Retrospective case–control study of hyperglycemia in group‐housed,mature female cynomolgus macaques (Macaca fascicularis)

Background Captive cynomolgus macaques are prone to obesity, increasing their risk for developing hyperglycemia and type 2 diabetes mellitus (T2DM). Social rank may be a contributing risk factor predisposing macaques to adverse health events. Methods Using retrospective health records from 259 animals, a matched case–control study was conducted to assess risk factors for developing hyperglycemia in group‐housed, adult females aged 10 or older. Univariable exact and conditional logistic regression models were used to analyze the data. Result The odds of developing hyperglycemia were significantly greater in animals with more frequent counts of injury. Similarly, subordinate animals had higher odds of developing hyperglycemia than affiliates. Conclusions Subordinate social status may increase the risk of hyperglycemia in mature female cynomolgus macaques. Opportunities for subordinates to alter feeding strategies are reduced in captivity. This may be associated with increased social stress around feeding, and for animals housed long‐term could predispose them to obesity and hyperglycemia.     

Sex hormones, insulin sensitivity, and diabetes mellitus

Sex differences and the role of gonadal hormones in modulating insulin sensitivity and glucose tolerance are of increasing interest and importance because of the increasing prevalence of type 2 diabetes mellitus and the metabolic abnormalities associated with aging. Body composition is closely associated with insulin sensitivity, and increased body fat, particularly in the visceral compartment, is a risk factor for developing type 2 diabetes mellitus. Sex differences in body composition and/or insulin sensitivity are evident in humans throughout the lifespan. Ovarian hormones influence insulin sensitivity across the menstrual cycle, during pregnancy, and in the menopausal transition. Similarly, estrogens and progestins used for contraception and hormone replacement therapy affect glucoregulation. Nonhuman primates and humans have similar life histories and reproductive characteristics. As a result, nonhuman primates provide a valuable model for investigating factors related to insulin sensitivity. Studies of nonhuman primates have contributed significantly to our understanding of sex differences and the influence of sex steroids in this context. This brief review surveys present knowledge of the sex differences in body composition, insulin sensitivity, and risk for development of type 2 diabetes mellitus derived from studies in humans and nonhuman primates. The influences of endogenous and exogenous gonadal steroids are emphasized.     

Causes of obesity in captive cynomolgus macaques: influence of body condition, social and management factors on behaviour around feeding

Similar to other primate species, captive cynomolgus macaques (Macaca fascicularis) are prone to becoming overweight. The relationship between body condition and feeding behaviour in group-housed animals has not been reported. This study evaluated the effect of daily feeding routines on behaviour patterns in cynomolgus macaques to determine whether overweight macaques displayed different behaviours and activity levels. In this prospective observational study, 16 macaques (m = 4, f = 12) from four separate troops (n = 4 per troop) were selected from a colony of 165 animals. Observational data were collected over six months during morning and afternoon feedings by scan sampling. Behaviours of interest included foraging, eating, aggressive and positive social interactions, inactivity and physical activities. Multivariable mixed logistic regression modelling was used for data analysis. Results indicated that overweight animals were more likely to be inactive, dominant animals had increased probabilities of eating compared with non-dominants, and aggressive behaviours were more likely to occur in the morning and before feeding, suggesting feeding anticipation. Positive social interaction before feeding was seen and may be a strategy used to avoid aggressive encounters around food resources. Individual animal caregivers had an unintentional impact on behaviour, as decreased eating and an increase in inactivity were noted when certain individuals fed animals. These findings illustrate the complexities of feeding group-housed cynomolgus macaques to avoid overweight body condition. Feeding routines may require more care and attention to distribute food in a way that ensures equitable food intake among troop animals, while not disturbing group cohesion.     

Urinary C-peptide measurement as a marker of nutritional status in macaques

Studies of the nutritional status of wild animals are important in a wide range of research areas such as ecology, behavioural ecology and reproductive biology. However, they have so far been strongly limited by the indirect nature of the available non-invasive tools for the measurement of individual energetic status. The measurement of urinary C-peptide (UCP), which in humans and great apes shows a close link to individual nutritional status, may be a more direct, non-invasive tool for such studies in other primates as well and possibly even in non-primate mammals. Here, we test the suitability of UCPs as markers of nutritional status in non-hominid primates, investigating relationships between UCPs and body-mass-index (BMI), skinfold fatness, and plasma C-peptide levels in captive and free-ranging macaques. We also conducted a food reduction experiment, with daily monitoring of body weight and UCP levels. UCP levels showed significant positive correlations with BMI and skinfold fatness in both captive and free-ranging animals and with plasma C-peptide levels in captive ones. In the feeding experiment, UCP levels were positively correlated with changes in body mass and were significantly lower during food reduction than during re-feeding and the pre-experimental control condition. We conclude that UCPs may be used as reliable biomarkers of body condition and nutritional status in studies of free-ranging catarrhines. Our results open exciting opportunities for energetic studies on free-ranging primates and possibly also other mammals.     

