Morfología de los deltas

Early studies by Mayer et al, (1951) showed that ob/ob mice with established obesity tend to choose more fat than lean controls when allowed to select caloric sources. Such studies have yet to be carried out in SLOB rats and thus it is not yet known whether this is also the case for SLOB rats. However, my studies have shown that when allowed free access to a diet higher in fat, SLOB animals consume more food than normal animals on a similar diet. Although ob/ob mice prefer a diet higher in fat than normal mice, ob/ob mice can develop a degree of obesity even in the complete absence o f dietary fat from the time of weaning (Mayer et al, 1951). When compared to lean mice similarly restricted, this is true in both the relative sense (increased percentage of body fat) and in the absolute sense (increased total body fat). In comparison, SLOB males normally fed a low fat diet consisting o f just 4% fat also develop severe obesity. However, analysis o f whether obesity develops in the complete absence of dietary fat, is still to be determined in SLOB rats. Conversely, when allowed free access to a high fat diet from the time of weaning, obesity occurs more readily in ob/ob mice (Genuth 1976) as I also found in SLOB males and females, with high fat feeding starting at 100 days of age. Thus both the ob/ob mouse and SLOB rats respond similarly to the challenge of a high fat diet. On a low fat diet both these animal models are genetically predisposed to develop obesity and on a higher fat diet animals are predisposed to rapidly develop obesity.

My cumulative food intake data in SLOB males on a high fat diet is informative; high fat fed SLOB males continued to consume almost as much food as chow fed SLOB males, whereas a significant decrease was observed in high fat fed normal and dw arf

rats. The food intake in high-fat fed SLOB males was also significantly greater than that in high fat fed normal males. Thus, young SLOB males who have an incipient obesity phenotype, when challenged with a high fat diet, induces severe obesity comparable to that seen in old SLOB males and is reflected in increased food intake, increased weight gain, elevated fat pad weights, and elevated plasma leptin levels. This apparent lack of reducing food intake suggests SLOB rats may be leptin resistant as is suspected in the obese human population (Schwartz et al, 1996c; Kennedy et al,

Chapter 5________________________________Manipulation o f the SLOB Rat Phenotype

when challenged with a high fat diet resulting in a further elevation o f plasma leptin levels, they are unable to respond to this increase in leptin and thus do not reduce their food consumption.

In females the effects of high fat feeding are more pronounced in both normal and

dw arf rats as well as SLOB rats when compared to male rats. The marked effects on bodyweight gain and fat pad weight in dwarf females confirmed the results o f Clark et al, (1996) who also showed obesity could be induced by high fat feeding female

dw arf rats much more readily than in males. What is interesting again is that despite elevated fat pad mass and plasma leptin levels in dwarf females they do significantly reduce their cumulative food intake whereas only a non-significant reduction was observed in SLOB and normal females. As Abodyweight gain is greatest in SLOB females, as in young SLOB males, high fat feeding also induced a severe obesity phenotype in young SLOB female rats. It is possible that on a low fat diet (4% fat) SLOB females are protected from developing obesity and even with elevated plasma leptin levels at a young age, the onset of severe obesity is delayed to a much later age than that seen in SLOB males. However, when challenged with a diet o f higher fat content, young SLOB females are unable to resist diet-induced obesity and thus like young SLOB males become obese, and perhaps leptin resistant. As dw arf females on high fat diet also show some obesity phenotype and d w a rf males do not, there is a possibility that both GH-deficiency and sex-specificity have a role in the development or protection from severe obesity in SLOB females. At least two explanations are possible: sex-steroid differences and/or the sexual dimorphic pattern of GH secretion (Tannenbaum et al, 1976; Edén, 1979; Clark et al, 1987). GH treatment in SLOB female rats has not yet been carried out, however, the role of oestrogens are discussed in 5.6.5.

Gender differences in feeding high-fat diets have also been found in Zucker rats. Male Zucker rats on a low-fat content diet (12.3kcal% fat) develop diabetes, the process being accelerated as a function of dietary fat-content, whereas only diets of high fat-content (48 kcal% fat) induce the development o f non-insulin dependent diabetes mellitus (NIDDM) in obese Zucker females (Corsetti et al., 2000). Both this study and my results indicate significant differences between Zucker males and females and SLOB males and females in development o f diabetes {Zucker rats) and

Chapter 5________________________________ Manipulation o f the SLOB Rat Phenotype

obesity (SLOB rats) as a function of dietary fat-content. From these observations it is reasonable to conclude that a low fat diet is enough to induce obesity in Zucker and SLOB males but a diet higher in fat content is required to induce obesity in Zucker

and SLOB females. Studies on cold-acclimatised Zucker rats have also indicated that feeding high-fat diets can specifically increase thermogenesis in brown adipose tissue (Rothwell et al, 1983), an organ now regarded as the major site o f heat production by nonshivering mechanisms in small mammals. Further studies on high fat feeding SLOB rats have yet to be carried out to establish the mechanisms underlying the results o f high fat feeding so far shown in this chapter. I have largely concentrated on calorie intake; differences in diet-induced thermogenesis, lipolysis stimulation and fat oxidation have all been proposed in order to explain adiposity increase induced by high fat feeding, these studies are clearly warranted in SLOB rats.