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Department of Medicine, Divisions of Geriatrics, Endocrinology and the Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY 10461
3To whom correspondence should be addressed. E-mail: barzilai{at}aecom.yu.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONFM, CR and peripheral...CR affects hepatic insulin...Fat distribution with aging...Fat-derived peptides, their...REFERENCES |
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KEY WORDS: • caloric restriction • fat mass • visceral fat • obesity • insulin sensitivity • fat-derived peptides
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONFM, CR and peripheral...CR affects hepatic insulin...Fat distribution with aging...Fat-derived peptides, their...REFERENCES |
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. As will be discussed, increased body weight and FM in
humans results in insulin resistance and is closely associated with the
development of dyslipidemia, hypertension, diabetes and coronary heart
disease, leading to early death. |
FM, CR and peripheral insulin sensitivity |
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TOPABSTRACTINTRODUCTIONFM, CR and peripheral...CR affects hepatic insulin...Fat distribution with aging...Fat-derived peptides, their...REFERENCES |
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,3)
. Indeed, insulin sensitivity in a
large number of lean older individuals was similar to that of
weight-matched young individuals (4)
. A recent
multi-center study demonstrated that FM, and not age, caused
decreased peripheral insulin sensitivity. Thus, FM has an overwhelming
effect on peripheral insulin sensitivity with aging. Increased visceral
fat (VF) was shown to be associated with a decrease in skeletal muscle
insulin sensitivity measured by leg balance studies and a decrease in
insulin responsiveness in BMI-matched women with upper versus lower
body obesity (5
,6)
. While improved insulin action is
typical for CR and may be involved in mechanisms affecting longevity,
impaired insulin action in humans is associated with morbidity and
mortality. As in humans, rodents display an increase in basal plasma
glucose and insulin levels with aging (7)
. The advantage
in studying animal models is the ability to intervene by diet, drugs or
surgery in a relatively homogeneous obese group and to relate the
physiologic and molecular aspects of these changes.
We examined the relationship between FM, peripheral insulin and age in
rats (8)
. We studied body composition and rates of (LBM)
glucose uptake in a group of 2-, 4-, 6-, 12- and 18-mo-old rats. The
results showed a significant gradual increase in FM from 2 to 18 mo of
age (316% increase), with a high correlation between body weight, FM
and epididimal fat. The rate of insulin-stimulated glucose uptake
decreased significantly (
14%) from 2 to 4 mo of age. Surprisingly,
we found that there was no further change in insulin responsiveness in
rats that were much older. Analyzing the data using a best fitted model
of two regression lines joined in a knot (spline curve model)
demonstrated that when body weight was 350 g or 14% fat, no
change in glucose uptake was noted with further increased body weight.
This analysis suggests that the effect of body weight was saturable for
the decrease in glucose uptake. Using the same statistical methodology
to analyze the relationship between glucose uptake and FM and
epididimal fat showed similar results (8)
. Because this
saturable effect occurred at a relatively young age, it indicates that
aging per se is not associated with further decrease in peripheral
insulin sensitivity. We next set to prove this concept by examining
whether a cause-effect relationship exists between FM and
age-related decrease in peripheral insulin responsiveness
(plasma insulin levels of 100 pmol/L). We used the same
age-group animals as the above ad libitum fed and compared them
with chronically CR rats (Fig. 1
). When CR young and older adult rats (2–4 mo) were studied, their
insulin responsiveness significantly increased. At this time, their FM
decreased to below 13% of their body weight. Interestingly, insulin
responsiveness in older calorie-restricted animals did not improve;
however, their FM percentage was higher (17%). We recently studied an
additional group of more CR [50% food intake (18 mo; n
= 5)] to decrease their FM to 13%. This resulted in a
dramatic improvement in insulin responsiveness that has not been noted
when CR resulted in a decrease from 27 to 17% in FM (Fig. 1)
.
Saturating effects of FM on peripheral insulin action had been
previously demonstrated in Pima Indians (9)
, suggesting
that once a certain critical level of fat accretion is achieved,
further alterations in glucose metabolism are difficult to detect. In
addition, this suggests that chronic benefits of weight reduction may
be obtained not by losing any weight but by losing weight below
a certain amount of fat. Furthermore, this suggests that FM
accumulation, rather than aging, is responsible for the
age-dependent insulin resistance.
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CR affects hepatic insulin sensitivity |
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TOPABSTRACTINTRODUCTIONFM, CR and peripheral...CR affects hepatic insulin...Fat distribution with aging...Fat-derived peptides, their...REFERENCES |
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. However,
suppression of HGP by insulin was significantly impaired in younger
subjects with increased abdominal obesity (11)
. To better
examine this question, we used chronic CR to maintain FM and VF at
youthful levels and to abolish the overwhelming negative effect of fat
on hepatic insulin action in 8- and 20-mo-old Brown Norway Fisher rats
(n = 344). Using the pancreatic clamp technique, we
measured their basal HGP and by inducing mild physiological
hyperinsulinemia, we measured the ability of insulin to suppress HGP
(Fig. 2
). The results demonstrated that basal HGP was similar in all groups.
