Obese patients after gastric bypass surgery have lower brain-hedonic responses to food than after gastric banding.

OBJECTIVES: Roux-en-Y gastric bypass (RYGB) has greater efficacy for weight loss in obese patients than gastric banding (BAND) surgery. We hypothesise that this may result from different effects on food hedonics via physiological changes secondary to distinct gut anatomy manipulations. DESIGN: We used functional MRI, eating behaviour and hormonal phenotyping to compare body mass index (BMI)-matched unoperated controls and patients after RYGB and BAND surgery for obesity. RESULTS: Obese patients after RYGB had lower brain-hedonic responses to food than patients after BAND surgery. RYGB patients had lower activation than BAND patients in brain reward systems, particularly to high-calorie foods, including the orbitofrontal cortex, amygdala, caudate nucleus, nucleus accumbens and hippocampus. This was associated with lower palatability and appeal of high-calorie foods and healthier eating behaviour, including less fat intake, in RYGB compared with BAND patients and/or BMI-matched unoperated controls. These differences were not explicable by differences in hunger or psychological traits between the surgical groups, but anorexigenic plasma gut hormones (GLP-1 and PYY), plasma bile acids and symptoms of dumping syndrome were increased in RYGB patients. CONCLUSIONS: The identification of these differences in food hedonic responses as a result of altered gut anatomy/physiology provides a novel explanation for the more favourable long-term weight loss seen after RYGB than after BAND surgery, highlighting the importance of the gut-brain axis in the control of reward-based eating behaviour.

Acute and chronic effects of kisspeptin-54 administration on GH, prolactin and TSH secretion in healthy women.

BACKGROUND: The peptide hormone kisspeptin is essential for human reproduction, acting on the hypothalamus to stimulate gonadotrophin-releasing hormone (GnRH) secretion. Kisspeptin is currently being evaluated as a novel therapeutic for women with infertility. However, some animal studies suggest that kisspeptin may also stimulate growth hormone (GH), prolactin and thyroid-stimulating hormone (TSH) secretion, with implications for its safety; no previous study has investigated whether kisspeptin stimulates these pituitary hormones in humans. AIM: To determine whether kisspeptin-54 modulates GH, prolactin and TSH secretion in healthy women. DESIGN AND PARTICIPANTS: Prospective, single-blinded, placebo-controlled, one-way crossover study. Five healthy women received 7 days of twice-daily subcutaneous bolus vehicle (month 1) or 6·4 nmol/kg kisspeptin-54 (month 2). MEASUREMENTS: Serum samples were analysed post hoc for GH, prolactin and TSH. RESULTS: Mean serum GH, PRL and TSH did not change during the first 4 h following kisspeptin-54 injection when compared with vehicle. The mean frequency or amplitude of GH pulses (which influence GH function) did not change acutely following kisspeptin-54 injection when compared with vehicle. No chronic changes in serum GH, PRL or TSH were observed over the 7-day period of twice-daily kisspeptin-54 injections when compared with vehicle. CONCLUSION: While we cannot exclude any effect of kisspeptin-54 on GH, prolactin or TSH secretion, we observed no significant changes in these hormones at a dose of kisspeptin-54 administration known to stimulate gonadotrophin secretion in a small study of healthy women. These data have important implications for the potential of kisspeptin to treat patients with infertility.

Hypophysiotropic gonadotropin-releasing hormone projections are exposed to dense plexuses of kisspeptin, neurokinin B and substance p immunoreactive fibers in the human: a study on tissues from postmenopausal women.

