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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 7 3177-3183
Copyright © 2003 by The Endocrine Society

Ghrelin and Adipose Tissue Regulatory Peptides: Effect of Gastric Bypass Surgery in Obese Humans

Camilla Holdstock, Britt Edén Engström, Margareta Öhrvall, Lars Lind, Magnus Sundbom and F. Anders Karlsson

Departments of Medical Sciences/Internal Medicine (C.H., B.E.E., L.L., F.A.K.), Public Health and Caring Sciences/Geriatrics (M.O.), and Surgery (M.S.), Uppsala University Hospital, S-751 85 Uppsala, Sweden

Address all correspondence and requests for reprints to: Anders Karlsson, M.D., Ph.D., Department of Medical Sciences, Section of Medicine, University Hospital, S-751 85 Uppsala, Sweden. E-mail: anders.karlsson{at}medsci.uu.se.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Presently surgery is the most effective way to obtain a controlled weight reduction in morbidly obese patients. Roux-en-Y gastric bypass (RYGBP) surgery is effective and used worldwide, but the exact mechanism of action is unknown. The effect of RYGBP on ghrelin, insulin, adiponectin, and leptin levels was investigated in 66 obese subjects; mean weight 127 kg (range, 96–195 kg) and mean body mass index (BMI) 45 kg/m2 (range, 33–64) before and after surgery. Ghrelin levels were also compared in 10 nonoperated and 10 operated obese, BMI-matched women. RYGBP resulted in 22% and 30% weight loss at 6 and 12 months, respectively. Ghrelin increased by 44% and 62% and adiponectin by 36% and 98%, but insulin declined by 57% and 62% and leptin by 60% and 64%. The changes were all related to the reduction in BMI. In addition, ghrelin and insulin were inversely correlated at all time points as were changes of the peptides at 12 months (F = 4.9, P = 0.031), independent of the change in BMI. No evidence for RYGBP surgery per se having an effect on ghrelin levels, independent of weight loss, was obtained. The profound changes in the regulatory peptides are likely to reflect the new state of energy balance achieved. A close inverse association between ghrelin and insulin was observed, supporting an important role for ghrelin in glucose homeostasis.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
OBESITY IS A HYPERCALORIC state associated with an increased risk of developing type 2 diabetes and cardiovascular diseases (1). Treatment of morbid obesity [body mass index (BMI) >=40 kg/m2] with Roux-en-Y gastric bypass (RYGBP) surgery causes a marked reduction in adipose tissue mass and reduces morbidity (1). The operation decreases food intake (2), hastens early satiety (3), and causes malabsorption of dietary nutrients leading to a new state of negative energy balance (4). Recently it has become apparent that adipose tissue is not only a supply of calories acted upon by insulin and ghrelin (5) but also a producer of regulatory peptides, e.g. leptin and adiponectin, that influence metabolism (6).

Ghrelin, an endogenous ligand for the GH secretagogue receptor, was first identified in rat gastric mucosa (7) and has been localized specifically to A cells in the fundal oxyntic glands (8). It has also been detected in the gastrointestinal mucosa (9); a new pancreatic islet cell type (10); the hypothalamic nuclei (7), kidneys (11) and pituitary gland (12). Central and peripheral administration of ghrelin into rats has been found to increase body mass and adiposity by stimulating food intake and reducing fat utilization (5). An increase in appetite and food intake has also been observed after a ghrelin infusion into humans (13). Preprandially ghrelin levels rise in healthy humans and fall postprandially within 1 h (14), suggesting that it plays a role in meal initiation as a hunger signal (15, 16). The mechanism by which feeding decreases the ghrelin level (17, 18) has not yet been identified. Conflicting reports regarding an effect of insulin on the regulation of ghrelin have appeared. For example, parenteral administration of insulin and glucose did not suppress serum ghrelin, suggesting that the suppressive effect of food intake or oral glucose on serum ghrelin is unlikely mediated by changes of plasma insulin or glucose (19). More recently insulin infusion into humans via a euglycemic clamp resulted in a dramatic decrease in plasma ghrelin, which returned to basal levels after withdrawal of the infusion (20). In obesity, ghrelin is suppressed (21, 22) and may serve as a counterregulatory mechanism to limit the development of dietary-induced adiposity when a high-calorie diet is consumed in rats (23). Following dietary weight loss, increased ghrelin levels have been described (24, 25). Cummings et al. (24) recently reported the remarkable finding of a group of five surgical patients having a 72% lower ghrelin level, no meal-related oscillations, and no diurnal secretory pattern, compared with matched obese controls.

