Long-Term Modulation of Appetitive Hormones and Sweet Cravings After Adjustable Gastric Banding and Roux-en-Y Gastric Bypass.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) produces greater weight loss compared with a purely restrictive procedure such as laparoscopic adjustable gastric banding (LAGB). OBJECTIVE: The objective of this study was to quantify changes in hormones that regulate energy homeostasis and appetitive sensations before and after LAGB (n = 18) and RYGB (n = 38) in order to better understand the mechanisms underlying the greater weight loss after RYGB. METHODS: A standardized test meal was administered prior to surgery, at 6 months, and annually thereafter to year 2 after LAGB and year 4 after RYGB. Blood samples were obtained in the fasted state and 30, 60, 90, and 120 min post-meal. RESULTS: Progressive increases in fasting PYY were observed after RYGB together with increases in postprandial area under the curve (AUC) levels that were unchanged after LAGB. GLP-1 AUC increased only after RYGB. There was a weight loss-related increase in fasting ghrelin levels after LAGB that was unchanged 1 year after RYGB despite greater percentage weight loss; ghrelin subsequently increased at years 2-4 post-RYGB. HOMA-IR decreased after both procedures but correlated with weight loss only after LAGB, whereas leptin correlated with weight loss in both groups. Sweet cravings decreased after RYGB. CONCLUSION: A number of weight loss-independent changes in the gut hormonal milieu likely act in concert to promote a decrease in insulin resistance and greater weight loss efficacy after RYGB. A progressive change in hormone levels over time may reflect gut enteroplasticity after RYGB. A decrease in sweet cravings specific to RYGB may further promote superior weight loss outcomes.

A prospective study of appetite and food craving in 30 patients with Cushing's disease.

CONTEXT: Glucocorticoid (GC) exposure increases food intake, but the mechanisms in humans are not known. Investigation of appetite and food craving has not been done in patients with chronic GC exposure due to Cushing's disease (CD), either before or after treatment, and could provide insight into mechanisms of food intake and obesity in these patients. PURPOSE: To examine whether surgical remission of CD changes appetite (prospective consumption, hunger, satisfaction, and fullness) and food cravings (sweet, salty, fatty, and savory); and to identify predictors of appetite and craving in CD remission. METHODS: 30 CD patients, mean age 40.0 years (range 17-70), mean BMI 32.3 ± 6.4, were prospectively studied before and at a mean of 17.4 mo. after remission. At each visit fasting and post-test meal (50% carbohydrate, 35% protein, 15% fat) appetite and craving scores were assessed. RESULTS: Remission decreased prospective consumption, sweet and savory craving (p < 0.05), but did not change hunger, satisfaction, fullness, or fat craving, despite decreases in BMI and fat mass. In CD remission, serum cortisol predicted lower satisfaction and fullness, and masses of abdominal fat depots predicted higher hunger and consumption (p < 0.05). CONCLUSIONS: Chronic GC exposure in CD patients may stimulate the drive to eat by enhancing craving, rather than regulating the sensation of hunger. Continued alterations in appetite regulation due to abdominal fat mass and circulating cortisol could play a role in the cardiovascular and metabolic risk that has been reported in CD patients despite remission.

Prospective study of surgical treatment of acromegaly: effects on ghrelin, weight, adiposity, and markers of CV risk.