Neuronal populations that synthesize kisspeptin (KP), neurokinin B (NKB) and substance P (SP) in the hypothalamic infundibular nucleus of humans are partly overlapping. These cells are important upstream regulators of gonadotropin-releasing hormone (GnRH) neurosecretion. Homologous neurons in laboratory animals are thought to modulate episodic GnRH secretion primarily via influencing KP receptors on the hypophysiotropic fiber projections of GnRH neurons. To explore the structural basis of this putative axo-axonal communication in humans, we analyzed the anatomical relationship of KP-immunoreactive (IR), NKB-IR and SP-IR axon plexuses with hypophysiotropic GnRH fiber projections. Immunohistochemical studies were carried out on histological samples from postmenopausal women. The neuropeptide-IR axons innervated densely the portal capillary network in the postinfundibular eminence. Subsets of the fibers formed descending tracts in the infundibular stalk, some reaching the neurohypophysis. KP-IR, NKB-IR and SP-IR plexuses intermingled, and established occasional contacts, with hypophysiotropic GnRH fibers in the postinfundibular eminence and through their lengthy course while descending within the infundibular stalk. Triple-immunofluorescent studies also revealed considerable overlap between the KP, NKB and SP signals in individual fibers, providing evidence that these peptidergic projections arise from neurons of the mediobasal hypothalamus. These neuroanatomical observations indicate that the hypophysiotropic projections of human GnRH neurons in the postinfundibular eminence and the descending GnRH tract coursing through the infundibular stalk to the neurohypophysis are exposed to neurotransmitters/neuropeptides released by dense KP-IR, NKB-IR and SP-IR fiber plexuses. Localization and characterization of axonal neuropeptide receptors will be required to clarify the putative autocrine and paracrine interactions in these anatomical regions.

Selective ablation of peptide YY cells in adult mice reveals their role in beta cell survival.

BACKGROUND AND AIMS: In the pancreas, peptide YY (PYY) is expressed by a subpopulation of nonbeta cells in the islets of Langerhans. We investigated the function of these cells in the pancreas of adult mice. METHODS: We generated mice in which administration of diphtheria toxin (DT) led to specific ablation of PYY-expressing cells. We investigated the effects of loss of PYY cells on glucose homeostasis. RESULTS: Loss of PYY cells in adult mice resulted in severe hyperglycemia, which was associated with significant loss of pancreatic insulin and disruption of islet morphology. In vitro administration of DT to isolated islets significantly reduced numbers of PYY-expressing cells and levels of insulin. Administration of either pancreatic polypeptide (a strong agonist of the receptor Y(4)) or PYY(3-36) (a selective agonist of the receptor Y(2)) did not restore loss of pancreatic insulin following administration of DT. However, a long-acting PYY analogue reduced the loss of insulin, and administration of this analogue reduced the hyperglycemia and insulin loss induced by streptozotocin in mice. CONCLUSIONS: PYY appears to regulate beta cell function and survival via the receptor Y(1/2). These findings might be developed to treat and prevent loss of beta cells in patients with diabetes mellitus.

Gut hormone release and appetite regulation in healthy non-obese participants following oligofructose intake. A dose-escalation study.

Prevention of weight gain in adults is a major public health target. Animal experiments have consistently demonstrated a relationship between fermentable carbohydrate intake, such as oligofructose, anorectic gut hormones, and appetite suppression and body weight control. This study was designed to determine the dose of oligofructose which would augment the release of anorectic gut hormones and reduce appetite consistently in non-obese humans. Twelve non-obese participants were recruited for a 5-week dose-escalation study. Following a 9-14-day run-in, participants increased their daily oligofructose intake every week from 15, 25, 35, 45, to 55 g daily. Subjective appetite and side effects were monitored daily. Three-day food diaries were completed every week. Appetite study sessions explored the acute effects of 0, 15, 35, and 55 g oligofructose on appetite-related hormones, glycaemia, subjective appetite, and energy intake. In the home environment, oligofructose suppressed hunger, but did not affect energy intake. Oligofructose dose-dependently increased peptide YY, decreased pancreatic polypeptide and tended to decrease ghrelin, but did not significantly affect appetite profile, energy intake, glucose, insulin, or glucagon-like peptide 1 concentrations during appetite study sessions. In conclusion, oligofructose supplementation at ≥ 35 g/day increased peptide YY and suppressed pancreatic polypeptide and hunger; however, energy intake did not change significantly.

