may reduce cardiovascular risk. Other potential benefits of GI might have been masked by weight loss in the low GI group. Larger-scale studies need to follow.

Central relaxin-3 administration causes hyperphagia in male Wistar rats.

Relaxin-3 (INSL-7) is a recently discovered member of the insulin superfamily. Relaxin-3 mRNA is expressed in the nucleus incertus of the brainstem, which has projections to the hypothalamus. Relaxin-3 binds with high affinity to the LGR7 receptor and to the previously orphan G protein-coupled receptor GPCR135. GPCR135 mRNA is expressed predominantly in the central nervous system, particularly in the paraventricular nucleus (PVN). The presence of relaxin-3 and these receptors in the PVN led us to investigate the effect of central administration of relaxin-3 on food intake in male Wistar rats. The receptor involved in mediating these effects was also investigated. Intracerebroventricular injections of human relaxin-3 (H3) to satiated rats significantly increased food intake 1 h post administration in the early light phase [0.96 +/- 0.16 g (vehicle) vs. 1.81 +/- 0.21 g (180 pmol H3), P < 0.05] and the early dark phase [2.95 +/- 0.45 g (vehicle) vs. 4.39 +/- 0.39 g (180 pmol H3), P < 0.05]. Intra-PVN H3 administration significantly increased 1-h food intake in satiated rats in the early light phase [0.34 +/- 0.16 g (vehicle) vs. 1.23 +/- 0.30 g (18 pmol H3), P < 0.05] and the early dark phase [4.43 +/- 0.32 g (vehicle) vs. 6.57 +/- 0.42 g (18 pmol H3), P < 0.05]. Feeding behavior increased after intra-PVN H3. Equimolar doses of human relaxin-2, which binds the LGR7 receptor but not GPCR135, did not increase feeding. Hypothalamic neuropeptide Y, proopiomelanocortin, or agouti-related peptide mRNA expression did not change after acute intracerebroventricular H3. These results suggest a novel role for relaxin-3 in appetite regulation.

Peptide YY and appetite control.

Peptide YY (PYY) is an important gut hormone synthesized and secreted by the gastrointestinal tract. Peripheral administration of PYY(3-36), one of the circulating forms of PYY, is known to inhibit food intake. This anorexigenic effect is masked by stress inhibition of appetite, and it is therefore important for animals to be thoroughly acclimatised for PYY(3-36) to be effective. Evidence suggests that PYY(3-36) acts via the hypothalamic Y(2) receptor. Levels of the anorexigenic hormone PYY(3-36) are low in overweight volunteers and could provide an important therapeutic avenue in the quest to combat the obesity epidemic.

Deep vein thrombosis followed by internal jugular vein thrombosis as a complication of in vitro fertilization in a woman heterozygous for the prothrombin 3' UTR and factor V Leiden mutations.

Thrombosis of the internal jugular vein is a rare event but one that can have serious consequences. Most cases reported in the literature have occurred in patients with indwelling central venous catheters, in association with head and neck sepsis, or in hypercoagulable states. However, a small number of cases have been associated with in vitro fertilization and more often with the ovarian hyperstimulation syndrome (OHSS). We report the case of a 30-year-old woman heterozygous for both the prothrombin 3' UTR mutation and for the factor V Leiden mutation who presented with a proximal deep vein thrombosis following in vitro fertilization. She subsequently developed an internal jugular vein thrombosis extending into the subclavian and axillary vein despite therapeutic anticoagulation with a low molecular weight heparin. Thromboembolic events can occur in the absence of other clinical features of OHSS, especially in patients with underlying prothrombotic abnormalities. Neck pain and swelling in a pregnant woman, especially one that has undergone in vitro fertilization, should be taken seriously and investigated with duplex scanning and/or MRI. Women with a personal or family history of thrombosis undergoing in vitro fertilization should be made fully aware of the potential thrombotic risks and should be considered for a thrombophilia screen.