CONTEXT: Although epidemiological studies have found that GH and IGF-1 normalization reduce the excess mortality of active acromegaly to expected rates, cross-sectional data report some cardiovascular (CV) risk markers to be less favorable in remission than active acromegaly. OBJECTIVE: The objective of the study was to test the hypothesis that remission of acromegaly after surgical therapy increases weight and adiposity and some CV risk markers and these changes are paralleled by a rise in ghrelin. DESIGN: Forty-two adults with untreated, active acromegaly were studied prospectively. Changes in outcome measures from before to after surgery were assessed in 26 subjects achieving remission (normal IGF-1) and 16 with persistent active acromegaly (elevated IGF-1) after surgery. SETTING: The study was conducted at tertiary referral centers for pituitary tumors. MAIN OUTCOME MEASURES: Endocrine, metabolic, and CV risk parameters, anthropometrics, and body composition by dual-energy X-ray absorptiometry were measured. RESULTS: Remission increased total ghrelin, body weight, waist circumference, C-reactive protein, homocysteine, high-density lipoprotein, and leptin and reduced systolic blood pressure, homeostasis model assessment score, triglycerides, and lipoprotein (a) by 6 months and for 32 ± 4 months after surgery. The ghrelin rise correlated with the fall in the levels of GH, IGF-1, and insulin and insulin resistance. Weight, waist circumference, and ghrelin did not increase significantly in the persistent active acromegaly group. Total body fat, trunk fat, and perentage total body fat increased by 1 year after surgery in 15 remission subjects: the increase in body fat correlated with the rise in total ghrelin. CONCLUSIONS: Although most markers of CV risk improve with acromegaly remission after surgery, some markers and adiposity increase and are paralleled by a rise in total ghrelin, suggesting that these changes may be related. Understanding the mechanisms and long-term implications of the changes that accompany treatment of acromegaly is important to optimizing management because some aspects of the postoperative profile associate with the increased metabolic and CV risk in other populations.

Recombinant human leptin does not alter gut hormone levels after gastric bypass but may attenuate sweet cravings.

Bariatric surgery improves glucose homeostasis and alters gut hormones partly independent of weight loss. Leptin plays a role in these processes; levels are decreased following bariatric surgery, creating a relative leptin insufficiency. We previously showed that leptin administration in a weight-reduced state after Roux-en-Y gastric bypass (RYGB) caused no further weight loss. Here, we discuss the impact of leptin administration on gut hormones, glucostasis, and appetite. Weight stable women after RYGB were randomized to receive placebo or recombinant human metreleptin (0.05 mg/kg twice daily). At weeks 0 and 16, a liquid meal challenge was performed. Glucose, insulin, C-peptide, GLP-1, PYY, glucagon, and ghrelin (total, acyl, and desacyl) were measured fasting and postprandially. Appetite was assessed using a visual analog scale. Mean post-op period was 53 ± 2.3 months; mean BMI was 34.6 ± 0.2 kg/m(2). At 16 weeks, there was no significant change in weight within or between groups. Fasting PYY was significantly different between groups and the leptin group had lower sweets craving at week 16 than the placebo group (P < 0.05). No other differences were observed. Leptin replacement does not alter gut hormones or glucostasis but may diminish sweet cravings compared to placebo in this population of post-RYGB women.

Very low-calorie diet mimics the early beneficial effect of Roux-en-Y gastric bypass on insulin sensitivity and ß-cell Function in type 2 diabetic patients.

Marked improvement in glycemic control occurs in patients with type 2 diabetes mellitus shortly after Roux-en-Y gastric bypass surgery (RYGB) and before there is major weight loss. The objective of this study was to determine whether the magnitude of this change is primarily due to caloric restriction or is unique to the surgical procedure. We studied eleven subjects who underwent RYGB and fourteen subjects mean-matched for BMI, HbA1c, and diabetes duration who were admitted to our inpatient research unit and given a very low-calorie diet (VLCD) of 500 kcal/day with a macronutrient content similar to that consumed by patients after RYGB. Frequently sampled intravenous glucose tolerance tests were performed before and after interventions. Both groups lost an equivalent amount of weight over a mean study period of 21 days. Insulin sensitivity, acute insulin secretion after intravenous glucose administration, and ß-cell function as determined by disposition index improved to a similar extent in both groups. Likewise, changes in fasting glucose and fructosamine levels were similar. Based on these data, VLCD improves insulin sensitivity and ß-cell function just as well as RYGB in the short term.

Randomized double-blind placebo-controlled study of leptin administration after gastric bypass.

