Chronic Nephropathy in Ad Libitum Overfed Sprague-Dawley Rats and Its Early Attenuation by Increasing Degrees of Dietary (Caloric) Restriction to Control Growth

Abstract

The early development and progression of chronic nephropathy and its amelioration by moderate and marked dietary restriction (DR) was determined in Sprague-Dawley (SD)

Diabesity: A Polygenic Model of Dietary-Induced Obesity from Ad Libitum Overfeeding of Sprague–Dawley Rats and Its Modulation by Moderate and Marked Dietary Restriction

“…In summary, the marked DR-fed group 4 animals had the smallest and least adversely affected kidneys. The AL-fed rats had the largest and most diseased kidneys, and these findings correlated with glomerular and total nephron hypertrophy, the early development of glomerular sclerosis and other degenerative changes in the tubules and the interstitium (Keenan et al, 2000b). These data were consistent with large nephrons undergoing chronic persistent metabolic stress, injury and leading to chronic nephropathy.…”

“…Obesity and Type 2 diabetes are known to be a polygenic syndrome in heterozygous human populations, and more polygenic rodent models are needed in which genetic trait loci can be identified for their interactions with each other, and with the environmental factors that elicit obesity syndromes and lead to diabetes (Masoro, 1996;Keenan et al, 2000aKeenan et al, , 2000bLeiter, 2002;Axen et al, 2003;O'Rahilly et al, 2005;Park and Prolla, 2005). Although monogenic obesity mutations in rodents such as those in leptin or its receptor have been extensively used to test anti-obesity and anti-diabetic drugs, the monogenic basis of these rodent obesity models is not reflective of the more common forms of human obesity that have been documented to be polygenic in origin (Whitaker et al, 1997;Bray, 2002;Konstantinov, 2003).…”

“…Therefore, targeting the metabolic syndrome as a whole rather than specifically dissecting each one of its subcomponents should be considered as a key objective in the development of models to test treatments and management programs of this important human syndrome. In this regard, the Charles River outbred SD rat appears to represent an excellent polygenic model that is only now beginning to be thoroughly phenotyped and understood from the perspective of an animal model of diabesity (Gumprecht et al, 1993;Klinger et al, 1996;Keenan et al, 1997Keenan et al, , 1994aKeenan et al, , 1994bKeenan et al, , 1995Keenan et al, , 1996Keenan et al, , 1999Keenan et al, , 2000aKeenan et al, , 2000bHubert et al, 1997Hubert et al, , 2000Laroque et al, 1997;Levin et al, 1997Levin et al, , 2000Hoe et al, 1998;Vermorel et al, 1998;Molon-Noblot et al, 2001Kemi et al, 2000). While not all of the phenotypic and genetic characteristics of this stock have yet been well defined, the results of this study and previous work indicate that when ALfed this animal clearly has a well-developed set of phenotypic characteristics that would be best described as diabesity.…”

“…Rather, it is the complex interactions of the environment and diet (total caloric intake) with the SD rat's genome that produces or prevents the polygenic phenotype of diabesity from being expressed. It also appears that feeding modified diets with lowered protein, reduced metabolizable energy content, and increased fiber does not necessarily result in the control of diabesity or improved survival if the diets are provided ad libitum (Tucker, 1979;Iwasaki et al, 1988;Masoro et al, 1989;Keenan et al, 1994aKeenan et al, , 1994bKeenan et al, , 1995aKeenan et al, , 1995bKeenan et al, , 2000aKeenan et al, , 2000bRoe et al, 1995;Yu, 1995;Masoro, 1996;Whitaker et al, 1997;Masoro et al, 1996). Only dietary restriction (DR) of all diets tested in rodents consistently improves survival and delays the onset of the spontaneous development of obesity and the degenerative diseases referred to as "diabesity.…”

“…The lesions comprising chronic nephropathy were subjectively graded separately and included glomerulosclerosis, cellular infiltration, tubular basophilia and tubular dilatation. Stereological analyses of these lesions have been published separately (Keenan et al, 2000b). In summary, the marked DR-fed group 4 animals had the smallest and least adversely affected kidneys.…”