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Calorie Restriction in Obesity: Prevention of Kidney Disease in Rodents^{1 ,2}

Judith S. Stern^*,, Mathew D. Gades^*, Carrie M. Wheeldon^* and Andrea T. Borchers^*

^* Department of Nutrition, University of California, Davis, CA 95616 and Division of Endocrinology, Clinical Nutrition and Vascular Disease, University of California, Davis, CA 95616

³To whom correspondence should be addressed. E-mail: jsstern{at}ucdavis.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION Glomerulosclerosis in nonobese... REFERENCES

 
The incidence of end-stage renal disease (ESRD) has risen considerably in the past two decades. This trend is partly due to the alarming rise in the incidence of type 2 diabetes over the same period, which in turn might be linked to the staggering increase in overweight and obesity. If these trends continue, ESRD can be expected not only to cause suffering of ever growing numbers of patients, but also to become an increasing financial as well as logistical burden on the health care system. Therefore, it is imperative not only to gain a better understanding of the molecular, cellular and metabolic mechanisms involved in renal pathology, but also to uncover treatment modalities, including lifestyle changes, that can help prevent and/or slow the progression of kidney pathogenesis. Insights into both of these aspects are provided by animal models of obesity and diabetes. It has long been known that food restriction, more so than restriction of any particular dietary component, can greatly enhance longevity in laboratory rodents. These findings are being extended into a variety of other mammals, including nonhuman primates. These studies have indicated that caloric restriction in nonobese laboratory animals does not primarily affect specific disease processes but rather nonspecifically slows the aging process. In contrast, a growing body of evidence suggests that in genetically obese animals, food restriction can prevent or greatly delay the onset of specific degenerative lesions, in particular glomerulonephritis associated with obesity and diabetes.

KEY WORDS: • renal disease • diabetes • obesity • caloric restriction

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Glomerulosclerosis in nonobese... REFERENCES

 
Over the last two decades, there has been a continuous increase in the incidence of end-stage renal disease (ESRD)⁴ in patients with diabetes not only in the United States but also worldwide (Ritz et al. 1999 , U.S. Renal Data System 1997 , U.S. Renal Data System 1998 ). At the same time, the incidence of type 2 diabetes has also been rising at an alarming pace, particularly among adolescents (Rosenbloom et al. 1999 ). This same group has suffered from an increased incidence of obesity. Of patients with diabetes receiving renal dialysis, over 60% have noninsulin-dependent diabetes [type 2 diabetes (American Diabetes Association 1997 )], and type 2 diabetes has become the single most frequent cause of ESRD, accounting for 36% of all U.S. patients receiving renal replacement therapy (Ritz et al. 1999 ). Although the reasons for this increase are not well understood, it is worth noting that type 2 diabetes is commonly associated with overweight and obesity, which have reached epidemic proportions, particularly in the United States (Flegal 1999 ). Based on a survey conducted between 1988 and 1994, the prevalence of overweight [body mass index (BMI) 25] among men was reported to be 59% and that for women 50%, up from 48 and 39%, respectively, compared with a similar survey conducted between 1960 and 1962. Between 1962 and 1994, the prevalence of obesity (BMI 30) also rose substantially from 10 to 15% among men and from 20 to 25% in women. Although harder to assess due to the lack of a simple definition for pediatric obesity, the prevalence rates for overweight and obesity in children have doubled from the time of the first National Health and Nutrition Examination Survey (1963–1965) to the third one [1988–1994 (Flegal 1999 , Trent and Ludwig 1999 , Troiano and Flegal 1998 )].

The total number of patients in the United States with type 2 diabetes and ESRD is reported to be 68,000 based on 1991–1995 figures (Ritz et al. 1999 ). At a cost of $30,000 per renal transplant and an annual expenditure of $50,000 per ESRD patient maintained on dialysis (Kobrin 1998 ), the cost for treating these patients is likely to exceed $3 billion annually. With the rising prevalence of both obesity and type 2 diabetes as well as ESRD among patients with diabetes, it is expected that ESRD will not only negatively impact quality of life in increasing numbers of patients but will impose an ever growing financial as well as logistical burden on the health care system. Although some experts believe that ESRD is to a large extent, if not completely, preventable when appropriate measures, such as glycemic control and antihypertensive treatment are implemented, it is critical to note the sharp rise in renal disease cases even though these therapies are widely available and commonly prescribed (American Diabetes Association 1997 ). This suggests that an additional, and yet unrecognized, mechanism may be at work. One possibility is that hyperlipidemia may be causative, and a growing body of work supports this theory. Interestingly, hyperglycemia, hypertension and hyperlipidemia are often ameliorated by weight loss when begun early enough and as part of an interdisciplinary approach.

