Peptide YY (PYY) levels and bone mineral density (BMD) in women with anorexia nervosa

doi:10.1016/j.bone.2008.03.007

Bone

Volume 43, Issue 1, July 2008, Pages 135-139

https://doi.org/10.1016/j.bone.2008.03.007 Get rights and content

Abstract

Introduction

Anorexia nervosa (AN) is a psychiatric illness that results in significant bone loss. Studies examining the neuroendocrine dysregulation that occurs in AN may increase understanding of endocrine systems that regulate bone mass. Peptide YY (PYY) is an anorexigenic peptide derived primarily from the intestine, with actions mediated via activation of Y receptors. We have previously shown that PYY levels are elevated in adolescents with AN. Y2 receptor knockout mice have increased bone mineral density (BMD) and thus PYY may play a role in regulating bone mass. We hypothesized that PYY levels would be inversely associated with BMD in women with AN.

Methods

This was a cross-sectional study performed in a General Clinical Research Center of 12 adult women with AN, (mean ± SEM) mean age 30.9 ± 1.8 years, BMI 17.1 ± 0.4 kg/m², and % ideal body weight 77.5 ± 1.7%. PYY concentrations were measured hourly from 20:00 h to 08:00 h. BMD was measured using dual X-ray absorptiometry (DXA).

Results

In women with AN, mean overnight PYY levels strongly inversely correlated with BMD at the PA spine (r = − 0.77, p = 0.003), lateral spine (r = − 0.82, p = 0.002), total hip (r = − 0.75, p = 0.005), femoral neck (r = − 0.72, p = 0.009), total radius (r = − 0.72, p = 0.009) and 1/3 distal radius (r = − 0.81, p = 0.002). Body mass index was inversely correlated with PYY level (r = − 0.64, p = 0.03). Multivariate stepwise regression analysis was performed to determine the contribution of age, duration of AN, BMI, fat-free mass, and PYY to BMD. For PA and lateral spine, PYY was the primary determinant of BMD, accounting for 59% and 67% of the variability, respectively. Fat-free mass and duration of anorexia nervosa were the primary determinants of BMD at other skeletal sites.

Conclusions

In women with anorexia nervosa, an elevated PYY level is strongly associated with diminished BMD, particularly at the spine. Therefore further investigation of the hypothesis that PYY may contribute to the prevalent bone pathology in this disorder is merited.

Introduction

Recent data suggest that the hypothalamus plays a direct role in the regulation of BMD [1], [2], [3], [4], [5]. The discovery of the molecular circuitry that links leptin signaling to alterations in bone mineral density (BMD) initiated an active area of investigation [1]. It has been established that leptin receptors are expressed in high density on neuropeptide Y (NPY)-secreting neurons in the arcuate nucleus [6] and that suppression of NPY release by leptin mediates anorexigenic effects [7], [8], [9]. However, a decline in NPY does not appear to be the mechanism for leptin's negative effect on BMD, as intracerebroventricular infusion of NPY also has a deleterious impact on BMD [1]. These data have inspired studies, primarily via knockout mouse models, to examine the role of NPY neuron signaling in the regulation of BMD [3], [4].

NPY is a member of the neuropeptide Y family of molecules, which additionally includes peptide YY (PYY) and pancreatic polypeptide (PP). These peptides bind with differing affinities to receptors of the Y-receptor family (Y1, Y2, Y3, Y4, and Y5 in humans, plus Y6 in rodents) [10]. Whereas Y1 and Y5 receptors are believed to primarily mediate feeding behavior [11], [12], studies of Y2 and Y4 receptors suggest a role in controlling BMD [3], [4]. Y2 receptors are expressed on NPY-secreting neurons in the arcuate nucleus and are believed to act as auto-receptors to decrease the release of NPY [13], [14], [15]. Peptide YY (PYY) is a gut-derived hormone that is released from intestinal endocrine cells in response to food intake [16]. PYY circulates in two forms, PYY_1–36 and PYY_3–36, with PYY_3–36 predominating [17]. Whereas PYY_1–36 has affinity for Y1, Y2, and Y5 receptors, PYY_3–36 is selective for Y2 receptors [18], [19]. As Y2 receptor knockout mice demonstrate an increase in trabecular bone volume and BMD by increased formation via hypothalamic signaling [3], we hypothesized that an increase in Y2 signaling may lead to a decline in BMD and that Y-receptor ligands may impact bone dynamics in humans. Thus conditions that increase or are associated with elevated levels of PYY may lead to detrimental effects on BMD.

Anorexia nervosa (AN) is a disease of severe caloric restriction that is commonly associated with low BMD, such that almost one-third of adults have osteoporosis [21]. Therefore mechanisms leading to bone loss are important to identify. Several previous studies have suggested that females with anorexia nervosa have elevated PYY levels relative to normal weight or obese individuals [22], [23], [24], [25]. This is the first study to demonstrate a strong association between elevated PYY values and lower BMD in women with anorexia nervosa, suggesting a possible contribution of PYY to the severely low BMD found in this disorder. These data demonstrate an inverse correlation between body mass index and PYY values and suggest that further studies are needed to determine whether PYY has an independent deleterious effect on BMD.