Adipose tissue is the source of circulating leptin and adiponectin. In obesity, leptin levels are elevated, mainly because of an increase in sc adipose tissue mass (26, 27). Administration of leptin into obese diabetic rodents, with reduced or absent leptin production, ameliorates impaired glucose tolerance via an increase in energy expenditure, fat depletion, and weight loss (28). In humans, adiponectin levels are low in conditions associated with insulin resistance, such as lipodystrophy (29) and obesity (30, 31), and an inverse relationship between adiponectin and insulin has been observed (30, 32). The impact of BMI or body fat on adiponectin levels seems more complex. Adiponectin has been suggested to improve insulin resistance by inhibiting gluconeogenesis (31) by interfering with TNF{alpha} production (33) and increasing fatty acid oxidation (34). In in vivo insulin-resistant models, replenishment of adiponectin in deficient states has been shown to improve insulin sensitivity (35, 36).

In the present study, we examined adipose tissue regulatory peptides in patients with marked obesity undergoing RYGBP. The interplay among the peptides basally and at 6 and 12 months postoperatively, as well as the changes in the variables induced by surgery, were determined. Furthermore, ghrelin levels in BMI-matched, nonsurgical and surgical patients were investigated in light of the recent report claiming that surgical patients have lower levels than obese-matched controls (24).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Potential subjects were recruited from the obesity program register at Samariterhemmet Hospital in Uppsala, Sweden. Their written informed consent was obtained. The study group consisted of 66 obese patients: 12 men and 54 women with a mean age of 39 yr (range, 24–50), mean weight of 127 kg (range, 96–195), and mean BMI of 45 kg/m2 (range, 33–64). All patients had previous attempts at weight loss. Some patients had also undergone prior operations; three had adjustable gastric banding and five had vertical banded gastroplasty. Two of the patients were on medical treatment for type 2 diabetes, one received metformin, and the other glipizide and insulin.

The patients underwent RYGBP at the Department of Surgery, University Hospital, Uppsala. RYGBP is both a restrictive and malnutritive procedure excluding the stomach and duodenum from the passage of food. A small gastric pouch (15 ml) is created along the lesser curvature that is totally separated from the main stomach by cutting linear staplers. The small bowel is divided 30 cm distal to the ligament of Treitz and a 50-cm-long Roux limb is connected to the small gastric pouch directly below the esophagus. The small bowel continuity is maintained by an enteroenterostomy. This creates the Y-shaped junction at which the ingested food via the Roux limb and the gastric acid and bile is mixed (37) (Fig. 1Go). At preoperative assessment, blood was taken after an overnight fast and body height and weight measured to determine BMI. The blood was permitted to clot for 30–60 min at room temperature before separation of serum and storage at -70 C until analysis. At 6- and 12-month postoperative consultations, these same procedures were performed. Sera were analyzed for levels of ghrelin, adiponectin, insulin, leptin, glucose, and lipids.



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  		FIG. 1. Principle of RYGBP. The main part of the stomach and duodenum is bypassed, and the ingested food passes directly into the small bowel. The gastric acid and bile enter the jejunum at the Y-shaped junction (arrow) distal to the ligament of Treitz.