Vomiting in Wild Bonnet Macaques

Researchers have not studied vomiting that is not associated with pathological behavior in nonhuman primates. Scientists generally assume that vomiting provides protection by ejecting toxins from the body, but the explanation is not fully supported by the literature. We report on 163 instances of vomiting from 2 groups of free-ranging bonnet macaques in southern India. The macaques routinely reingested their vomit. The reingestion was unlike that in abnormal behavior of both humans and nonhuman primates. We suggest that the tendency to hoard food in their cheek pouches explains why they reingested the vomit.     

Determining overweight and underweight with a new weight‐for‐height index in captive group‐housed macaques

Housing primates in naturalistic groups provides social benefits relative to solitary housing. However, food intake may vary across individuals, possibly resulting in overweight and underweight individuals. Information on relative adiposity (the amount of fat tissue relative to body weight) is needed to monitor overweight and underweight of group‐housed individuals. However, the upper and lower relative adiposity boundaries are currently only known for macaques living solitarily in small cages. We determined the best measure of relative adiposity and explored the boundaries of overweight and underweight to investigate their incidence in group‐housed adult male and female rhesus macaques and long‐tailed macaques living in spacious enclosures at the Biomedical Primate Research Centre (BPRC), the Netherlands. During yearly health checks different relative adiposity measures were obtained. For long‐tailed macaques, comparable data on founder and wild animals were also available. Weight‐for‐height indices (WHI) with height to the power of 3.0 (WHI3.0) for rhesus macaques and 2.7 (WHI2.7) for long‐tailed macaques were optimally independent of height and were highly correlated with other relative adiposity measures. The boundary for overweight was similar in group‐housed and solitary‐housed macaques. A lower boundary for underweight, based on 2% body fat similar to wild primates, gave a better estimate for underweight in group‐housed macaques. We propose that for captive group‐housed rhesus macaques relative adiposity should range between 42 and 67 (WHI3.0) and for long‐tailed macaques between 39 and 62 (WHI2.7). The majority of group‐housed macaques in this facility have a normal relative adiposity, a considerable proportion (17–23%) is overweight, and a few (0–3%) are underweight.     

High prevalence of antibodies against hepatitis A virus among captive nonhuman primates

Hepatitis A virus (HAV) can infect not only humans but also several other nonhuman primates. This study has been conducted to evaluate the comprehensive anti-HAV seroprevalence in captive nonhuman primate populations in Thailand. The prevalence of antibodies against HAV in 96 captive nonhuman primates of 11 species was evaluated by competitive enzyme immunoassay (EIA). HAV antibodies were found in 64.7% (11/17) of macaques, 85.7% (6/7) of langurs, 28.4% (10/35) of gibbons, and 94.6% (35/37) of orangutans. However, anti-HAV IgM was not found in any sera. These results indicate that the majority of captive nonhuman primates in Thailand were exposed to HAV. It is possible that some of the animals were infected prior to capture.     

Diabetes mellitus in nonhuman primates: recent research advances and current husbandry practices

Primates can be utilized for a variety of studies to give insight into the mechanisms of the onset and progression of diabetes mellitus and obesity, and into the development of secondary manifestations. Results can be used to understand the etiologies and effects of diabetes in human beings. Investigators and animal care personnel should be continually aware of the potential for development of diabetes among primates and should seek to identify the earlier stages before the appearance of overt diabetes. In addition to updating recent research in which nonhuman primates have been used in studies on the different forms of diabetes, this review also furnishes some information about therapeutic management and husbandry of monkeys with predispositions toward diabetes or with overt diabetes.     