Pharmacokinetics, adverse effects and tolerability of a novel analogue of human pancreatic polypeptide, PP 1420.

AIMS: The objectives of this phase 1 study were to confirm the tolerability of single ascending subcutaneous doses of PP 1420 in healthy subjects, to assess its adverse effects and to investigate the drug's pharmacokinetics and dose proportionality. METHODS: This was a double-blind, placebo-controlled, randomized study. There were three dosing periods. Each subject (n= 12) was randomized to receive one dose of placebo and two ascending doses of PP 1420, given as a subcutaneous injection. Blood samples were taken over 24 h to assess pharmacokinetics. Standard safety and laboratory data were collected. The primary endpoint was the tolerability of PP 1420. The secondary endpoint was exposure to PP 1420 as assessed by C(max) and AUC(0,∞). RESULTS: PP 1420 was well tolerated by all subjects with no serious adverse effects. Following single subcutaneous doses of PP 1420 at 2, 4 and 8 mg to male subjects, C(max) was reached at a median t(max) of approximately 1 h post dose (range 0.32-2.00 h). Thereafter, plasma concentrations of PP 1420 declined with geometric mean apparent terminal elimination t(1/2) ranging from 2.42-2.61 h (range 1.64-3.95 h) across all dose levels. CONCLUSIONS: Subcutaneous PP 1420 was well tolerated in healthy human subjects at single doses between 2-8 mg, with no tolerability issues arising. Where observed, adverse events were not serious, and there was no evidence of a dose-relationship to frequency of adverse events. The results therefore support the conduct of clinical trials to investigate efficacy, tolerability and pharmacokinetics during repeated dosing.

The nutriceutical bovine colostrum truncates the increase in gut permeability caused by heavy exercise in athletes.

Heavy exercise causes gut symptoms and, in extreme cases, "heat stroke" partially due to increased intestinal permeability of luminal toxins. We examined bovine colostrum, a natural source of growth factors, as a potential moderator of such effects. Twelve volunteers completed a double-blind, placebo-controlled, crossover protocol (14 days colostrum/placebo) prior to standardized exercise. Gut permeability utilized 5 h urinary lactulose-to-rhamnose ratios. In vitro studies (T84, HT29, NCM460 human colon cell lines) examined colostrum effects on temperature-induced apoptosis (active caspase-3 and 9, Baxα, Bcl-2), heat shock protein 70 (HSP70) expression and epithelial electrical resistance. In both study arms, exercise increased blood lactate, heart rate, core temperature (mean 1.4°C rise) by similar amounts. Gut hormone profiles were similar in both arms although GLP-1 levels rose following exercise in the placebo but not the colostrum arm (P = 0.026). Intestinal permeability in the placebo arm increased 2.5-fold following exercise (0.38 ± 0.012 baseline, to 0.92 ± 0.014, P < 0.01), whereas colostrum truncated rise by 80% (0.38 ± 0.012 baseline to 0.49 ± 0.017) following exercise. In vitro apoptosis increased by 47-65% in response to increasing temperature by 2°C. This effect was truncated by 60% if colostrum was present (all P < 0.01). Similar results were obtained examining epithelial resistance (colostrum truncated temperature-induced fall in resistance by 64%, P < 0.01). Colostrum increased HSP70 expression at both 37 and 39°C (P < 0.001) and was truncated by addition of an EGF receptor-neutralizing antibody. Temperature-induced increase in Baxα and reduction in Bcl-2 was partially reversed by presence of colostrum. Colostrum may have value in enhancing athletic performance and preventing heat stroke.

A kisspeptin-10 analog with greater in vivo bioactivity than kisspeptin-10.