The pathogenesis of nephropathy, particularly that observed in diabetes, is still poorly understood, and much of the existing insight has come from studies in rodents. The advancement of the field of how genetics influence renal disease has greatly benefited from the use of congenic strains of rats and chromosomal mapping techniques (Jacob and Kissebah 2000). The effects of dietary modulation on the prevention and/or amelioration of existing renal pathology have also been investigated mostly in rat models. In the following, we will review some of the relevant literature regarding the effects of food restriction on renal disease, with particular emphasis on studies conducted in genetically obese rodents.

	Glomerulosclerosis in nonobese rats

TOP ABSTRACT INTRODUCTION Glomerulosclerosis in nonobese... REFERENCES

 
Glomerulosclerosis is a relatively frequent cause of death among nonobese rat strains. Since the report by McCay et al. (McCay et al. 1935 ), it has been known that food restriction prolongs the life span of laboratory rats. However, it has only been in the last two decades that several groups of researchers have documented a reduction in the incidence and severity of glomerular sclerosis by restricting the food intake of nonobese laboratory rat strains, such as Wistar (Davis et al. 1983 , Everitt et al. 1982 ), Sprague-Dawley (Gumprecht et al. 1993 , Keenan et al. 1995 ) and Fischer 344 (Masoro et al. 1989 ). Most of these studies were conducted in male rats in whom the incidence and severity of nephropathy appears to be generally higher than in females. For example, male Munich Wistar rats showed significantly higher levels of proteinuria than did females as early as 7 wk of age, the difference becoming even more pronounced at 21 wk (Remuzzi et al. 1988 ). Similar results have been reported by others (Baylis 1994 ). More severe renal pathology was again noted in male compared with female Sprague-Dawley rats at 52 wk (Gumprecht et al. 1993 ) as well as at 106 wk (Keenan et al. 1995 ). Therefore, in the course of a food restriction study, the beneficial effects of reduced food intake on glomerular lesions were greater in males.

Numerous investigators have attempted to address the question of whether the restriction of individual food components rather than energy restriction in general is responsible for the life-prolonging and renal protective effects observed after decreased food intake. Protein restriction in particular has been intensively investigated, but to date the results are contradictory. Reducing the dietary protein content delays glomerulosclerosis after partial nephrectomy in rats [reviewed in (Meyer et al. 1983 )]. In animals with intact kidneys, low protein diets were associated with less glomerulosclerosis than were high protein diets in some studies, but not in others (Bertani et al. 1989 , Masoro et al. 1989 , Meyer et al. 1983 ). In addition, compared with the significant protection provided by energy restriction, limiting the dietary protein content appears to have only a slight protective effect against the development of renal lesions (Masoro et al. 1989 ). Interestingly, not just the amount but the source of dietary protein can have a distinct effect on longevity and degenerative lesions. In particular, Fischer rats fed a casein-based diet had a higher incidence of renal pathology compared with soy-fed animals (Iwasaki et al. 1988 ). Similar observations have been made in animal models of other types of kidney disease (Ogborn et al. 2000 , Tomobe et al. 1998 ). Our own laboratory has found that obese Zucker rats fed a casein-based diet had more extensive glomerular damage than did animals fed an albumin-based diet, whereas soy-protein was associated with the least renal pathology (unpublished observation; Gades, Kaysen and Stern). Whether the different responses to casein and soy protein are attributable to differences in amino acid composition or to other constituents, such as phosphate level or the isoflavones in soy, remains to be established.

It is worth noting that in nonobese laboratory rats, protein restriction appears to be beneficial mostly for kidney function, whereas caloric restriction seems to affect the aging process in general rather than to prevent the onset of specific diseases. A somewhat different situation exists in experimental models of obesity, which have become invaluable tools in elucidating the mechanisms of diabetic nephropathy and in evaluating therapeutic approaches, particularly those involving dietary modifications (Janssen et al. 1999 ). Among these models, obese Zucker rats (fa/fa) are characterized by obesity due to a single autosomal recessive trait (fa), which represents a defect in the leptin receptor (Chua et al. 1996 , Iida et al. 1996 ). Obese Zucker rats exhibit hyperphagia, decreased energy expenditure, hyperinsulinemia, insulin resistance and hyperlipidemia, particularly hypertriglyceridemia (Johnson et al. 1991 ). These rats develop renal disease early in life and over 90% die from progressive ESRD (Johnson et al. 1997 ).

