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Early Appearance of the Metabolic Syndrome in Socially Reared Bonnet Macaques

Departments of Surgery (D.K., B.C.G., J.G.K.), Psychiatry (E.L.P.S., J.D.C., L.A.R.), and Medicine (M.B.), and Primate Behavior Laboratory, State University of New York Downstate Medical Center, Brooklyn, New York 11203

Address all correspondence and requests for reprints to: Dr. John G. Kral, Department of Surgery, Box 40, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, New York 11203. E-mail: jkral{at}downstate.edu.

	Abstract

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Among 250 laboratory-born bonnet macaques living in social groups and maintained on commercial monkey chow, we measured weight, crown-rump length, sagittal abdominal diameter (SAD), and fasting serum insulin, glucose, triglycerides, high-density lipoproteins, low-density lipoproteins, and total cholesterol. Body mass index (BMI = weight/crown-rump length²), and insulin resistance determined by the insulin/glucose ratio (IGR) and homeostasis model assessment, were measured. We defined the metabolic syndrome using a composite score based on morphometry, insulin resistance, and serum lipid levels, analogous to clinical criteria. Elevated BMI was associated with significantly greater SAD, insulin, IGR, homeostasis model assessment, and triglycerides. Among 120 adult monkeys aged 5–17 yr, males (n = 48) had higher BMI, SAD, insulin, and IGR levels than females, independent of age. Sixteen of 113 adult monkeys and five of 36 peripubertal subjects, aged 3–4 yr (14%), met our criteria for the metabolic syndrome, as did four of 12 monkeys, aged 20–28 yr. Markers of the metabolic syndrome are present by 3–4 yr of age in our colony and are observed across the life span in the absence of conventional obesifying interventions. Socially reared and housed bonnet macaques may provide a useful model for studying the pathogenesis, prevention, and treatment of the metabolic syndrome.

	Introduction

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THE METABOLIC SYNDROME denotes a clustering of four prominent components: visceral obesity, insulin resistance (IR), dyslipidemia, and hypertension (1). Each component generally reflects progressive pathophysiological processes, the developmental origins of which are often obscure. Recently, the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) defined the metabolic syndrome using various clinical markers of the metabolic derangements that are characteristic of the syndrome (2). We evaluated similar criteria in our colony of bonnet macaques, which has an obesity rate of approximately 10–15% (3), to identify an analogous syndrome relevant for studying the development of the metabolic syndrome in humans.

Various nonhuman primate models have been used to study the relationships between obesity and metabolic disease. Early models relied upon obesifying interventions such as hypothalamic lesions (4, 5, 6) and dietary manipulations (7, 8, 9, 10, 11, 12, 13, 14). Other models used conditions of restricted physical activity due to single housing (15, 16, 17, 18). In more naturalistic models of obesity, such as the colony of free-ranging rhesus macaques on the island of Cayo Santiago, a 7% incidence of obesity was found, with only marginal associations between measures of adiposity and various endocrine markers of the metabolic syndrome (19). More recently, free-ranging, wild, adult baboons with access to calorically dense human refuse were shown to have key markers of the metabolic syndrome (20, 21).

To our knowledge, no primate species, socially reared and maintained under laboratory-controlled dietary and environmental conditions, has been used to study spontaneously emerging components of the metabolic syndrome in both males and females from infancy through old age. The aim of the present study was to detect the metabolic syndrome in a nonhuman primate model with social living conditions, using clinical criteria relevant to human pathology, without confounding factors, such as brain lesions, dietary manipulation, or single housing.

	Subjects and Methods

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Subjects

The Downstate Primate Behavior Laboratory was established in 1961 and currently consists of 250 bonnet macaques (Macaca radiata), born and maternally reared in a seminaturalistic, temperature- and humidity-controlled environment with a 12-h light, 12-h dark cycle. Virtually all monkeys are descendents of an original founding group of approximately 40 animals native to southern India. Monkeys are reared and housed in social groups of 6–12, in multilevel pens with a volume of approximately 55–75 m³, although a number of adult males, and on rare occasions females, spend varying periods living either in individual cages or in smaller groups for treatment or husbandry purposes.