The kisspeptins are neuropeptides that stimulate the hypothalamo-pituitary-gonadal (HPG) axis. The smallest endogenous kisspeptin, kisspeptin-10 (KP-10), binds to the receptor KISS1R with a similar affinity to the full-length peptide, kisspeptin-54 (KP-54), but is less effective in vivo, possibly because of increased enzymatic breakdown or clearance. The kisspeptin system may have therapeutic potential in the treatment of reproductive disorders and endocrine cancers. We have rationally modified the structure of KP-10 and tested the binding affinity of these analogs for the KISS1R. Those analogs that bound with relatively high affinity to KISS1R were tested for ability to stimulate ERK1/2 phosphorylation in vitro and for their ability to stimulate the HPG axis in vivo. One analog, [dY](1)KP-10, bound to KISS1R with lower affinity to KP-10 and exhibited similar bioactivity in vitro. However, in vivo peripheral administration of [dY](1)KP-10 increased plasma LH and testosterone more potently than KP-10 itself at 20 min postinjection in mice. In addition, 60 min postinjection, 0.15 nmol [dY](1)KP-10 significantly increased total testosterone levels in mice whereas the same dose of KP-10 had no significant effect. Should manipulation of the kisspeptin/KISS1R signaling system prove therapeutically useful, long-lasting analogs such as [dY](1)KP-10 may have greater therapeutic potential than endogenous forms of kisspeptin.

Remission of type 2 diabetes after gastric bypass and banding: mechanisms and 2 year outcomes.

OBJECTIVE: To investigate the rate of type 2 diabetes remission after gastric bypass and banding and establish the mechanism leading to remission of type 2 diabetes after bariatric surgery. SUMMARY BACKGROUND DATA: Glycemic control in type 2 diabetic patients is improved after bariatric surgery. METHODS: In study 1, 34 obese type 2 diabetic patients undergoing either gastric bypass or gastric banding were followed up for 36 months. Remission of diabetes was defined as patients not requiring hypoglycemic medication, fasting glucose below 7 mmol/L, 2 hour glucose after oral glucose tolerance test below 11.1 mmol/L, and glycated haemoglobin (HbA1c) <6%. In study 2, 41 obese type 2 diabetic patients undergoing either bypass, banding, or very low calorie diet were followed up for 42 days. Insulin resistance (HOMA-IR), insulin production, and glucagon-like peptide 1 (GLP-1) responses after a standard meal were measured. RESULTS: In study 1, HbA1c as a marker of glycemic control improved by 2.9% after gastric bypass and 1.9% after gastric banding at latest follow-up (P < 0.001 for both groups). Despite similar weight loss, 72% (16/22) of bypass and 17% (2/12) of banding patients (P = 0.001) fulfilled the definition of remission at latest follow-up. In study 2, within days, only bypass patients had improved insulin resistance, insulin production, and GLP-1 responses (all P < 0.05). CONCLUSIONS: With gastric bypass, type 2 diabetes can be improved and even rapidly put into a state of remission irrespective of weight loss. Improved insulin resistance within the first week after surgery remains unexplained, but increased insulin production in the first week after surgery may be explained by the enhanced postprandial GLP-1 responses.

The effects of kisspeptin-54 on blood pressure in humans and plasma kisspeptin concentrations in hypertensive diseases of pregnancy.

AIMS: To investigate (i) if kisspeptin administration alters heart rate (HR) or blood pressure (BP) in healthy male and female volunteers, (ii) whether circulating plasma kisspeptin concentrations in healthy pregnant women and women with hypertensive diseases of pregnancy correlate with BP and (iii) whether women with hypertensive diseases of pregnancy have altered plasma kisspeptin concentrations. METHODS: We have previously reported the effects of administration of kisspeptin-54 on gonadotrophin secretion in healthy male and female volunteers. In these studies, cardiovascular parameters were not a primary endpoint. However, data were also collected on BP and HR for 4h post administration of kisspeptin-54. Blood samples were taken from 105 women in the third trimester of pregnancy (27 women with hypertensive diseases of pregnancy and 78 controls). Samples were assayed for plasma kisspeptin immunoreactivity (IR). RESULTS: Administration of kisspeptin was not associated with significant changes in HR or BP in healthy men or women. There was no significant correlation between plasma kisspeptin concentration and BP in healthy pregnant women or in those with hypertensive diseases of pregnancy. No significant differences in plasma kisspeptin-IR concentrations were observed between women with hypertensive diseases of pregnancy and normotensive pregnant controls, plasma kisspeptin concentrations ±SE: controls 2878 ± 157pmol l(-1) ; pregnancy-induced hypertension 2696 ± 299pmoll(-1) (95% CI vs. controls -514, 878pmoll(-1) ); pre-eclampsia 3519 ± 357 (95% CI vs. controls -1644, 362pmoll(-1) ). CONCLUSIONS: Elevation of plasma kisspeptin-IR is not associated with an alteration in BP in humans.