A new model for spontaneous diabetes mellitus with obesity and nephropathy was established in 1992, the Otsuka Long-Evans Tokushima Fatty (OLETF) rat (Kawano et al. 1992 ). In this strain, only males with unrestricted access to food develop mild obesity, hyperglycemia after 20 wk of age, followed by a mild and chronic course of type 2 diabetes. Obesity in this strain has been shown to be necessary, although not sufficient, for the development of type 2 diabetes (Ishida et al. 1996 ), and even a 15% restriction in food consumption compared with the ad libitum–fed group resulted in a dramatic decrease in the incidence of diabetes, while no diabetes occurred in animals restricted by 30% (Okauchi et al. 1995 ). Thus, the effects of life-long food restriction cannot be examined in this model. Nonetheless, it was recently reported that caloric restriction, begun after type 2 diabetes was established (at 25 wk of age) resulted in reductions in body weight, decreases in plasma insulin and glucose as well as plasma triglycerides (TG) and reduced accumulation of TG in various tissues (Man et al. 2000 ). As discussed in detail below, plasma TG appear to play an important role in kidney pathology. Several recent studies indicate that increased glomerular area is found in OLETF rats as early as 22 wk of age, renal hypertrophy is detectable in 5-mo-old males and mesangial matrix expansion and thickening of the basement membrane are significantly greater in 10-mo-old OLETF rats than in age-matched lean Long-Evans Tokushima Otsuka controls (Fukuzawa et al. 1996 , Uriu et al. 1999 , Yagi et al. 1997 ). To date, the effects of energy restriction on renal pathology in OLETF rats have not been examined, although such a study would be of great interest.

Relatively few studies have investigated how food restriction influences longevity of genetically obese rodents, and even fewer have established the cause of death of ad libitum–fed and food-restricted animals. For example, the first study to examine the effects of food restriction on life span in ob/ob mice reported that the mean life span of animals whose food intake was restricted in such a way as to maintain body weight at the level of lean siblings was significantly increased compared with ad–libitum fed animals (Lane and Dickie 1958 ). The actual food intake and, thus, the severity of the restriction were not reported and the cause of death was not established in any of these animals. Using a similar protocol, Harrison et al. (Harrison et al. 1984 ) also noted an extension of the mean life span by almost 50% in food-restricted ob/ob mice, and their maximum longevity was similar to food-restricted normal B6 mice. In this study, the degree of restriction necessary to keep the obese animals at the same weight as ad libitum–fed normal mice was reported to be 33%. Again, cause of death was not established. In genetically obese and spontaneously hypertensive Koletsky rats, severe food restriction to one-third of the level consumed by ad libitum–fed animals resulted in greatly increased longevity (Koletsky and Puterman 1976 ). Although the authors stated that death in this rat strain is commonly due to either renal failure or atherosclerosis, they did not establish cause of death. They did, however, report that proteinuria was greatly diminished in food-restricted compared with ad libitum–fed animals, suggesting that glomerulosclerosis was attenuated by caloric restriction.