In our laboratory, bonnet monkeys begin eating solids at approximately 2 months of age, with weaning beginning at 7 months and virtually complete by 10 months. In most instances, monkeys are separated from their mothers and socially housed with peers at the end of the first year of life to allow rebreeding of the mothers. Males and females reach puberty at approximately 4–4.5 and 3–3.5 yr, respectively; full maturity is attained at 7–8 yr of age. The life span of bonnet macaques in our colony is approximately 25–30 yr. Water is always available ad libitum, as is a commercial laboratory diet (Monkey Diet 5038, LabDiet, Richmond, IN; 4 kcal/g; 69% carbohydrate, 18% protein, and 13% fat), occasionally supplemented with fresh fruit and/or vegetables, provided once in the midafternoon. In this study, monkeys taking part in rearing experiments were excluded. Thus, a total of 120 normatively reared adult subjects (48 males and 72 females, aged 5–17 yr) comprised the primary sample. Four male and eight female monkeys, aged 20–28 yr, and a peripubertal cohort of 21 males and 22 females, aged 3–4 yr, were also evaluated. All monkeys were treated humanely, under careful veterinary supervision and care in accordance with the State University of New York Downstate Medical Center institutional animal care and use committee. The Downstate Primate Behavior Laboratory is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International.

Blood assays

Venous blood was drawn in plain nonheparinized tubes between 0800–1100 h after an overnight fast. On the day before blood sampling, food was withdrawn at 1600 h, and water remained available ad libitum. Using a routine procedure, monkeys were individually captured in carrying cages, placed in single-animal squeeze cages, and anesthetized with ketamine (10–15 mg/kg). Complete anesthesia was achieved for the duration of the procedure, with full recovery obtained within 3–4 h. Blood from antecubital or femoral veins was immediately placed on ice, centrifuged for serum separation, and stored at –80 C within 1 h. Samples were analyzed in one batch by routine laboratory procedures at the University Hospital of Brooklyn Clinical Chemistry Laboratory. Serum glucose was measured by glucose oxidase; serum triglycerides (TG) were determined enzymatically using Ektachem Clinical Chemistry Slide; high density lipoprotein (HDL), low density lipoprotein (LDL), and total cholesterol were measured using the Vitros Chemistry Magnetic Reagent (Clinical Diagnostics Operator’s Manual 1995, Johnson & Johnson, New Brunswick, NJ); and serum insulin was determined by immunoassay (Beckman Access Immunoassay System, Beckman Coulter, Fullerton, CA). The intraassay coefficients of variation for insulin were 2.0% and 2.1% at 12.9 and 99.3 µU/ml, respectively. The insulin/glucose ratio (IGR) and the homeostasis model assessment (HOMA) (22) were used as measures of IR.

Morphometry

During anesthesia for blood sampling, weight, sagittal abdominal diameter (SAD), and crown-rump length (CRL) were measured. SAD is the distance from the surface of the examination table to the top of the abdomen at its highest point with the animal lying flat on its back. CRL is the length from the vertex of the head to the base of the tail. Measurements were performed by a team of three trained investigators to ensure consistency and reliability. A modified body mass index (BMI) was calculated as mass in kilograms divided by CRL in meters squared (23).

Data treatment and definition of the metabolic syndrome

Monkeys were grouped into tertiles in three categories: 1) morphometry (BMI and SAD), 2) IR (insulin and HOMA), and 3) lipid levels (TG and HDL). Although hypertension is an integral part of the human metabolic syndrome, the use of anesthesia in the current study precluded meaningful analysis of blood pressure. In analogy with the NCEP ATP III clinical criteria (2), we created a metabolic syndrome composite score based on tertile assignments.

Due to the sexual dimorphism in adults of this species (24), male and female morphometric data (BMI and SAD) were analyzed separately when generating tertiles for the metabolic syndrome composite score. There were no significant sex differences in age-adjusted mean lipid levels (TG, HDL, LDL, or total cholesterol). Thus, unlike the NCEP ATP III, we pooled male and female data to generate the lipid tertiles. One point was assigned for each appearance of a subject in the third (highest) tertile of BMI, SAD, insulin, HOMA, or TG or in the first (lowest) tertile of HDL. Metabolic syndrome was defined as a score of 4 or more points, with at least 1 point from each of the three above-named diagnostic categories. Monkeys with three or more missing values were excluded from this analysis. Inclusion criteria for identifying the metabolic syndrome in the older subsample were based on the actual numerical values corresponding to the various cut-off levels of the primary sample tertiles. Older monkeys with values of BMI, SAD, insulin, HOMA, and TG that were higher than these numerical values (lower for HDL) were assigned points accordingly. When analyzing data from the 3- to 4-yr-old monkeys, we noted early age-related morphometric and metabolic differences compared with the 5- to 6-yr-old and 7- to 8-yr-old subjects included in the adult population. To account for these age-related effects separate tertile groupings were generated for the 3- to 4-yr-old subsample; presence of the metabolic syndrome was then similarly scored across the diagnostic categories.