 
Human serum ghrelin was measured using a commercial RIA (Phoenix Pharmaceuticals, Inc., Belmont, CA). It employs 125I-labeled bioactive ghrelin as a tracer and a polyclonal antibody raised in rabbits against the full-length, octanoylated human ghrelin. Intraassay and interassay coefficients of variance were 5.3% and 13.6%, respectively (38). The ghrelin values from all three serum samples (each in duplicates) from each individual were analyzed in the same assay run. Adiponectin serum levels were measured using the human adiponectin RIA (Linco Research, Inc., St. Charles, MO), which uses 125I-labeled murine adiponectin and a multispecies adiponectin rabbit antiserum. The assay’s sensitivity limit was 1 ng/ml and the intra- and interassay coefficients of variation 6.1% and 9.3%, respectively. Leptin was tested with a RIA kit (Linco Research, Inc.) that employed a rabbit antiserum against human leptin and 125I-labeled human leptin. The assay’s sensitivity limit was 0.5 ng/ml and the intra- and interassay coefficients of variation 6.2% and 8.3%, respectively. Fasting plasma glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TGs), and free fatty acids (FFAs) were measured with routine clinical chemistry laboratory techniques and insulin with an AutoDELFIA automatic immunoassay system (Wallac, Inc., Oy, Turku, Finland).

Means and SDs were calculated for weight loss changes, BMI, and the blood test variables. Logarithmic transformations for adiponectin, glucose, and TGs were performed to obtain normal distributions. A statistic computer package (Statview 5 for Windows, SAS Institute Inc., Cary, NC) was employed to carry out ANOVAs for all variables, simple regression analyses to determine univariate relationships, and forward stepwise regression analyses to explore interrelations between variables. A subgroup comparison was made, using the unpaired t test, for BMI-matched surgical and nonsurgical patients to assess any difference in ghrelin level because of the operative procedure. Statistical significance was taken at P less than 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Before surgery, the subjects were markedly obese, with the men weighing more than the women, mean 145 kg (range, 107–195) vs. 123 kg (range, 96–190). BMIs did not differ because the men were taller. RYGBP was followed by significant changes at 6 and 12 months in body weight, BMI, and circulating levels of total cholesterol, LDL cholesterol, TGs, glucose, ghrelin, insulin, adiponectin, and leptin (Table 1Go). HDL cholesterol and FFAs had changed significantly at 12 months. At 6 months, mean body weight was 99 kg (range, 69–159) and BMI 35 kg/m2 (range, 25–50), and at 12 months the mean weight was 89 kg (range, 55–155) and BMI 32 kg/m2 (range, 21–46). Between 6 and 12 months, significant further changes occurred with respect to BMI, TGs, ghrelin, insulin, and adiponectin.


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  		TABLE 1. Patient characteristics (n = 66) before and 6 and 12 months after RYGBP surgery, and percentage change ({Delta}) in the variables at 6 and 12 months, compared with preoperative levels

 
Univariate regression analyses for BMI and the four regulatory peptides were performed at each time point examined and for percentage changes from baseline at 6 and 12 months (Table 2Go). At baseline, BMI was negatively correlated with ghrelin, but positive correlations were displayed with insulin and leptin (Fig. 2Go). BMI showed no preoperative correlation with adiponectin (Fig. 2Go). The changes in ghrelin, insulin, adiponectin, and leptin were all correlated to the change in BMI at 12 months (Fig. 3Go). Ghrelin levels were inversely correlated with insulin at baseline (Fig. 4AGo), and 6 and 12 months, as were the changes of the peptides at 12 months. At every time point, positive correlations were found between insulin and BMI and leptin and BMI. Adiponectin was inversely correlated to BMI as percentage change at 12 months. Neither insulin nor adiponectin was related to leptin at baseline, but the relationships (positive and negative, respectively) gained in strength at 12 months following surgery. The change in insulin and adiponectin were both related to the change in leptin at 12 months, indicating that these relationships were disclosed by the weight loss operation.