Optimization of a Novel Non-invasive Oral Sampling Technique for Zoonotic Pathogen Surveillance in Nonhuman Primates

Free-ranging nonhuman primates are frequent sources of zoonotic pathogens due to their physiologic similarity and in many tropical regions, close contact with humans. Many high-risk disease transmission interfaces have not been monitored for zoonotic pathogens due to difficulties inherent to invasive sampling of free-ranging wildlife. Non-invasive surveillance of nonhuman primates for pathogens with high potential for spillover into humans is therefore critical for understanding disease ecology of existing zoonotic pathogen burdens and identifying communities where zoonotic diseases are likely to emerge in the future. We developed a non-invasive oral sampling technique using ropes distributed to nonhuman primates to target viruses shed in the oral cavity, which through bite wounds and discarded food, could be transmitted to people. Optimization was performed by testing paired rope and oral swabs from laboratory colony rhesus macaques for rhesus cytomegalovirus (RhCMV) and simian foamy virus (SFV) and implementing the technique with free-ranging terrestrial and arboreal nonhuman primate species in Uganda and Nepal. Both ubiquitous DNA and RNA viruses, RhCMV and SFV, were detected in oral samples collected from ropes distributed to laboratory colony macaques and SFV was detected in free-ranging macaques and olive baboons. Our study describes a technique that can be used for disease surveillance in free-ranging nonhuman primates and, potentially, other wildlife species when invasive sampling techniques may not be feasible.     

Olfactory responsiveness to two odorous steroids in three species of nonhuman primates

Social communication by means of odor signals is widespread among mammals. In pigs, for example, the C19-steroids 5-alpha-androst-16-en-3-one and 5-alpha-androst-16-en-3-ol are secreted by the boar and induce the mating stance in the sow. In humans, the same substances have been shown to be compounds of body odor and are presumed to affect human behavior. Using an instrumental conditioning paradigm, we here show that squirrel monkeys, spider monkeys and pigtail macaques are able to detect androstenone at concentrations in the micromolar range and thus at concentrations at least as low as those reported in pigs and humans. All three species of nonhuman primates were considerably less sensitive to androstenol, which was detected at concentrations in the millimolar range. Additional tests, using a habituation-dishabituation paradigm, showed that none of the 10 animals tested per species was anosmic to the two odorous steroids. These results suggest that androstenone and androstenol may be involved in olfactory communication in the primate species tested and that the specific anosmia to these odorants found in approximately 30% of human subjects may be due to their reduced number of functional olfactory receptor genes compared with nonhuman primates.     

In vitro manipulation of nonhuman primate gametes for embryo production and embryo transfer.

Since nonhuman primates are closely related to humans and share many physical similarities, they are important for use in research areas such as human infectious diseases, reproduction, physiology, endocrinology, metabolism, neurology and longevity. To develop and maintain these animals, we must establish techniques for in vitro manipulation of spermatozoa and eggs. For a decade my research group has been conducting basic research to establish embryo manipulation techniques and to clarify the reproductive phenomena in nonhuman primates. This article summarizes the past research on in vitro manipulation of nonhuman primate gametes, from collection of reproductive cells and in vitro fertilization to the birth of offspring after embryo transfer, as well as the current status of these research areas. The studies summarized here will directly lead to the development of standard techniques for practical and comprehensive use in nonhuman primates.     

Nonhuman primate infections after organ transplantation

Nonhuman primates, primarily rhesus macaques (Macaca mulatta), cynomolgus macaques (Macaca fascicularis), and baboons (Papio spp.), have been used extensively in research models of solid organ transplantation, mainly because the nonhuman primate (NHP) immune system closely resembles that of the human. Nonhuman primates are also frequently the model of choice for preclinical testing of new immunosuppressive strategies. But the management of post-transplant nonhuman primates is complex, because it often involves multiple immunosuppressive agents, many of which are new and have unknown effects. Additionally, the resulting immunosuppression carries a risk of infectious complications, which are challenging to diagnose. Last, because of the natural tendency of animals to hide signs of weakness, infectious complications may not be obvious until the animal becomes severely ill. For these reasons the diagnosis of infectious complications is difficult among post-transplant NHPs. Because most nonhuman primate studies in organ transplantation are quite small, there are only a few published reports concerning infections after transplantation in nonhuman primates. Based on our survey of these reports, the incidence of infection in NHP transplant models is 14%. The majority of reports suggest that many of these infections are due to reactivation of viruses endemic to the primate species, such as cytomegalovirus (CMV), polyomavirus, and Epstein-Barr virus (EBV)-related infections. In this review, we address the epidemiology, pathogenesis, role of prophylaxis, clinical presentation, and treatment of infectious complications after solid organ transplantation in nonhuman primates.     