Statistical analysis

The mean ± SE are reported throughout. Missing data led to exclusion on a measure by measure basis. ² analyses were used for determining differences in sex distribution within groups. Simple between-group comparisons used two-tailed t tests or analysis of covariance covaried for age, sex, and/or BMI, as indicated. Post hoc paired comparisons were calculated using the Bonferroni correction for multiple comparisons. Partial correlations were controlled for age. All statistical analyses were made using SPSS for Windows (release 10.0.1, SPSS, Inc., Chicago, IL), with P 0.05 as the criterion for significance.

	Results

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Primary sample

Of the 120 adult bonnet macaques (48 males and 72 females) in the primary sample, aged 5–17 yr, females were significantly older than males (10.1 ± 0.43 vs. 8.5 ± 0.39 yr; P = 0.009). After adjusting for age differences, the two sexes differed significantly in weight, CRL, BMI, and SAD, reflecting sexual dimorphism (Table 1). Sex differences in fasting insulin, IGR, and HOMA (higher in males) were no longer significant after covarying for age and BMI.

Nine males and seven females (14.2% of the primary sample), aged 6–16 yr, met the criteria for the nonhuman primate metabolic syndrome. The seven females were older (P = 0.04; Table 3), and after covarying for age, the nine males weighed more (P = 0.001). Among indexes of insulin resistance, insulin, IGR, and HOMA showed strong positive correlations across all ages (insulin-IGR, P < 0.001; insulin-HOMA, P < 0.001; IGR-HOMA, P < 0.001). Consequently, using any two of these three parameters in generating tertiles for the metabolic syndrome score, the same 16 monkeys were identified.

Twelve older monkeys (four males and eight females), aged 20–28 yr, were also examined. The males were significantly heavier than the older females (12.1 ± 0.59 vs. 6.1 ± 0.48 kg; P < 0.001) and had greater BMI (49.4 ± 1.71 vs. 30.8 ± 2.73 kg/m²; P = 0.001) and SAD (16.7 ± 1.7 vs. 10.6 ± 0.62 cm; P = 0.031). Compared with the 48 male adults of the primary sample, the four older males weighed more (12.1 ± 0.59 vs. 8.4 ± 0.33 kg; P = 0.003) and had higher BMI (49.4 ± 1.71 vs. 34.2 ± 1.2 kg/m²; P = 0.001), SAD (16.7 ± 1.7 vs. 12.1 ± 0.33 cm; P = 0.001), HOMA (218.6 ± 112.21 vs. 83.4 ± 13.98; P = 0.022), and TG (85.8 ± 7.51vs. 53.1 ± 3.66 mg/dl; P = 0.011). The eight older females had lower TG levels than the 72 females in the primary sample (64.2 ± 3.53 vs. 84.7 ± 3.34 mg/dl; P = 0.055), with no differences in the other parameters. Four (three males and one female) of the 12 older monkeys (33.3%) met criteria for the metabolic syndrome.

Younger subjects

Forty-three peripubertal subjects (21 males and 22 females), aged 3–4 yr, were studied. In this group, there were more male 4-yr-olds (76%; P = 0.029) and fewer male 3-yr-olds (31%; P = 0.05). Sex differences in BMI (higher in males) were not statistically significant. After covarying for age and BMI, the females had significantly higher mean TG levels (42.8 ± 1.7 vs. 35.5 ± 1.75 mg/dl; P = 0.013) and lower fasting blood glucose levels (75.5 ± 1.88 vs. 83.4 ± 1.83 mg/dl; P = 0.005). Using separate tertile groupings for this sample and applying identical criteria to those set in the primary sample, five of 36 (two males and three females) eligible subjects (13.9%) had the metabolic syndrome. Compared with the rest of the eligible subjects, these five monkeys were no different in age, yet had significantly greater BMI (P = 0.013), insulin (P = 0.008), IGR (P = 0.016), HOMA (P = 0.005), and TG (P < 0.001) when covaried for age (Fig. 1). Similar to the adult population, strong positive correlations among insulin, IGR, and HOMA resulted in identification of the same five subjects using any two of these three indexes as metabolic syndrome criteria. Three of the five monkeys had IGR and HOMA levels that would have placed them in the third respective tertiles in the adult population. Among monkeys with the metabolic syndrome, after covarying for age, adults in the primary sample had significantly greater BMI (37.71 ± 1.44 vs. 27.22 ± 3.15 kg/m²; P = 0.014) and SAD (13.2 ± 0.41 vs. 8.46 ± 0.91 cm; P < 0.001) than the juvenile subjects, but showed no difference in means of insulin, glucose, IGR, HOMA, TG, HDL, LDL, or cholesterol.