Differential patterns of neuronal activation in the brainstem and hypothalamus following peripheral injection of GLP-1, oxyntomodulin and lithium chloride in mice detected by manganese-enhanced magnetic resonance imaging (MEMRI).

We have used manganese-enhanced magnetic resonance imaging (MEMRI) to show distinct patterns of neuronal activation within the hypothalamus and brainstem of fasted mice in response to peripheral injection of the anorexigenic agents glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM) and lithium chloride. Administration of both GLP-1 and OXM resulted in a significant increase in signal intensity (SI) in the area postrema of fasted mice, reflecting an increase in neuronal activity within the brainstem. In the hypothalamus, GLP-1 administration induced a significant reduction in SI in the paraventricular nucleus and an increase in the ventromedial hypothalamic nucleus whereas OXM reduced SI in the arcuate and supraoptic nuclei of the hypothalamus. These data indicate that whilst these related peptides both induce a similar effect on neuronal activity in the brainstem they generate distinct patterns of activation within the hypothalamus. Furthermore, the hypothalamic pattern of signal intensity generated by GLP-1 closely matches that generated by peripheral injection of LiCl, suggesting the anorexigenic effects of GLP-1 may be in part transmitted via nausea circuits. This work provides a framework by which the temporal effects of appetite modulating agents can be recorded simultaneously within hypothalamic and brainstem feeding centres.

Sustained appetite improvement in malnourished dialysis patients by daily ghrelin treatment.

Malnutrition is a common complication in patients on dialysis and is strongly associated with poor prognosis. Effective therapy could substantially improve morbidity and mortality, but neither enteral nor parenteral supplementation provide long-term benefit because of the strong appetite suppression seen in such patients. We performed a double-blinded randomized crossover study of a week-long treatment with daily subcutaneous ghrelin, a gut hormone that regulates hunger through the hypothalamus, in a group of 12 malnourished dialysis patients. Ghrelin administration increased ghrelin levels in circulation, modestly reduced blood pressure for up to 2 h, and immediately and significantly increased appetite, with an increase in energy intake noted at the first study meal. Persistence of this effect throughout the week was confirmed with food diaries and final study meals. Energy expenditure, measured with free-living pulse and motion monitors, was unchanged by ghrelin. Our study shows that daily treatment with ghrelin achieves a sustained positive change in energy balance in malnourished dialysis patients. Direct manipulation of appetite with ghrelin or its analogs represents an attractive and promising therapeutic strategy for this difficult clinical problem.

An increase in kisspeptin-54 release occurs with the pubertal increase in luteinizing hormone-releasing hormone-1 release in the stalk-median eminence of female rhesus monkeys in vivo.

