Genetically obese animals

Much work has sought to define a metabolic aetiology for obesity, but the comparison of lean and obese individuals does not, in general, allow differences to be identified as either causes or effects of the condition. The differences between genetically obese animals and their lean littermates have also been extensively studied in an attempt to clarify the potential metabolic predispositons that encourage obesity. However, most genetically obese animal models are complicated by the diverse nature of the metabolic lesions in the obese, some of which may not be related to the manifestation of excess adiposity (Bray and York, 1979). 

History. In the course of investigations on the fibrate class of hypolipidemic agents at Takeda (179, 180), a series of 5-(4-alkoxybenzyl)-2,4-thiazolidinediones were shown to reduce insulin resistance in genetically diabetic and obese animals. Ciglitazone (15), which became the prototypeforthis class... 

The endocannabinoid system is implicated in the physiological control of food intake and energy balance, not only after food deprivation but also in animal models of genetic obesity in which it appears to become overactive at the level of both the hypothalamus and adipocytes (Di Marzo et al. 2001c Bensaid et al. 2003). This possibly explains why, following treatment of mice and rats with rimonabant, a transient inhibition of food intake and a more persistent reduction of fat mass are observed (Ravinet-Trillou et al. 2003), and why CBi knockout mice show a reduced susceptibility to obesity in response to a fat diet (Ravinet-Trillou et al. 2004). 

Body weight and metabolism are regulated by the hypothalamus. In experimental animals diabetes, insulin resistance and dyslipidaemia can be corrected by weight loss (Brownell etal., 1986 Brindley and Russell, 1995), and this has recendy been demonstrated in humans (Benotti and Forse, 1995). Increased activity of the hypothalamic NPY system may contribute to the development of obesity in animals. The abnormalities seen in genetically obese rodents can be mimicked by central injection of NPY (Zarjevski etal., 1993). 

Obesity was observed in 26% of the animals after an intracerebral inoculation of CDV, while only 16% of animals become obese following an intraperitoneal inoculation. Body weights of the obese animals were comparable to those seen in genetic or hypothalamic models of obesity. When the body weight plateaued at 16-20 weeks postinoculation, mean weight of infected obese animals was 63.7 g versus 33.1 g in the uninfected group (Lyons et al., 1982). 

Leptin administratioii suppresses hypothalamic endocannabinoid levels in normal rats, while genetically obese, chronically hyperphagic rodents express leptin-reversible, elevated hypothalamic anandamide and 2-AG levels (J9). Moreover, fasting seems to inaease levels of both anandamide and 2-AG in the limbic forebrain and, to a lesser extent, of 2-AG in the hypothalamus, whereas in fed animals the hypothalamic content of 2-AG declines (72). However, another study has shown that while food deprivation failed to alter anandamide levels in whole brain, hunger did increase intestinal anandamide content, which normalized following feeding (79). 

Chronic ingestion of simple carbohydrates such as sucrose or fructose has been shown to increase the SBP in several rat strains. This was attenuated by the inclusion of a vitamin Bg supplement (five times the normal intake) in the diet. The possibility that a dietary supplement of vitamin Bg could attenuate the elevation of SBP in genetically hypertensive animal models such as the Zucker obese or the spontaneously hypertensive rat (SHR) was examined. Male Zucker obese rats (fa/fa) fed a commercial rat chow developed hypertension in three to four weeks. The inclusion of a dietary vitamin Bg supplement (five times the normal intake) resulted in a complete attenuation of the hypertension in the obese strain. This was reversible. In contrast to the effect seen in the Zucker obese rats, there was no response to the inclusion of a dietary vitamin Bg supplement in SHRs. The changes in SBP in the Zucker as well as in the sucrose- or fructose-fed rats correlated with the changes in the uptake of calcium by the caudal artery segments in these groups (55). 

Further studies showed that the administration of leptin to the genetically obese diabetic falfa) rat had no effect on body weight, and indeed these rats secreted a normal or greater than normal amount of leptin. The defect in these animals is a mutation in the membrane receptor for leptin. 

This chapter will present methods that are widely used for screening and validating new therapeutic drugs using in vivo mouse models. These models can roughly be divided in two types first, genetic models where animals develop symptoms of diabetes, even in absence of environmental changes, and second, diet-induced obesity, which results in increased insulin resistance (see Note 1). 

Type 2 Diabetes Mellitus This is the most prevalent form of diabetes and is characterized by both an insulin secretion defect and insulin resistance. Maturity-onset diabetes of the young (MODY), attributable to mutations of the glucose kinase gene (discussed earlier), may also be classified as type 2 diabetes mellitus. Obesity is a contributory factor and may predispose to insulin resistance with eventual development of type 2 diabetes mellitus. The precise mechanism by which obesity leads to insulin resistance in the target tissues is not understood. However, in several animal models (e.g., ob/ob mouse, db/db mouse) mutations have been identified that cause both obesity and diabetes mellitus. Unlike type 1 diabetes mellitus, type 2 is not an autoimmune disease. Studies with monozygotic twins have revealed a 90% concordance rate for type 2 diabetes mellitus, suggesting the involvement of genetic factors in the development of the disease. 

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