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  		TABLE 2. Correlation coefficients (r) and levels of significance in univariate analyses of the relationships between peptide hormones and BMI before and 6 and 12 months after GBP surgery, as well as between the percentage changes ({Delta}) of the variables at 6 and 12 months

 


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  		FIG. 2. Relationships between circulating levels of ghrelin (A), insulin (B), adiponectin (C), leptin (D), and BMI, determined in 66 obese patients before RYGBP surgery.

 


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  		FIG. 3. Relationships between changes in serum levels ghrelin (A), insulin (B), adiponectin (C), leptin (D), and BMI in 66 subjects 12 months after RYGBP surgery.

 


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  		FIG. 4. Relationships between ghrelin and insulin at baseline (A) and the changes in ghrelin and insulin 12 months after RYGBP (B).

 
Stepwise regression analysis showed that the change in insulin significantly predicted the change in ghrelin at 12 months (F = 4.9, P = 0.031), independent of the change in BMI, suggesting a close connection between these peptides. Further stepwise regression analysis showed that leptin was related to BMI at all time points, independently of the other regulatory peptides.

To assess the effect of the RYGBP surgery per se on the circulating levels of ghrelin, the levels in a group of 10 operated women were compared with the ghrelin levels of another 10 women who, before surgery, had a BMI similar to the operated group. No difference in ghrelin was detected (Table 3Go).


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  		TABLE 3. Ghrelin, insulin, and glucose levels (mean ± SD) in operated and nonoperated obese women, matched for BMI

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, RYGBP surgery caused marked changes in body weight, markers of the metabolic syndrome, and regulators of adipose tissue metabolism; increases in ghrelin and adiponectin; and decreases in insulin and leptin. The increase in ghrelin was related to the reduction in BMI achieved, in support of earlier reports on ghrelin following dietary weight loss (24, 25). A consistent inverse relationship between ghrelin and insulin levels was observed at all time points examined, including the percentage changes 12 months after surgery. Such a negative relationship between ghrelin and insulin is suggested by previous findings of low levels of ghrelin in obesity (21, 22), high levels in anorexia (22, 39), and ghrelin changes opposite to insulin following feeding (14). An interaction between ghrelin and insulin is also supported by a study of insulin infusion in humans, which caused a decrease in ghrelin (20) in eu-, hypo-, and hyperglycemic conditions (40). The effect occurred with a delay, i.e. insulin did not appear to inhibit the ghrelin-secreting cells directly. Similarly, in an opposite experiment when ghrelin was administered iv into healthy young humans, it took 30 min to achieve a significant reduction in insulin levels (16). Collectively, the present findings, observations on ghrelin and insulin levels in relation to food intake (14), and infusion experiment (20) indicate a close physiological relationship between the two hormones.

Ghrelin levels in rats have been reported to be 80% lower after fundectomy and gastrectomy (8), and gastrectomy patients experienced a 65% decrease (41), demonstrating the stomach as the major source of circulating ghrelin. A recent study reported that ghrelin levels were lower in five gastric bypass surgery patients than in five BMI-matched obese subjects, who had completed a 6-month dietary weight loss program (24). The low levels of ghrelin in the five RYGBP patients made the authors suggest that the disconnection of the stomach had led to hypoghrelinemia and speculate that the hypoghrelinemia would lessen appetite and improve the outcome of RYGBP. Our data are in conflict with this report because we found similar ghrelin levels in two BMI-matched groups of women, nonoperated and operated. Furthermore, we observed in the material of 66 patients that the ghrelin levels had increased after surgery, compared with preoperative levels. In the previous study (24), ghrelin levels were not examined before surgical weight loss. The present findings indicate that circulating ghrelin levels in RYGBP patients may continue to be primarily produced by the disconnected stomach and the control of the ghrelin-producing endocrine cells is unaltered. We have observed that serum levels of pepsinogen, a secretory product of gastric chief and mucous head cells, on the other hand, are lowered in subjects treated with RYGBP (Sundbom, M., E. Mardh, S. Mardh, M. Ohrvall, and S. Gustavsson, submitted for publication). Apparently, further detailed studies are needed to fully elucidate the effect of gastrointestinal surgery on circulating ghrelin levels and clarify the regulation of diurnal ghrelin secretion in patients treated with gastric bypass.