OBJECTIVE: Obese individuals have high levels of circulating leptin and are resistant to the weight-reducing effect of leptin administration at physiological doses. Although Roux-en-Y gastric bypass (RYGB) is an effective weight loss procedure, there is a plateau in weight loss and most individuals remain obese. This plateau may be partly due to the decline in leptin resulting in a state of relative leptin insufficiency. The main objective of this study was to determine whether leptin administration to post-RYGB patients would promote further weight reduction. DESIGN AND METHODS: This was a randomized, double-blind, placebo-controlled cross-over study of 27 women who were at least 18 months post-RYGB and lost on average 30.8% of their presurgical body weight. Subjects received either leptin or placebo via subcutaneous injection twice daily for 16 weeks, then crossed over to receive the alternate treatment for 16 weeks. RESULTS: Weight change after 16 weeks of placebo was not significantly different from that after 16 weeks of leptin. No changes were observed in percent fat mass, resting energy expenditure, thyroid hormones, or cortisol levels. CONCLUSION: Contrary to our hypothesis, we did not observe a significant effect of leptin treatment on body weight in women with relative hypoleptinemia after RYGB.

Effects of estradiol on cerebrospinal fluid levels of agouti-related protein in ovariectomized rhesus monkeys.

Hypothalamic proopiomelanocortin (POMC)-derived MSH peptides and the melanocortin receptor antagonist, agouti-related protein (AgRP), interact to regulate energy balance. Both POMC and AgRP neurons express estrogen receptors, but little is known about estrogen regulation of the melanocortin system in the primate. We have therefore examined the effects of physiological doses of estradiol (E2) on POMC and AgRP in lumbar cerebrospinal fluid (CSF) of ovariectomized monkeys. POMC prohormone was measured by ELISA. AgRP was measured by RIA (sensitive for the more biologically active C-terminal AgRP(83-132) but also detects full-length AgRP) and by ELISA (measures primarily full length AgRP). In the first experiment, 14 animals were studied before and after 3 wk of E2. CSF POMC did not change, but AgRP(RIA) decreased from 7.9 +/- 1.2 to 4.7 +/- 1.2 fmol/ml after E2 (P = 0.03) and the POMC/AgRP(RIA) ratio increased from 4.2 +/- 0.89 to 6.8 +/- 1.04 (P = 0.04). AgRP(ELISA) did not change, but the ratio of AgRP(RIA) compared with AgRP(ELISA) was reduced after E2 (P = 0.02). In the second experiment, 11 animals were studied after 6 wk of E2, and similar changes were noted. The degree of AgRP(RIA) suppression with E2 was inversely related to body mass index (r = 0.569; P = 0.03). These results show for the first time that E2 suppresses AgRP(C-terminal) in CSF, increases the POMC to AgRP ratio, and may decrease AgRP processing, thus leading to increased melanocortin signaling. Furthermore, obesity was associated with resistance to the suppressive effects of E2 on AgRP, analogous to what is seen with obesity and leptin resistance.

Effects of selective modulation of the central melanocortin-3-receptor on food intake and hypothalamic POMC expression.

Hypothalamic POMC neurons regulate energy balance via interactions with brain melanocortin receptors (MC-Rs). POMC neurons express the MC3-R which can function as an inhibitory autoreceptor in vitro. We now demonstrate that central activation of MC3-R with ICV infusion of the specific MC3-R agonist, [D-Trp(8)]-gamma-MSH, transiently suppresses hypothalamic Pomc expression and stimulates food intake in rats. Conversely, we also show that ICV infusion of a low dose of a selective MC3-R antagonist causes a transient decrease in feeding and weight gain. These data support a functional inhibitory role for the MC3-R on POMC neurons that leads to changes in food intake.

Differential effects of gastric bypass and banding on circulating gut hormone and leptin levels.