The G-protein coupled receptor GPR54 and its ligand, KiSS-1-derived peptide kisspeptin-54, appear to play an important role in the mechanism of puberty. This study measures the release of kisspeptin-54 in the stalk-median eminence (S-ME) during puberty and examines its potential role in the pubertal increase in LHRH-1 release in female rhesus monkeys. First, developmental changes in release of kisspeptin-54 and LHRH-1 were assessed in push-pull perfusate samples obtained from the S-ME of prepubertal, early pubertal, and midpubertal female rhesus monkeys. Whereas LHRH-1 levels in 10-min intervals had been measured previously for other experiments, kisspeptin-54 levels in 40-min pooled samples were newly measured by RIA. The results indicate that a significant increase in kisspeptin-54 release occurred in association with the pubertal increase in LHRH-1 release and that a nocturnal increase in kisspeptin-54 release was already observed in prepubertal monkeys and continued through the pubertal period. Second, we measured kisspeptin-54 release in the S-ME of midpubertal monkeys at 10-min intervals using a microdialysis method. Kisspeptin-54 release in the S-ME was clearly pulsatile with an interpulse interval of about 60 min, and approximately 75% of kisspeptin-54 pulses were correlated with LHRH-1 pulses. Finally, the effect of kisspeptin-10 on LHRH-1 release was examined with the microdialysis method. Kisspeptin-10 infusion through a microdialysis probe significantly stimulated LHRH-1 release in a dose-dependent manner. Collectively, the results are consistent with the hypothesis that kisspeptin plays a role in puberty.

Pyroglutamylated RFamide peptide 43 stimulates the hypothalamic-pituitary-gonadal axis via gonadotropin-releasing hormone in rats.

Although it is established that other members of the RFamide family stimulate the hypothalamic-pituitary-gonadal axis, the influence of the novel pyroglutamylated RFamide peptide 43 (QRFP43) is not known. We show intracerebroventricular (icv) administration of QRFP43 (2 nmol) to male rats increased plasma LH and FSH levels at 40 min after injection. icv administration of 3 nmol QRFP43 did not affect food intake in ad-libitum-fed male rats. The icv administration of 2 nmol QRFP43 did not significantly influence behavior in male rats. Intraperitoneal administration of doses up to 1200 nmol/kg QRFP43 in male rats did not significantly influence circulating gonadotropin or sex steroid levels. In vitro, QRFP43 stimulated GnRH release from hypothalamic explants from male rats and from GT1-7 cells. Pretreatment with a GnRH receptor antagonist, cetrorelix, blocked the increase in plasma LH levels after icv administration of QRFP43 (2 nmol). These results suggest that icv QRFP43 activates the hypothalamic-pituitary-gonadal axis via GnRH.

Elevated cocaine- and amphetamine-regulated transcript immunoreactivity in the circulation of patients with neuroendocrine malignancy.

CONTEXT: Cocaine- and amphetamine-regulated transcript (CART) codes for a peptide widely distributed in nervous and endocrine tissues. CART immunoreactivity (CART-LI) has been detected in human insulinomas. OBJECTIVE: The objective of the study was to investigate the measurement of plasma CART-LI as a tumor marker of neuroendocrine malignancy. DESIGN AND SUBJECTS: Plasma CART-LI levels were measured in 401 patients with a range of diagnoses: neuroendocrine malignancy (n = 131), after removal of neuroendocrine malignancy (n = 27), without any form of tumor or renal impairment (n = 192), with renal impairment (n = 17) and with nonneuroendocrine tumors (n = 34). Chromatography methods were used to investigate CART-LI circulating in human plasma. RESULTS: The upper limit of normal calculated for CART-LI was 150 pmol/liter. Mean circulating plasma CART-LI among neuroendocrine tumor patients was 440 pmol/liter, 56% of subjects having levels greater than 150 pmol/liter. Measuring CART-LI in addition to chromogranin (Cg)-A improved the sensitivity for neuroendocrine malignancy from 85 to 91%, whereas combined use of CgA and CgB had a joint sensitivity of 89%. Of 38 patients with pancreatic neuroendocrine tumors, 71% had plasma CART-LI levels greater than 150 pmol/liter, increasing to 95% in those classified with progressive disease (n = 20, mean CART-LI 625 pmol/liter), compared with 80% for CgA. Chromatographic analysis suggests that circulating CART-LI is present as one major form, which may correspond to CART (62-102) or another unknown form. CONCLUSIONS: We demonstrate CART-LI as a specific tumor marker in patients with a range of neuroendocrine tumors. Used in combination with CgA, CART-LI measurement has the potential to improve sensitivity in diagnosis and follow-up of neuroendocrine tumors, in particular progressive pancreatic neuroendocrine tumors.

