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Obesity and Diabetes Research Center, School of Medicine, University of Maryland, Baltimore, MD 21201
3To whom correspondence should be addressed. E-mail: bchansen{at}aol.com
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONREFERENCES |
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KEY WORDS: • calorie restriction • obesity • weight loss
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONREFERENCES |
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). It is, however, calorie restriction
(CR)4
both during weight reduction and after weight loss in the formerly
obese that is the sine qua non for sustaining reduced body weight. CR,
however, has been shown to be extraordinarily difficult to sustain,
despite apparently high motivation to do so in the formerly obese.
Undoubtedly, this is due to the consequences of CR that accompany
weight reduction.
CR has many consequences, the majority of which are unknown at this
time. Neither the mechanisms by which life extension takes place (in
rodents) nor the mechanisms by which the complex features associated
with insulin resistance and the Metabolic Syndrome X are prevented by
CR are understood (Bodkin et al. 1995
). Clearly,
advancements in this area will lead to better understanding of this
powerful nutritional tool. The estimate of changes induced in mammals
by the long-term application of CR is likely to involve thousands
of alterations, only a small portion of which causally influence
longevity and health. One step, the description of altered functions
and the protein changes underlying those, has been advanced by several
of the reports included in this symposium. The second step,
identification within this changed spectrum of those that are causal or
principal in the observed positive outcome, awaits a future
Experimental Biology symposium.
CR produces altered pathways of nutrient disposal, including reduced
plasma glucose, insulin and leptin levels (Hansen and Bodkin 1993
, Hansen et al. 1996
). Although glucose
tolerance is retained at normal levels under CR, there is evidence to
suggest alterations in the intermediary pathways of glucose metabolism.
In detailed studies of weight stable reduced individuals, energy
efficiency was increased, that is fewer calories per lean body mass
were required to maintain stable weight (Leibel et al. 1995
, DeLany et al. 1999
) .
Among the newest tools in molecular biology that hold promise for enhancing our understanding of the mechanisms by which CR extends life and enhances health are the application of high density oligonucleotide arrays to profile alterations in gene expression and the use of high performance liquid chromatography separations coupled with coulometric array detectors to examine simultaneous changes in serum metabolites. Each of these is featured in the present symposium.
Soon microarrays will be available to simultaneously assess the changes
induced by expression of >60,000 genes. The report here of the
Wisconsin group’s application of an array of 6347 genes, as presented
by Richard Weindruch, explores the efficacy of one nutritional
intervention, dietary restriction (DR) in rodents, as an approach to
understanding the effects of DR to retard the aging process
(Weindruch et al. 2000
). Weindruch et al. have reviewed
their own and the work of others aimed at evaluating the effects of CR
at the transcriptional level in mice, most commonly as seen in liver
tissue. Possible lowering of enzyme activity related to glycolysis and
increase in enzyme activity for glycogenolysis have been suggested
(Dhahbi et al. 1997
, Dhahbi et al. 1998
,
DeLany et al. 1999
).
Weindruch and colleagues have used oligonucleotide-based and cDNA-based arrays to examine CR effects in aging mice. They surveyed 6347 genes for increases or decreases of more than twofold with aging. They have focused attention on several genes that increased in expression related to the stress response and were possibly associated with increased production of reactive oxygen species or mitochondrial dysfunction in aging. They also identified several other genes related to energy metabolism, which are decreased in aging. Finally, they have sought to determine whether these age-related changes are affected by CR. More than 50% of those genes whose expression was increased or decreased with aging showed attenuation of these changes under CR.
One of the many challenges facing those who seek to identify the mechanisms underlying the positive effects of CR on health and aging is the undoubted fact that many aspects of metabolism are simultaneously altered by CR and that these changes do not take place as step functions but are changed progressively. Some reach asymptotes and remain at maximal or minimal values. Others show dynamic changes to which later adaptations occur, obscuring the initial shake down response to CR.
For this reason tools that permit multiple repeated measures over short periods (hours) and over long periods (years) and that permit simultaneous tracking of multiple interacting and changing steps in metabolism and endocrinology are greatly needed.
One such method is under development and testing using DR as the test
experimental condition. This symposium includes the first report on the
application of metabolic stereotype analysis to characterize the
changes induced by or resulting from DR. The joint efforts of Kristol
and colleagues are being applied to examine the effects of CR on some
1200 serum compounds with particular focus on the redox-active
components of rodent serum (Vigneau-Callahan 2000
).
Variations in nutritional and metabolic status are being assessed by
combining high performance liquid chromatography separations and
coulometric array analysis to serums differing only in degree of DR.
Many challenging problems have arisen including optimization of
analytic validity as well as handling of biological variability. Of the
1200 compounds examined to date, 
250 appear to be sufficiently
reliable for further analysis.
There is evidence that the response to CR may be genetically
determined. This was particularly suggested by the finding of Ortmeyer
et al. (Ortmeyer et al. 1994
) that nonhuman primates
maintained under constant identical conditions and held to the same
stable adult body weight, nevertheless differed significantly in the
way in which CR affected their glycogen metabolism, as presented in
this symposium (Ortmeyer 2000
).
CR of nonhuman primates has been shown to prevent or substantially
delay the development of type 2 diabetes mellitus (Hansen and Bodkin 1993
). Other degenerative lesions of aging, particularly
in obese animal models such as the fa/fa rat, have also been
shown to be substantially reduced by CR. In the present symposium,
Judith Stern (Stern et al. 2000
) has addressed the
effects of CR specifically on glomerulonephritis that is common in
obese aging rodents. End-stage renal disease has greatly increased
in recent years, particularly in patients with type 2 diabetes. The
rapidly increasing prevalence of obesity and of diabetes in the U.S.
population and, in fact, in much of the world, heightens the concern
about the human as well as economic costs of these diseases and of
their complications and presents a challenge to those seeking to delay
or prevent those disorders.