Recent studies from our own laboratory investigated the effects of food restriction not only on longevity, but also on renal pathology in lean and obese Zucker rats. The latter is of particular importance because > 90% of obese Zucker rats die from ESRD. Three groups each of male and female rats, barrier-housed, were followed from weaning at 4 wk of age until spontaneous death: ad libitum–fed obese, ad libitum–fed lean and obese pair-fed to the levels of food intake of the lean group (Johnson et al. 1997 ). Pair-feeding resulted in a mean restriction in food intake of 7.2% in males and of 18.2% in females between 4 and 60 wk of age, after which food intake in the obese ad libitum–fed animals declined to levels below that of lean animals (Fig. 1A , females). Food intake in obese Zucker rats peaked at 7 wk of age, at which point pair-fed obese animals consumed 30–35% less food. While food intake decreased in the ad libitum--fed obese Zucker rats after 12 wk of age, it still increased in ad libitum--fed lean, and thus in pair-fed obese, Zucker rats, resulting in a progressive decrease in the level of food restriction. In a separate food restriction study in our laboratory, we observed a 45% reduction in food intake in pair-fed compared with ad libitum–fed obese Zucker rats at 7 wk of age (Gades et al. 1999 ). By 21 wk, the restriction was only 26%. In both studies, despite ingesting the same amount of food as lean littermates, obese Zucker rats achieved considerably higher body weights, although lower than ad libitum–fed obese rats (Gades et al. 1999 , Johnson et al. 1997 ) (Fig. 1B ). In the longevity study, we measured the total and the percentage of carcass fat at the time of death and found them to be not significantly different in pair-fed and ad libitum–fed obese animals (Johnson et al. 1997 ). Nonetheless, pair feeding resulted in significantly prolonged 50th and 10th percentile survivorship as well as maximum life span in both male and female obese rats. Our most striking finding was that deaths attributable to ESRD decreased from 91 to 64% in obese males (P < 0.05) and from 93 to 51% (P < 0.001) in obese females, in whom renal injury occurred earlier and with greater severity (Fig. 2 ). However, these percentages were still significantly higher than in lean rats (22% in males and 11% in females). It is particularly noteworthy that marked extension of life span and reduction of renal pathology were achieved with an average food restriction of only 7% in males and 18% in females. In most studies reporting life-prolonging effects of reduced food intake, the degree of restriction was at least 30% or more. Another interesting observation was that total and percentage carcass fat was not significantly reduced by pair feeding. This agrees with the findings of earlier studies indicating that life-long food restriction (22%) failed to normalize body fat in male obese Zucker rats (Cleary et al. 1980 ). Similarly, food restriction in obese mice did not result in a significant reduction in percentage body fat, although body weight was significantly decreased and life span was greatly extended (Harrison et al. 1984 ). The authors concluded that the effects of food restriction were independent of the reduction in adiposity. A review of the existing literature presented essentially the same conclusion (Keenan 1996 ). However, in view of recent discoveries concerning the importance of adipose tissue as an endocrine gland, this interpretation has been challenged (Barzilai and Gupta 1999 ).

View larger version (25K): [in this window] [in a new window]   Figure 1. Weekly food intake (A) and body weight (B) in obese and lean Zucker rats fed ad libitum. A third group of obese rats was pair-fed to lean rats. Results at the start of the experiment represent the average of 45 rats per group (adapted from Johnson et al. 1997 ).

View larger version (16K): [in this window] [in a new window]   Figure 2. Cumulative death attributed to ESRD. Female obese and lean Zucker rats were fed ad libitum. A third group of rats, obese rats, was pair-fed to lean rats. Necropsies were performed within 24 h of spontaneous death (adapted from Johnson et al. 1997 ).

Our laboratory became interested in the opposite question, namely whether early food restriction results in benefits past the time when access to food is no longer limited. In order to address this question, we pair-fed female obese Zucker to lean controls from 6 to 21 wk of age, then allowed ad libitum access to food (Gades et al. 1999 ). Pair-fed animals showed no signs of glomerular histopathology at 21 wk, whereas kidneys of ad libitum–fed obese animals already exhibited marked glomerular damage. When the previously pair-fed animals were given ad libitum access to food, it took 6 wk for their average food intake to increase. Within a matter of weeks thereafter, hyperphagia resulted in dramatically increased urinary albumin excretion (UAE), indicating glomerular injury. Whereas the reduction of serum TG and cholesterol did not reach significance in the previously discussed study (Shimamura 1982 ), we noted that pair-fed animals at 20 wk had similar TG and cholesterol levels as lean animals, which differed significantly from the high levels observed in the ad libitum–fed animals. Due to an increase in the pair-fed group once they were no longer food-restricted and a decrease from maximal levels in ad libitum obese animals, TG and cholesterol levels were similar in the two groups after 35 wk of age. Thus, plasma lipids might have played a role in the renal injury observed in ad libitum–fed obese animals and their reduction might have accounted for at least some of the protective effects of food restriction. Kidney damage itself can result in alterations in lipid metabolism (Appel et al. 1985 ). It is, therefore, difficult to determine whether the hyperlipidemia in obese Zucker rats is a cause or an effect of renal pathology. It has been shown that dietary cholesterol supplementation can increase focal glomerular sclerosis in rats (Fischer et al. 1983 ). In obese Zucker rats fed a high fat diet (20%), TG levels were not significantly different from those seen in obese Zucker rats fed a low fat diet [1% (Matsuda et al. 1999 )]. Low density lipoprotein cholesterol, however, was significantly higher in the high fat group. Interestingly, the high fat diet increased tubulointerstitial lesions, but not glomerular lesions, in obese Zucker rats, but had the opposite effect in lean animals. In addition, treatment of hyperlipidemia with pharmacological agents was able to reduce glomerulosclerosis in obese Zucker rats (Kasiske et al. 1988 ). The fact that the agent lowering only cholesterol had similar effects to the agent reducing both cholesterol and TG suggested that the changes in cholesterol played the most important role in reducing glomerulosclerosis. However, we observed that cholesterol levels peaked after UAE had already reached maximum, indicating that hypercholesterolemia resulted from, rather than caused, renal injury (Gades et al. 1999 ). In contrast, TG became elevated before, or at least concomitant with, the development of abnormal UAE (Gades et al. 1998 , Gades et al. 1999 ). Obese Zucker rats fed a diet containing the -glucosidase inhibitor, acarbose, remained not only normoglycemic but also exhibited reduced TG and were partially protected from glomerulosclerosis (Michel et al. 1997 ). This further suggested that TG played an important role in the renal pathology of obese Zucker rats.