OBJECTIVE: To quantify plasma concentrations of hormones that regulate energy homeostasis in order to establish possible mechanisms for greater weight loss after Roux-en-Y gastric bypass (RYGBP) compared with gastric banding (BND). RESEARCH METHODS AND PROCEDURES: Four groups of women were studied: lean (n = 8; mean BMI, 21.6 kg/m2); BND (n = 9; BMI, 35.8; 25% weight loss), RYGBP (n = 9; BMI, 34.2; 36% weight loss), and controls matched for BMI to the surgical groups (n = 11; BMI, 34.4). RESULTS: Fasting total peptide YY (PYY) and PYY(3-36) immunoreactivity were similar among all groups, but the postprandial response in the RYGBP group was exaggerated, such that 30 minutes after the meal, total and PYY(3-36) levels were 2- to 4-fold greater compared with all other groups. Maximal postprandial suppression of total ghrelin was blunted in the BND group (13%) compared with RYGBP (27%). Postprandial suppression of octanoylated ghrelin was also less in BND (29%) compared with RYGBP (56%). Fasting insulin was lower in RYGBP (6.6 microU/mL) compared with BND (10.0 microU/mL). Compared with lean controls, leptin concentrations were significantly higher in BND but not in RYGBP. There was a greater increase in post-meal satiety in the RYGBP group compared with BND and overweight controls. DISCUSSION: The differences between RYGBP and BND subjects in postprandial concentrations of PYY and ghrelin would be expected to promote increased satiety and earlier meal termination in RYGBP and may aid in greater weight loss. The differences in insulin and leptin concentrations associated with these procedures may also reflect differences in insulin sensitivity and energy partitioning.

Stimulation of the hypothalamic-pituitary-adrenal axis with the opioid antagonist nalmefene.

UNLABELLED: Nalmefene Stimulation of the HPA Axis. BACKGROUND: The Hypothalamic-pituitary-adrenal (HPA) axis plays a vital role in the body's response to stress. The traditional gold standard for evaluating the HPA axis, the insulin hypoglycemia test (IHT), has several known limitations, and a second test, the standard ACTH stimulation test, can detect severe deficiencies of cortisol, but often misses mild or early cases. Therefore, a better test for the evaluation of the HPA axis is needed. This study evaluated the opiate antagonist nalmefene as a stimulation test of the HPA axis. METHODS: 25 healthy subjects were studied, 9 women and 16 men, mean age 30.4 yr. (range 21-55), and mean BMI 24.1 kg/m2 (range 18.6-34.2). Subjects received one of 3 doses of intravenously administered nalmefene: 2 mg (n = 6), 6 mg (n = 12), or 10 mg (n = 7). Serum cortisol and plasma ACTH were measured before and serially over two hours after the administration of nalmefene. RESULTS: ACTH and cortisol levels rose significantly and similarly after the 10 mg dose and the 6 mg dose. After the 10 mg dose, mean peak ACTH was 82.4 +/- 22.6 pg/ml and mean peak cortisol was 25.2 +/- 1.8 microg/dl. After the 6 mg dose, mean peak ACTH was 70.3 +/- 7.7 pg/ml and mean peak cortisol was 24.7 +/- 1.7 microg/dl. Cortisol levels rose above 18 microg/dl in all subjects receiving 10 mg of nalmefene, and in all but two of the subjects receiving 6 mg of nalmefene. Side effects to nalmefene were of greater duration and intensity in the subjects receiving 10 mg of nalmefene vs. those receiving 6 or 2 mg. These included most notably fatigue, lightheadedness, nausea and vomiting. CONCLUSIONS: Of the nalmefene doses we studied, 6 mg achieved the best combination of stimulation of ACTH and cortisol and fewest side effects. If further studies show a concordance between nalmefene and IHT, nalmefene testing could be used to assess the HPA axis in patients at risk for dysfunction of this axis.

Effects of fasting, leptin, and insulin on AGRP and POMC peptide release in the hypothalamus.