CR is currently the only modality that has been shown to have the power to positively alter the course of these disorders. Judith Stern has presented here a review of the work of her group as well as the work of others that clearly demonstrates the significant positive effects of CR on renal disease. Also addressed is evidence that these studies in rodents have significant relevance to humans.
CR has as one of its consequences the reduction in body fat mass. In
order to specifically test the role of attenuated fat mass per se,
Barzilai and Gabriely have surgically ablated fat in rodents. The
results of these studies are reviewed here (Barzilai and Gabriely 2000
) and suggest that many of the beneficial effects
of CR are attributable to reduced fat stores.
CR carried out for 10 to 15 y in adult rhesus monkeys has been
shown to result in sustained alteration in glycogen metabolism, despite
apparent retention of normal insulin-stimulated glucose uptake,
normal glucose tolerance and normal fasting glucose and insulin levels.
Ortmeyer, in this symposium (Ortmeyer 2000
), has built
on previous reports of the effects of CR on insulin action on the
rate-limiting enzyme of glycogen storage, glycogen synthase. CR
appeared to unveil a predisposition in approximately one half of the CR
monkeys toward metabolic abnormalities in response to insulin.
Uniquely, CR, and no other experimental manipulation or condition, has
been found to produce insulin-stimulated inactivation of glycogen
synthase, rather than the normally expected activation of glycogen
synthase [by dephosphorylation (Ortmeyer et al. 1994
)]. Although glycogen content remained normal in all CR
monkeys, we suspect that the induction of abnormal insulin action on
glycogen synthase by long-term CR may represent a pointer toward
the underlying defect that, under ad libitum conditions, would lead to
obesity, insulin resistance and eventually type 2 diabetes in
approximately one half of aging rhesus monkeys.
The power of CR to mitigate, delay or prevent this clinical development of disease, despite the presence of underlying metabolic defects in insulin action, points to the critical need for effective CR mimetic approaches to slow or halt the consequences of the underlying genetic predispositions toward obesity and type 2 diabetes in humans (and in nonhuman primates).
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FOOTNOTES |
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2 Supported by National Institutes of Health Grant NO1-AG-0-2100.
4 Abbreviations used: CR, calorie restriction; DR, dietary restriction.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONREFERENCES |
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1.
Barzilai N., Gabriely I. The role of fat depletion in the biological benefits of caloric restriction. J. Nutr. 2000;131:903S-906S
2. Bodkin N. L., Ortmeyer H. K., Hansen B. C. Long-term dietary restriction in older-aged rhesus monkeys: effects on insulin resistance. J. Gerontol. Biol. Sci. 1995;50A:B142-B147[Abstract]
3. DeLany J. P., Hansen B. C., Bodkin N. L., Hannah J., Bray G. A. Long-term calorie restriction reduces energy expenditure in aging monkeys. J. Gerontol. Biol. Sci. 1999;54A:B5-B11[Abstract]
4.
Dhahbi J. M., Mote P. L., Tillman J. B., Walford R. L., Spindler S. R. Dietary energy tissue-specifically regulates endoplasmic reticulum chaperone gene expression in the liver of mice. J. Nutr. 1997;127:1758-1764
5. Dhahbi J. M., Tillman J. B., Cao S., Mote P. L., Walford R. L., Spindler S. R. Calorie intake alters the efficiency of catalase mRNA translation in the liver of old female mice. J. Gerontol. Biol. Sci. 1998;53:B180-B185[Abstract]
6. Hansen B., Ortmeyer H. K., Bodkin N. L. Ageing, energy restriction, and the progressive development of pathophysiology in obese nonhuman primates. Angel A. eds. Progress in Obesity Research 1996:541-547 John Libbey London, UK.
7. Hansen B. C., Bodkin N. L. Primary prevention of diabetes mellitus by prevention of obesity in monkeys. Diabetes 1993;42:1809-1814[Abstract]
8.
Leibel R. L., Rosenbaum M., Hirsch J. Changes in energy expenditure resulting from altered body weight. N. Engl. J. Med. 1995;332:621-628
9. National Institutes of Health, National Heart, Lung, and Blood Institute Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults 1998 Government Printing Office Washington, D.C.
10.
Ortmeyer H. K. In vivo insulin regulation of skeletal muscle glycogensynthase in calorie-restricted and in ad libitum–fed rhesus monkeys. J. Nutr. 2000;131(suppl. 2):907S-912S
11. Ortmeyer H. K., Bodkin N. L., Hansen B. C. Chronic caloric restriction alters glycogen metabolism in rhesus monkeys. Obes. Res. 1994;2:549-555
12.
Stern J. S., Gades M. D., Wheeldon C. M., Borchers A. T. Calorie restriction in obesity: prevension of kidney disease in rodents. J. Nutr. 2000;131(suppl. 2):913S-917S
13.
Vigneau-Callahan K. E., Shestopalov A. I., Milbury P. E., Matson W. R., Kristal B. S. High throughput characterization of diet-dependent metabolic serotypes: analytical and biological variability issues in rats. J. Nutr. 2000;131(suppl. 2):924S-932S
14.
Weindruch R., Kayo T., Lee C.-K., Prolla T. A. Microarray profiling of gene expression in aging and its alteration by caloric restriction in mice. J. Nutr. 2000;131:918S-923S
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