Normally, female rats are less likely to develop proteinuria and glomerular lesions than are males, and progression is slower; similar observations have been made in humans (Silbinger and Neugarten 1995 ). This is thought to be due to estrogen and its beneficial effects on hyperlipidemia. However, this is not the case in obese Zucker rats, and Nagase analbuminemic rats (NAR) constitute another exception in that females are characterized by high levels of TG and cholesterol in both very low density lipoproteins and low density lipoproteins and spontaneously develop proteinuria and glomerulosclerosis, whereas only mild proteinuria and no glomerulosclerosis are detected in males (Joles et al. 1995 ). Ovariectomy decreased TG and cholesterol levels as well as glomerulosclerosis (Joles et al. 1995 , Joles et al. 1996 ). However, cholesterol levels were significantly lowered only if ovariectomy was performed early enough to be effective in reducing proteinuria (Joles et al. 1996 ), suggesting that TG levels were the primary factor influencing renal pathology. Administration of estradiol to ovariectomized or orchidectomized NAR induced high levels of hypercholesterolemia and hypertriglyceridemia and resulted in severe glomerulosclerosis (Joles et al. 1998 ).

We performed similar experiments in ovariectomized (Ovx) obese female Zucker rats (Gades et al. 1998 ). As had been reported in NAR, we observed beneficial effects from ovariectomy, especially when accompanied by pair feeding to the sham-operated group, on plasma TG levels and the severity of renal pathology. However, plasma cholesterol was not significantly affected by ovariectomy even in the presence of food restriction. In contrast, continuous estradiol treatment resulted in significant increases in cholesterol and in dramatic elevations in TG levels and the most severe renal lesions of all groups. Of particular interest was the finding that severe hypercholesterolemia, hypertriglyceridemia and glomerulosclerosis occurred, even though food intake and body weight were significantly lower in the estrogen-treated than in any other group (Ovx, Sham-operated and Ovx pair-fed to Sham). Thus, estrogen administration more than counterbalanced the beneficial effects of reduced food consumption, most likely by inducing severe hypertriglyceridemia. It needs to be kept in mind, however, that estradiol is only one of many forms of estrogen and that administration was continuous, resulting in a cumulative dose that was most likely considerably higher than in cyclic female rats.

The data from animal studies that we reviewed here clearly demonstrate that food restriction can largely prevent renal pathology in nonobese rats and can substantially reduce the severity of and high mortality from glomerulosclerosis even in obese Zucker rats. In view of the consistency of these findings in experimental models, it is somewhat surprising that protein, but not energy, restriction is occasionally recommended as part of a treatment regimen for patients with glomerulosclerosis and ESRD (Kobrin 1998 , Mackenzie and Brenner 1998 ).

	FOOTNOTES

 
¹ Presented at the symposium "Calorie Restriction: Effects on Body Composition, Insulin Signaling and Aging" as part of the Experimental Biology 2000 meeting held April 15–18, 2000 in San Diego, California. This symposium was sponsored by the American Society for Nutritional Sciences and the American Society for Clinical. The proceedings of this symposium are published as a supplement to The Journal of Nutrition. Guest Editor for this supplement publication was Barbara Hansen, Obesity and Diabetes Research Center, School of Medicine, University of Maryland, Baltimore, Maryland.

² Supported by Nora Eccles Treadwell Foundation and DK 35747 and DK 07355.

⁴ Abbreviations used: ESRD, end-stage renal disease; BMI, body mass index; OLETF, Otsuka Long-Evans Tokushima Fatty; TG, triglycerides; UAE, urinary albumin excretion; NAR, Nagase analbuminemic rats; Ovx, ovariectomized.

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