Agouti-related protein (AGRP) and proopiomelanocortin (POMC) have opposing effects on melanocortin receptor (MC-R) signaling and energy balance, and are important targets for leptin and insulin in the hypothalamus. While food intake and leptin have documented effects on POMC and AGRP gene expression, and insulin has effects on POMC gene expression, little is known about their effects on POMC or AGRP peptide release. Here we have examined the effects of fasting, leptin, and insulin on the release of AGRP and the POMC-derived peptide gamma(3)-MSH from the perifused rat hypothalamus in vitro. In the first experiment, fasting (48 h) resulted in a significant overall decrease in gamma(3)-MSH release measured every 20 min during a 3-h baseline perifusion period and after depolarization with 56 mM KCl (p = 0.02); there was a trend towards an overall increase in the release of AGRP but this was not significant. When the ratio of gamma(3)-MSH/AGRP release was calculated at each time point, there was an overall decrease in gamma(3)-MSH/AGRP with fasting (p < 0.01). Further examination of the ratio of gamma(3)-MSH/AGRP revealed a 34% reduction (p < 0.05) in the basal area under the curve (AUC) and a 33% reduction (p < 0.01) in the post-KCl stimulated AUC in fasted vs. fed animals. In the second experiment, perifusion of hypothalamic slices with 10(-8) or 10(-7) M leptin for 2 h resulted in a significant decrease in the release of AGRP noted primarily after depolarization with KCl (p < 0.01); no effect was seen on gamma(3)-MSH release. Similarly, in a third experiment, perifusion with 10(-7) M insulin caused a significant decrease in AGRP release (p < 0.001) without affecting gamma(3)-MSH release. Thus, there is a significant decrease in gamma(3)-MSH and the ratio of gamma(3)-MSH to AGRP released during fasting, consistent with a net inhibition of hypothalamic MC-R signaling. In contrast, short-term treatment with leptin and insulin may inhibit MC-R signaling primarily by decreasing the release of AGRP.

Effects of Roux-en-Y gastric bypass surgery on fasting and postprandial concentrations of plasma ghrelin, peptide YY, and insulin.

To help understand the mechanisms by which weight loss is maintained after Roux-en-Y gastric bypass (RYGBP), we measured circulating concentrations of total and bioactive octanoylated ghrelin, peptide YY (PYY), glucose, and insulin in the fasted state and in response to a liquid test meal in three groups of adult women: lean (n = 8); weight-stable 35 +/- 5 months after RYGBP (n = 12; mean body mass index, 33 kg/m(2)); and matched to the surgical group for body mass index and age (n = 12). Fasting plasma total ghrelin levels were nearly identical between RYGBP (425 +/- 54 pg/ml) and the matched controls (424 +/- 28 pg/ml) and highest in lean controls (564 +/- 103 pg/ml). The response to the test meal was comparable between lean and RYGBP groups, with 27% and 20% maximal suppression, respectively, whereas the magnitude of suppression was significantly diminished in the matched controls (17%) compared with the lean group. Fasting levels of octanoylated ghrelin were highest in the lean controls, 220 +/- 36 pg/ml vs. 143 +/- 27 in the RYGBP group (P = 0.05) and 127 +/- 12 pg/ml in the matched controls (P < 0.05). The magnitude of maximal postmeal suppression of octanoylated ghrelin was more marked than with total ghrelin, but similar among groups, ranging from 44-47%. In response to the test meal, there was an early exaggerated rise in PYY in the RYGBP group, such that the peak PYY concentration was 163 +/- 24 pg/ml compared with 58 +/- 17 (P < 0.01) and 77 +/- 23 (P < 0.05) in the matched and lean controls, respectively; area under the curve at 90 min was significantly greater compared with both control groups. Leptin and fasting insulin concentrations and homeostasis model of assessment insulin resistance indices were nearly identical between lean and RYGBP subjects and significantly higher in the body mass index-matched controls. In summary, the absence of a compensatory increase in ghrelin concentrations that usually occurs with diet-induced weight loss, and the exaggerated postprandial PYY response after RYGBP, may contribute to weight loss and to the ability of an individual to maintain weight loss after this surgical procedure.

Serum ghrelin levels in acromegaly: effects of surgical and long-acting octreotide therapy.