Old world nonhuman primate models of type 2 diabetes mellitus

Type 2 diabetes mellitus is a major health problem of increasing incidence. To better study the pathogenesis and potential therapeutic agents for this disease, appropriate animal models are needed. Old World nonhuman primates (NHPs) are a useful animal model of type 2 diabetes; like humans, the disease is most common in older, obese animals. Before developing overt diabetes, NHPs have a period of obesity-associated insulin resistance that is initially met with compensatory insulin secretion. When either a relative or absolute deficiency in pancreatic insulin production occurs, fasting glucose concentrations begin to increase and diabetic signs become apparent. Pathological changes in pancreatic islets are also similar to those seen in human diabetics. Initially there is hyperplasia of the islets with abundant insulin production typically followed by replacement of islets with islet-associated amyloid. Diabetic NHPs have detrimental changes in plasma lipid and lipoprotein concentrations, lipoprotein composition, and glycation, which may contribute to progression of atherosclerosis. As both the prediabetic condition (similar to metabolic syndrome in humans) and overt diabetes become better defined in monkeys, their use in pharmacological studies is increasing. Likely due to their genetic similarity to humans and the similar characteristics of the disease in NHPs, NHPs have been used to study recently developed agonists of the peroxisome proliferators-activated receptors. Importantly, agonists of the different receptor subclasses elicit similar responses in both humans and NHPs. Thus, Old World NHPs are a valuable animal model of type 2 diabetes to study disease progression, associated risk factors, and potential new treatments.     

Specific pathogen-free macaques: definition, history, and current production

Specific pathogen-free (SPF) macaque colonies are now requested frequently as a resource for research. Such colonies were originally conceived as a means to cull diseased animals from research-dedicated colonies, with the goal of eliminating debilitating or fatal infectious agents from the colony to improve the reproductive capacity of captive research animals. The initial pathogen of concern was Mycobacterium tuberculosis (M.tb.), recognized for many years as a pathogen of nonhuman primates as well as a human health target. More recently attention has focused on four viral pathogens as the basis for an SPF colony: simian type D retrovirus (SRV), simian immunodeficiency virus (SIV), simian T cell lymphotropic/leukemia virus (STLV), and Cercopithecine herpesvirus 1 (CHV-1). New technologies, breeding, and maintenance schemes have emerged to develop and provide SPF primates for research. In this review we focus on the nonhuman primates (NHPs) most common to North American NHP research facilities, Asian macaques, and the most common current research application of these animals, modeling of human AIDS.     

The question of animal culture

In this paper I consider whether traditional behaviors of animals, like traditions of humans, are transmitted by imitation learning. Review of the literature on problem solving by captive primates, and detailed consideration of two widely cited instances of purported learning by imitation and of culture in free-living primates (sweet-potato washing by Japanese macaques and termite fishing by chimpanzees), suggests that nonhuman primates do not learn to solve problems by imitation. It may, therefore, be misleading to treat animal traditions and human culture as homologous (rather than analogous) and to refer to animal traditions as cultural.     

Relation of Food Intake Behaviors and Obesity Development in Young Common Marmoset Monkeys

Objective : Increasing prevalence of childhood obesity and associated risks of adult type disease have led to worldwide concern. It remains unclear how genetic predisposition, environmental exposure to obesogenic food, and developmental programming interact to lead to overweight and obese children. The development of a nonhuman primate model of obesity, and particularly juvenile obesity, is an important step to elucidating the factors associated with obesity and evaluating intervention strategies. Design and Methods : Infant marmosets were followed from birth to 12 months of age. Feeding phenotypes were determined through the use of behavioral observation, solid food intake trials, and liquid feeding trials monitored via lickometer. Results : Marmosets found to be obese at 12 months of age (more than 14%body fat) start consuming solid food sooner and initiate more time off of care givers. These individuals developed stable feeding phenotypes that included being more efficient consumers during liquid intake trials, drinking more grams of diet per contact with the licksit. Conclusions : The weaning process appears to be particularly important in the development of feeding phenotypes and the development of juvenile obesity for the marmosets, and thus this is the time that should be focused upon for intervention testing in both nonhuman primates and children.     