View larger version (18K): [in this window] [in a new window]   FIG. 1. Morphometric and metabolic parameters in 36 juvenile monkeys (aged 3–4 yr) with and without the metabolic syndrome. Values are the age-adjusted mean ± SE. Metabolic syndrome (MS), BMI, SAD, insulin (Ins), glucose (Glu), HOMA, TG, and HDL were measured. The IGR means are not shown. *, P < 0.05; **, P < 0.01; ***, P < 0.001 (by analysis of covariance, with age as the covariate).

	Discussion

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Although this cross-sectional study does not allow mechanistic analyses, it does provide a perspective on the role of sedentariness in the pathophysiology of metabolic obesity. Hansen’s studies of adult male rhesus macaques, individually housed over several years, yet provided with appropriate social housing intermittently, demonstrate the chronological progression of visceral obesity and IR (18). The increased adiposity and decreased insulin action with aging have generally been attributed to a decrease in physical activity. The presence of the metabolic syndrome in our highly active peripubertal cohort, which is very similar to the rate among our significantly older, more sedentary adult monkeys, implies the existence of factors other than reduced physical activity that may be of greater importance for the development of the metabolic syndrome.

Our finding of elevated serum TG in peripubertal females compared with males after correction for age and BMI, and a similar prevalence of the metabolic syndrome in peripubertal females and in older, more sexually mature, young males may reflect earlier sexual maturation in the females, which we did not investigate in this report. To our knowledge, no other nonhuman primate model has been used to study adolescent obesity. Thus, it is not known whether the normal puberty-related IR seen in humans (29, 30) may be present in our monkeys. Several indexes have been used to measure IR in large population studies (31). Recently, insulin, IGR, and HOMA were used to measure IR in baboons and were correlated inversely with the adipocyte-derived peptide adiponectin level (32). In our study we showed strong positive correlations among insulin, IGR, and HOMA and found consistent results when using any two indexes to assess IR. Although these measures are adequate for this colony-wide survey, hyperinsulinemic euglycemic clamps in our juvenile cohort may help elucidate the possible mechanistic origins of IR.

One caveat in describing the obesity in our colony as spontaneous is our provision of ad libitum food, as is routine for most laboratory animals. In humans, readily available food coupled with a decreased exertional cost of procurement in industrialized societies since the 19th century have fueled the epidemic of obesity and its attendant comorbidities (33). In the case of other nonhuman primate models of obesity, we speculate that under ad libitum conditions, single housing is more likely to contribute to increased food intake than is social housing in large pens, partly from inactivity in the sedentary range (34).

Recent advances in the genetic characterization of nonhuman primates (35) demonstrate the potential for identifying obesity genes in our macaques. Much like modern-day humans carrying genes adapted for intermittent periods of feast and famine displaced into an environment of ample caloric supply (36), our macaques are genetic transplants from the wild into the laboratory. This inbred colony has evolved over 42 yr from a founder group native to southern India, with limited subsequent additions. The relatively isolated genetic pool of our monkeys may provide insights into the expression of candidate susceptibility genes underlying their obese phenotype. Furthermore, we have the ability to perform challenge studies for the detection of potential mechanisms of the emergence of phenotypic obesity.

In summary, we demonstrate the presence of the metabolic syndrome in our colony of socially reared bonnet macaques, with juvenile onset, persisting with increasing prevalence into senescence, without brain lesions, dietary manipulation, or single housing. Using relevant clinical criteria, we found distinct similarities with human obesity, providing a useful model to study the prevention and treatment of the metabolic syndrome.

	Acknowledgments

 
We thank Shirn Baptiste, Mohammed Arif, M.D., and Douglas Rosenblum for their contributions to this study.

	Footnotes

 
This work was supported by a grant from the Smart Family Foundation.

First Published Online October 14, 2004

Abbreviations: BMI, Body mass index; CRL, crown-rump length; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; IGR, insulin/glucose ratio; IR, insulin resistance; LDL, low-density lipoprotein; SAD, sagittal abdominal diameter; TG, triglyceride.

Received March 5, 2004.

Accepted September 21, 2004.

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This Article Abstract Full Text (PDF) All Versions of this Article: 90/1/404    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kaufman, D. Articles by Rosenblum, L. A. Search for Related Content PubMed PubMed Citation Articles by Kaufman, D. Articles by Rosenblum, L. A. Related Collections Diabetes and Insulin