In the present study, the two adipocyte products, adiponectin and leptin, changed in opposite directions following RYGBP surgery. Circulating levels of adiponectin, in contrast to the levels of leptin, are not directly correlated to adipose tissue mass, as illustrated by low adiponectin levels in both lipodystrophy (29) and obese patients with type 2 diabetes (31). We found the changes in adiponectin and BMI inversely related at 12 months. Recently a similar correlation was observed in patients with type 2 diabetes (31) and obese surgical (gastric partition) patients, in whom changes in adiponectin and BMI were related in univariate but not in multivariate regression when adjusted for age, sex, and hip and waist circumference (30).

We found an inverse correlation between adiponectin and insulin 12 months after surgery, independent of BMI. A negative correlation was reported in biliopancreatic diversion (weight loss) surgery patients (42) and in a study of obese Caucasians and Pima Indians (32). The exact pathways depicting the interactions between adiponectin and insulin are largely unknown. Injection of adiponectin into animals had been found to decrease plasma glucose levels, by suppressing glucose production in the liver (35, 36, 43) and increasing fatty acid oxidation in muscle (34, 35). More recently a recent gene knockout study showed adiponectin-deficient mice to be insulin resistant (44), suggesting that adiponectin is involved in the regulation of glucose homeostasis in vivo. Interestingly, when combined with leptin at physiological doses, adiponectin appears to completely reverse insulin resistance in lipoatrophic mice (35).

Preoperatively adiponectin and leptin were not related, and following surgery, these hormones changed in different directions. The changes at 6 and 12 months were related, i.e. a negative association appeared as both hormones approached more normal ranges. An inverse correlation between adiponectin and leptin, independent of BMI, was also recently shown in normal-weight and obese women (6).

Leptin levels were highly correlated to BMI pre- and postoperatively, and the reduction in leptin was explained by the decrease in body mass. Leptin is a strong marker of adipose tissue mass as supported by earlier findings in different cohorts (26, 27), including gastric bypass patients with type 2 diabetes or impaired or normal glucose tolerance (45). An in vivo and in vitro study revealed that insulin may affect leptin in the long term by regulating ob gene expression and leptin production indirectly through trophic effects on adipocytes (46), which could contribute to the association of adiposity with insulinemia. Leptin showed only a weak univariate association with insulin at 12 months in our study. A positive correlation has also been observed in biliopancreatic diversion surgery patients and overweight controls preoperatively (42) as well as in patients with type 2 diabetes (31).

In conclusion, this study showed that weight loss induced by RYGBP is associated with marked changes in adipose tissue regulatory peptides, increases in ghrelin and adiponectin, and reductions in insulin and leptin. These changes were all related to changes in BMI and reflect the new state of energy balance achieved. No evidence for RYGBP surgery per se having an effect on ghrelin levels was obtained. A lowered caloric intake will directly affect ghrelin and insulin secretion and in the long term reduce leptin and increase adiponectin secretion. Overall, the metabolic resetting plays an important role in reducing the risk of diabetes and cardiovascular disease associated with morbid obesity.


   Acknowledgments
 
We thank Margareta Ericson for expert laboratory assistance.


   Footnotes
 
This work was supported by research grants from the Medical Research Council, Swedish Diabetes Foundation, Children’s Diabetes Fund, and Family Ernfors Fund.

Abbreviations: BMI, Body mass index; FFA, free fatty acid; HDL, high-density lipoprotein; LDL, low-density lipoprotein; RYGBP, Roux-en-Y gastric bypass; TG, triglyceride.

Received November 6, 2002.

Accepted January 13, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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