Peptide YY: a gut hormone associated with anorexia during infectious diarrhea in children.

OBJECTIVE: To evaluate the effects of diarrhea on appetite among Peruvian children age 12 to 71 months and to assess whether elevated plasma levels of peptide YY, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta contribute to anorexia in this population. STUDY DESIGN: A total of 46 Peruvian children with diarrhea and 46 healthy controls underwent an observed feeding trial that was repeated when cases were healthy. Blood samples were obtained from 30 cases and 30 controls at the first trial and from 30 cases at the second trial and assayed for peptide YY, TNF-alpha, and IL-1beta. RESULTS: In the cases, mean consumption was less when sick than when healthy. The mean plasma level of peptide YY was higher for cases than controls and higher for cases when sick than when healthy. TNF-alpha levels were higher in cases than controls at visit 1 and also higher in cases when sick than when healthy. There were no differences in IL-1beta levels between cases and controls or between cases when sick and healthy. Peptide YY levels in children with diarrhea correlated with the likelihood of them eating less when sick than when healthy. CONCLUSIONS: Elevated serum peptide YY may be a mechanism for anorexia in children with diarrhea.

Supraphysiological doses of intravenous PYY3-36 cause nausea, but no additional reduction in food intake.

BACKGROUND: Peptide YY (PYY(3-36)) infused to levels within the physiological range reduces appetite and food intake in humans without nausea. However, PYY(3-36) has previously been shown to cause nausea at higher doses. METHODS: We studied the relationship of PYY(3-36), nausea and food intake in six volunteers, using three different PYY(3-36) preparations infused to achieve supraphysiological PYY plasma levels. RESULTS: Supraphysiological levels of PYY caused nausea in five subjects (P < 0.05). Although PYY(3-36) increased satiety (P < 0.05) and reduced food intake (P < 0.05), no greater enhancement of satiety or inhibition of food intake was observed compared with previous reports. CONCLUSIONS: This study cautions against the use of supraphysiological doses of PYY(3-36) as it may increase nausea with no benefit in food reduction.

Kisspeptin-54 stimulates gonadotropin release most potently during the preovulatory phase of the menstrual cycle in women.

CONTEXT: Kisspeptin, the endogenous ligand of the G protein-coupled receptor 54, is a key regulator of the hypothalamo-pituitary-gonadal (HPG) axis. GPR54-null mice exhibit reproductive dysfunction, and exogenous kisspeptin potently stimulates the HPG axis in rodents, primates, and human males. The effects of kisspeptin administration to human females are unknown. OBJECTIVE: Our objective was to investigate the effects of kisspeptin on LH release during the menstrual cycle in female volunteers. DESIGN: Bolus sc kisspeptin-54 was administered to female volunteers, and plasma gonadotropins were measured. SETTING: The study took place at a hospital clinical research facility. VOLUNTEERS: Subjects were healthy female volunteers with regular menstrual cycles. INTERVENTION: 1) Volunteers received a sc bolus injection of kisspeptin-54 (0, 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 nmol/kg; n = 3-4 per dose) in the follicular phase; and 2) volunteers (n = 8) received a sc bolus injection of either kisspeptin-54 (0.4 nmol/kg) or saline in random order during each phase of the menstrual cycle. MAIN OUTCOME MEASURES: Plasma gonadotropins were measured. RESULTS: 1) Kisspeptin-54 caused a dose-dependent increase in mean LH over time at doses from 0.2-6.4 nmol/kg. 2) Kisspeptin-54 increased plasma LH compared with saline injection in all phases of the cycle. The effect of kisspeptin was greatest in the preovulatory phase and least in the follicular phase of the cycle [mean increase in LH over baseline (IU/liter) +/- sem for follicular phase was 0.12 +/- 0.17; preovulatory phase, 20.64 +/- 2.91 (P < 0.001 vs. follicular phase); luteal phase, 2.17 +/- 0.79 (P < 0.01 vs. follicular phase)]. CONCLUSION: Elevation of plasma kisspeptin in human females potently stimulates LH release in the preovulatory phase and provides a novel mechanism for manipulation of the HPG axis in women.