Section snippets

Subjects

Twelve women with anorexia nervosa, as defined by DSM-IV criteria, were recruited for this study. Inclusion criteria were a weight less than 85% of ideal body weight as defined by the 1983 Metropolitan Life Insurance Tables, age 18 to 45 years old, normal TSH or free T4 levels, and BMD T-score < − 1.0. Women were excluded if they had conditions or were receiving medications known to affect bone in AN. All but one woman had previously used combination oral contraceptive pills, and two women were

Results

Twelve women with anorexia nervosa, as defined by DSM-IV criteria, were studied. Clinical characteristic data are presented in Table 1.

PYY levels were measured hourly beginning at 20:00 h and ending at 08:00 h. Hourly sampling enables an integrated measure of PYY levels overnight. A mean PYY value was calculated over the 12-hour sampling period for each subject. Mean PYY levels were inversely correlated with BMI (r = − 0.64, p = 0.03, n = 12) (Fig. 1) and fat-free mass (r = − 0.71, p = 0.01), but not fat

Discussion

Although the role of hypothalamically active hormones in regulating eating behaviors has received significant attention over the last decade, the dual function of these hormones in controlling BMD is a new area of investigation. Previous studies in mice have revealed that leptin signaling and Y receptor activation are involved in the central nervous system control of BMD [1]. Leptin has been proposed to activate the sympathetic nervous system and adrenergic activity, via β2 receptors, which in

Acknowledgments

We would like to thank the study subjects for their participation in this study. Additionally, we would like to thank the nursing, bionutrition, and laboratory staff of the Massachusetts General Hospital General Clinical Research Center and the Massachusetts Institute of Technology Clinical Research Center.

References (33)

P. Ducy et al.
Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass
Cell
(2000)
S. Takeda et al.
Leptin regulates bone formation via the sympathetic nervous system
Cell
(2002)
P.J. King et al.
Effect of a selective neuropeptide Y Y2 receptor antagonist, BIIE0246 on neuropeptide Y release
Eur J Pharmacol
(2000)
T.E. Adrian et al.
Human distribution and release of a putative new gut hormone, peptide YY
Gastroenterology
(1985)
D. Grandt et al.
Two molecular forms of peptide YY (PYY) are abundant in human blood: characterization of a radioimmunoassay recognizing PYY 1–36 and PYY 3–36
Regulatory Pept
(1994)
K.E. Wortley et al.
Peptide YY regulates bone turnover in rodents
Gastroenterology
(2007)
A.R. Frisancho et al.
Elbow breadth as a measure of frame size for US males and females
Am J Clin Nutr
(1983)
P.A. Baldock et al.
Hypothalamic Y2 receptors regulate bone formation
J Clin Invest
(2002)
A. Sainsbury et al.
Synergistic effects of Y2 and Y4 receptors on adiposity and bone mass revealed in double knockout mice
Mol Cell Biol
(2003)
F. Elefteriou et al.
Serum leptin level is a regulator of bone mass
Proc Natl Acad Sci U S A
(2004)

J.G. Mercer et al.

Coexpression of leptin receptor and preproneuropeptide Y mRNA in arcuate nucleus of mouse hypothalamus

J Neuroendocrinol

(1996)

T.W. Stephens et al.

The role of neuropeptide Y in the antiobesity action of the obese gene product

Nature

(1995)

M.W. Schwartz et al.

Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice

Diabetes

(1996)

J.C. Erickson et al.

Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y

Science

(1996)

M.C. Michel et al.

International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors

Pharmacol Rev

(1998)

D.J. Marsh et al.

Role of the Y5 neuropeptide Y receptor in feeding and obesity

Nat Med

(1998)

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^☆: Support: This work was supported in part by National Institutes of Health Grants R01-DK52625 and M01-RR-01066 National Center for Research Resources General Clinical Research Centers Program.

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Peptide YY (PYY) levels and bone mineral density (BMD) in women with anorexia nervosa☆

Abstract

Introduction

Methods

Results

Conclusions

Introduction

Section snippets

Subjects

Results

Discussion

Acknowledgments

Cell

Cell

Eur J Pharmacol

Gastroenterology

Regulatory Pept

Gastroenterology

Am J Clin Nutr

Hypothalamic Y2 receptors regulate bone formation

J Clin Invest

Synergistic effects of Y2 and Y4 receptors on adiposity and bone mass revealed in double knockout mice

Mol Cell Biol

Serum leptin level is a regulator of bone mass

Proc Natl Acad Sci U S A

Coexpression of leptin receptor and preproneuropeptide Y mRNA in arcuate nucleus of mouse hypothalamus

J Neuroendocrinol

The role of neuropeptide Y in the antiobesity action of the obese gene product

Nature

Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice

Diabetes

Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y

Science

International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors

Pharmacol Rev

Role of the Y5 neuropeptide Y receptor in feeding and obesity

Nat Med