The orexigenic peptide, ghrelin, is regulated by acute and chronic nutritional state. Although exogenously administered ghrelin stimulates pituitary GH secretion, little is known about the role of ghrelin in endogenous GH secretion or how high GH and IGF-I levels in acromegaly could affect ghrelin secretion and vice versa. Therefore, we evaluated fasting and post oral glucose tolerance test serum ghrelin levels in 19 patients with active acromegaly at baseline and after either surgery in 9 of these or administration of long-acting octreotide (Sandostatin LAR) in the other 10 patients. After surgical cure, fasting ghrelin rose from 312 +/- 56 pg/ml to 548 +/- 97 pg/ml (P = 0.013). Fasting serum ghrelin levels were higher in all patients after surgery and ranged between 112% and 349% of presurgery levels. Ghrelin levels fell significantly during long-acting octreotide therapy from 447 +/- 34 pg/ml to 206 +/- 15 pg/ml (P < 0.0001); ghrelin levels on octreotide ranged between 26% and 70% of baseline levels. Serum ghrelin levels were suppressed significantly during the oral glucose tolerance test in both groups. Pretherapy ghrelin levels correlated negatively with serum insulin levels (r = -0.494; P = 0.03) and insulin resistance as estimated by the homeostasis model assessment score (r = -0.573; P = 0.01). In patients without diabetes mellitus, serum insulin levels in the surgical group were 19.7 +/- 5.4 microU/ml before surgery and fell to 9.7 +/- 0.93 microU/ml after surgery (P = 0.05); levels in the octreotide group were 13.9 +/- 2.8 microU/ml before and fell to 11.2 +/- 2.8 microU/ml on octreotide (P = 0.03). Pretherapy ghrelin levels did not correlate with weight or body mass index, but after therapy in the surgery group ghrelin correlated negatively with weight (r = -0.823, P = 0.012) as has been demonstrated by others in healthy subjects. Ghrelin secretion is dysregulated in active acromegaly; lowered serum levels of ghrelin in active acromegaly rise along with the postsurgery normalization of GH and IGF-I and improved insulin resistance. In contrast to surgical therapy, long-acting octreotide therapy persistently suppressed serum ghrelin levels. It remains to be determined whether altered circulating ghrelin concentrations could impact on body composition changes in acromegaly.

Effects of adrenalectomy on AGRP, POMC, NPY and CART gene expression in the basal hypothalamus of fed and fasted rats.

Glucocorticoids regulate body energy balance through both peripheral and central mechanisms. In order to understand the central mechanisms that mediate these effects of glucocorticoids we studied the effects of adrenalectomy (ADX) and food deprivation on the expression of four neuropeptide genes (measured by S1 nuclease protection assay) in the medial basal hypothalamus (MBH), which are known to regulate energy balance: pro-opiomelanocortin (POMC), agouti-related peptide (AGRP), neuropeptide Y (NPY), and cocaine and amphetamine regulated transcript (CART). Adult male rats were ADX or sham operated (SHAM), and studied 1-2 weeks later. In the first study effects of ADX and corticosterone replacement on POMC and AGRP expression were determined. ADX decreased POMC and AGRP gene expression in the MBH by 27 and 38%, respectively, compared to SHAM rats. Corticosterone treatment increased the expression of POMC by 87% and AGRP by 45% in ADX rats. The second study was designed to determine if glucocorticoids are necessary for the fasting induced changes in POMC, AGRP, NPY and CART in the MBH. ADX caused a 20-30% decrease in the expression of all four neuropeptide genes in the MBH. As expected, fasting suppressed POMC and CART expression and increased AGRP and NPY expression. The fasting-induced increases in AGRP and NPY persisted after ADX but no further significant decreases in POMC or CART were noted after fasting in ADX rats. Plasma leptin and insulin declined significantly after ADX and increased with corticosterone replacement; both leptin and insulin declined further in fasted, ADX animals. In conclusion, ADX decreases both anorexigenic, POMC and CART, and orexigenic, AGRP and NPY, neuropeptide gene expression in the MBH. AGRP and NPY decrease after ADX despite the fall in plasma leptin and insulin concentrations which in other situations would increase these neuropeptides. Furthermore, glucocorticoids are not required for fasting-induced upregulation of AGRP and NPY expression.