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Obesity develops slowly and spontaneously in some rodent strains and in non-human primates, with peak body weight reached in 'middle-age' or in older age. The animal models of obesity may be classified as: (a) spontaneous naturally occurring (of unknown genetic and physiologic cause(s)); (b) specific genetic models of known or unknown single gene mutations occurring spontaneously (and selected for by breeding), or produced by transgenic approaches; (c) dietary or nutritionally induced obesity usually by high fat and/or highly palatable diets in rodents (a form of obesity which is likely to be polygenic), or by high fat diets or forced overfeeding in non-human primates; and (d) neuroendocrine disorders causing obesity, such as via hy-pothalamic lesions or chemical infusions (e.g. the injection of gold thioglucose into mice), as detailed in Table 14.1. The present review will focus principally upon the spontaneously occurring form of obesity in non-human primates and in rodents, the form(s) of obesity that are highly likely to be directly relevant to most human obesity.

OBESITY AS A DISEASE OF AGING IN PRIMATES: THE NATURAL HISTORY OF CHANGES IN BODY ADIPOSITY

Obesity has been identified in many primate species, including orangutans, gorillas (1), chimpanzees (2), baboons (Papio ursinus) (3), vervet monkeys (Cercopithecus aethiops) (4), cynomolgus monkeys (Macacafascicularis) (5), bonnet macaques (Macaca radiata) (6), pigtail macaques (Macaca nemistrina) (7), squirrel monkeys (8), and the Celebes ape (Macaca nigra) (9), although the species most studied is the rhesus monkey (Macaca mulatta) (10-12). Several rodent species develop a similar adult-onset obesity, including the Sprague-Dawley rat (13), the gerbil (Psammomys obesus, Israeli desert sand rat) (14), the New Zealand Obese mouse, the

Table 14.1 Animal models of obesity and diabetes

Classification of animal models of obesity and diabetes

Examples of models/methods

Spontaneous, naturally occurring-of unknown genetic/physiologic causes

Specific genetic models of single gene mutations of known or unknown function (spontaneous, bred, or transgenic)

Dietary induced obesity Neuroendocrine disorders

Probable genetic Gene-gene interactions Gene-environment interactions Aging-associated e.g. non-human primates, aging Sprague-Dawley rats

Ob/ob mouse Db/db mouse Fa/fa rat Tub mouse Ay mouse Others

High fat diet fed rodents 'Cafeteria' (highly palatable) diet fed rodents Hypothalamic or related brain area lesions or stimulation (including electrolytic, knife cut, chemical, viral)

BSB mouse (Mus spretus and other strains), and the spiny mouse (Acomys caharinus). Spontaneous obesity also develops in some cats (15) and dogs, as well as in many other species, when the individuals are maintained in an unfettered environment.

Spontaneous adult-onset obesity develops in primates and rodents in an environment that is either permissive of, or facilitative to, weight gain. The usual laboratory setting of ad libitum food availability and of protection from predators and disease is sufficient to produce adult-onset obesity in many, but not all, non-human primates (16,17). (Some 20-30% remain lean all of their lives despite a facili-tative environment, and further, among the obese, the amount of excess weight and fat varies widely.) The peak body weight in these laboratory housed monkeys is usually not reached until about 15 years of age ('middle-age'), with the weight gained after age 7 being composed primarily of adipose tissue. Thus, obesity in non-human primates must be considered to be a disease of aging. Although primates are able to reproduce by about the age of 4 years, no spontaneously obese younger monkeys (under the age of 6 years) have ever been described, and thus, primates do not provide a model for childhood-onset obesity in humans.

Does obesity occur in primates living in their natural environment? The best evidence comes from the identification of obese monkeys in the protected environment offered by the island of Cayo Santiago off the coast of Puerto Rico (18). On that island, large colonies of monkeys are provi sioned with primate chow to provide ad libitum intake in a free-ranging, but predator-free, environment. In a reported survey of these monkeys, the obese monkeys ranged from 9 to 16 years of age

(19). In some matrilines, the prevalence of obesity ranged as high as 20% in these free-living monkeys

(20). Obesity has also been observed in other freely feeding and protective environments, including in some zoological collections. The relationship between obesity, diabetes and aging in monkeys has been reviewed recently (21).

Fat Mass and Distribution: Abdominal or Central Obesity

Obesity in humans and monkeys develops very gradually and progressively in 'middle-age'. Specifically, percent body fat begins to increase in monkeys after about the age of 7 years, and continues, in some monkeys, to increase into late maturity. This increase in fat mass can be detected widely in subcutaneous tissue and also in intra-abdominal adipose mass. Its distribution is heavily abdominal in both males and females (22,23). The abdominal circumference shows a consistent increase with increasing body weight in middle age (age 7 to 20 in monkeys), as shown in Figure 14.1 for one monkey (D-7), and as previously described for a large group of monkeys (24).

In many monkeys, this change in body fat com-

Figure 14.1 Longitudinal changes in abdominal circumference and in body weight of a monkey (D-7) followed from age ~ 5 to age ~ 20 years

position is accompanied by a progressive series of changes in fasting plasma glucose and insulin, as shown for monkey A-7 in Figure 14.2. Also shown is the later decline in insulin sensitivity (M rate, or glucose uptake rate as measured by a euglycemic hyperinsulinemic clamp), and the slight later decline in glucose tolerance as measured by an intravenous glucose tolerance test.

Figure 14.3 summarizes the overall pattern or sequence of events seen in a large group of monkeys, arrayed by phase, or stage in the progression from young lean adult (phase 1) to overt severe diabetes (phase 9).

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