Constitutional thinness and lean anorexia nervosa display opposite concentrations of peptide YY, glucagon-like peptide 1, ghrelin, and leptin.

BACKGROUND: Food intake is controlled by the arcuate nucleus through integration of peripheral hormonal signals such as leptin, ghrelin, peptide YY (PYY), and glucagon-like peptide 1 (GLP-1). The most common condition resulting in underweight young women in the developed world is restrictive anorexia nervosa (AN). However, constitutional thinness (CT) is also known to exist in the same low-weight range. Women with CT have normal menstrual periods and do not have the psychological or hormonal features of AN. Little is currently known about regulation of food intake in subjects with CT. OBJECTIVE: We tested the hypothesis that concentrations of leptin, ghrelin, PYY, and GLP-1 in persons with AN are significantly different from those in persons with CT. DESIGN: Concentrations of PYY, GLP-1, ghrelin, and leptin were measured in 3 groups of young women: normal weight (n = 7), CT (n = 10), and AN (n = 12). Samples were collected every 4 h for 24 h. RESULTS: PYY concentrations were significantly higher in CT subjects than in AN or control subjects. GLP-1 concentrations were significantly higher in AN than in CT subjects, whereas ghrelin was significantly higher in AN subjects than in control and CT subjects. CT subjects had the lowest ghrelin concentrations. Leptin concentrations were significantly lower in AN subjects. PYY and leptin circadian variations were not significantly different between CT and control subjects, whereas these profiles were blunted in AN subjects. CONCLUSIONS: Orexigenic and anorexigenic hormones in CT contrast with an adaptative profile characterizing AN. The hormones appear to be valuable biomarkers for distinguishing these 2 categories of severely underweight subjects.

Inhibition of food intake in obese subjects by peptide YY3-36.

BACKGROUND: The gut hormone fragment peptide YY3-36 (PYY) reduces appetite and food intake when infused into subjects of normal weight. In common with the adipocyte hormone leptin, PYY reduces food intake by modulating appetite circuits in the hypothalamus. However, in obesity there is a marked resistance to the action of leptin, which greatly limits its therapeutic effectiveness. We investigated whether obese subjects were also resistant to the anorectic effects of PYY. METHODS: We compared the effects of PYY infusion on appetite and food intake in 12 obese and 12 lean subjects in a double-blind, placebo-controlled, crossover study. The plasma levels of PYY, ghrelin, leptin, and insulin were also determined. RESULTS: Caloric intake during a buffet lunch offered two hours after the infusion of PYY was decreased by 30 percent in the obese subjects (P<0.001) and 31 percent in the lean subjects (P<0.001). PYY infusion also caused a significant decrease in the cumulative 24-hour caloric intake in both obese and lean subjects. PYY infusion reduced plasma levels of the appetite-stimulatory hormone ghrelin. Endogenous fasting and postprandial levels of PYY were significantly lower in obese subjects (the mean [+/-SE] fasting PYY levels were 10.2+/-0.7 pmol per liter in the obese group and 16.9+/-0.8 pmol per liter in the lean group, P<0.001). Furthermore, the fasting PYY levels correlated negatively with the body-mass index (r = -0.84, P<0.001). CONCLUSIONS: We found that obese subjects were not resistant to the anorectic effects of PYY. Endogenous PYY levels were low in the obese subjects, suggesting that PYY deficiency may contribute to the pathogenesis of obesity.