IgG Fc receptor III homologues in nonhuman primate species: genetic characterization and ligand interactions

Ig Fc receptors bind to immune complexes through interactions with the Fc regions of specific Ab subclasses to initiate or inhibit the defense mechanisms of the leukocytes on which they are expressed. The mechanism of action of IgG-based therapeutic molecules, which are routinely evaluated in nonhuman primate models, involves binding to the low-affinity FcRIII (CD16). The premise that IgG/CD16 interactions in nonhuman primates mimic those present in humans has not been evaluated. Therefore, we have identified and characterized CD16 and associated TCR zeta-chain homologues in rhesus macaques, cynomolgus macaques, baboons, and sooty mangabeys. Similar to humans, CD16 expression was detected on a lymphocyte subpopulation, on monocytes, and on neutrophils of sooty mangabeys. However, CD16 was detected only on a lymphocyte subpopulation and on monocytes in macaques and baboons. A nonhuman primate rCD16 generated in HeLa cells interacted with human IgG1 and IgG2. By contrast, human CD16 binds to IgG1 and IgG3. As shown for humans, the mAb 3G8 was able to block IgG binding to nonhuman primate CD16 and inhibition of nonhuman primate CD16 N-glycosylation enhanced IgG binding. Clearly, differences in interaction with IgG subclasses and in cell-type expression should be considered when using these models for in vivo evaluation of therapeutic Abs.     

Use of primates in research: a global overview

We assessed the use of nonhuman primates and nonhuman primate biological material in research by reviewing studies published in 2001 in peer-reviewed journals. The number and species of primates used, the origin of the animals, the type of study, the area of research of the investigation, and the location at which the research was performed were tabulated. Additionally, factors related to the animals that may have affected the outcome of the experiments were recorded. A total of 2,937 articles involving 4,411 studies that employed nonhuman primates or nonhuman primate biological material were identified and analyzed. More than 41,000 animals were represented in the studies published in 2001. In the 14% of studies for which re-use could be determined, 69% involved animals that had been used in previous experiments. Published studies most commonly used nonhuman primates or nonhuman primate biological material from the species Chlorocebus aethiops (19%), Macaca mulatta (18%), M. fascicularis (9%), and Papio spp. (6%). Of these studies, 54% were classified as in vitro studies, 14% as noninvasive, 30% as chronic, and 1% were considered acute. Nonhuman primates were primarily used in research areas in which they appear to be the most appropriate models for humans. The most common areas of research were microbiology (including HIV/AIDS (26%)), neuroscience (19%), and biochemistry/chemistry (12%). Most (84%) of the primate research published in 2001 was conducted in North America, Europe, and Japan. The animals and conditions under which they were housed and used were rarely described. Although it is estimated that nonhuman primates account for an extremely small fraction of all animals used in research, their special status makes it important to report the many husbandry and environmental factors that influence the research results generated. This analysis has identified that editors rarely require authors to provide comprehensive information concerning the subjects (e.g., their origin), treatment conditions, and experimental procedures utilized in the studies they publish. The present analysis addresses the use of primates for research, including the effects of a shortage of suitable nonhuman primate subjects in many research areas.     

A field study of infection with human T-cell leukemia virus among asian primates

Asian nonhuman primates were surveyed seroepidemiologically for natural infection with human T-cell leukemia virus (ATLV/HTLV) or a closely related agent. Materials from various primates (three genera [Macaca, Presbytis, and Hylobates], 17 species, totalling 1,079 animals) under natural conditions were obtained in the field study. Virus infection was determined by the indirect immunofluorescence test using HTLV-specific antigens. Animals seropositive for HTLV were found only among macaques originating from various localities, toque monkeys in Sri Lanka (17.5%), crab-eating macaques in Thailand (1.3%), stumptailed macaques in Thailand (1.5%), rhesus monkeys in Thailand (3.3%), and Celebes macaques in Indonesia (16.9%). Langurs and gibbons were seronegative. Thus the wide distribution of HTLV in nature among various macaques suggests that the introduction of this virus into primates occurred in ancient times.     

Snowball construction by a feral troop of Japanese macaques (Macaca fuscata) living under seminatural conditions

Feral Japanese macaques (Macaca fuscata) living under seminatural conditions in Oregon constructed several large snowballs in their two-acre corral. This behavior did not involve the basic reward systems connected with agonistic or feeding behavior which are most commonly associated with tool-using in nonhuman primates.