However, insulin-induced suppression of HGP was significantly
increased in the calorie-restricted (8- and 20-mo-old) rats
compared with their ad libitum–fed controls (46 and 39%,
respectively). In parallel, the percentage of FM and VF was
significantly and proportionally lower in the CR groups. Importantly,
rats were chronically calorie-restricted from young adulthood to
maintain body composition at youthful levels. This study demonstrates
that insulin action on modulating HGP is not impaired by aging per se
but by age-related increases in FM and VF. This experimental
manipulation provided evidence to support the hypothesis that the
capacity of insulin to regulate hepatic glucose flux is not impaired
with aging (12)
.
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Fat distribution with aging and its metabolic effects |
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TOPABSTRACTINTRODUCTIONFM, CR and peripheral...CR affects hepatic insulin...Fat distribution with aging...Fat-derived peptides, their...REFERENCES |
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,14)
. The increase in VF can be detected
surgically (increased omental fat) or by CT scan or magnetic resonance
imaging. However, the most common epidemiological tools are the
observation of a pattern of upper body obesity, increased waist
circumference and increased waist to hip ratio. Most important, waist
to hip ratio in older men and women is increased independently of BMI
(13)
. CT scan studies in men and women of all ages
revealed a significant inverse correlation between the ratio of
subcutaneous to VF tissue with age (14)
and an increased
accumulation of fat between the muscles of the abdominal wall in older
compared with younger subjects (15)
. Thus, older men and
women show an increase in VF, although the BMI may be normal and LBM
may be decreased (16)
. VF has multi-factorial
associations with aging and may determine longevity in humans by
influencing atherosclerotic mechanisms (17)
. Numerous
studies in subjects of all ages have demonstrated that increased VF is
associated with increases in fasting and postprandial plasma insulin
levels and impaired glucose tolerance (18
,19)
.
This knowledge provided us with the opportunity to study specifically
one small fraction of fat to prove the effects that fat has on the
paradigm of ad libitum–fed and CR rats. Thus, removal of VF may
provide some cause-effect relationship in the understanding of
their metabolic impact. To directly examine whether VF modulates
hepatic insulin action, we randomized moderately obese
Sprague-Dawley rats either to surgical removal of the epididymal
and perinephric fat pads or to sham operation and then studied them 3
wk later (20)
. Total VF was fourfold increased in the
sham-operated group. However, whole body FM was not significantly
different. While plasma glucose, FFA, glycerol and glucagon were
similar, plasma insulin levels were decreased by one half in rats with
surgically removed VF. The rate of insulin infusion needed to maintain
plasma glucose levels at baseline during the hepatic-pancreatic
clamp was dramatically decreased (twofold) after VF removal. These
results demonstrate that the hepatic responses to either endogenous
(basal) or exogenous (pancreatic clamp) insulin were markedly enhanced
by removing VF. The heightened hepatic insulin sensitivity was
supported by the decrease in the gene expression of both
glucose-6-phosphatase and phosphoenolpyruvate carboxykinase by
physiological hyperinsulinemia only in the rats without VF. This
improvement in hepatic insulin sensitivity was also supported by
70% decrease in the plasma levels of insulin-like growth factor
binding protein-1, a marker of insulin’s transcription regulation in
the liver. The marked increase in hepatic insulin action after surgical
removal of selective intra-abdominal fat depots indicates a
cause-effect relationship between them and explains the basal
hyperinsulinemia in aging. Subsequently, we generated similar decreases
in VF using leptin or ß-adrenoreceptor agonists and demonstrated that
hepatic insulin action was equally improved in all rats studied. While
we defined specific effects to specific fat tissue (VF), these studies
have also supported the general concept that fat has an overall
metabolic effect (20)
.
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Fat-derived peptides, their metabolic actions and risk factors for diseases |
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TOPABSTRACTINTRODUCTIONFM, CR and peripheral...CR affects hepatic insulin...Fat distribution with aging...Fat-derived peptides, their...REFERENCES |
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has been suggested to be
directly involved in the development of insulin resistance in obesity
by its effects on insulin signaling (21
,22)
. We studied
TNF- gene expression in a variety of fat depots after surgical
extraction of VF and compared the results with gene expression in
sham-operated rats with intact VF (20)
. Most
impressively, the gene expression of TNF- in the subcutaneous fat
(the largest fat depot) was decreased by fourfold to fivefold in
rats without VF. Marked (45%) decreases in TNF- gene expression
have been demonstrated in fat obtained from obese humans who lost
weight (23)
and after dietary manipulations in obese mice.
Leptin, the most investigated fat-derived peptide, also has
tremendous implications in glucose metabolism (24)
; during
physiological hyperinsulinemia (insulin clamp), leptin markedly
enhanced the action of insulin on inhibiting HGP (fourfold lower in
leptin than in the control groups). This may have been through its
effect on decreasing VF. However, leptin had an additional effect in
improving peripheral insulin action; the rate of glucose uptake in the
leptin group was 52 and 33% higher than in saline-administered and
pair-fed groups, respectively. Interestingly, leptin may be
responsible for many of the neuroendocrine adaptations to starvation
and CR; during weight loss or fasting, both humans and animals
(25
,26)
exhibit low levels of leptin gene expression and
plasma levels. These conditions are associated with a marked
neuroendocrine adaptation, including increased steroid stress hormones,
decreased reproductive function, decreased thyroid function and delayed
puberty (27)
. Angiotensinogen (AT), another peptide
[expressed in liver and adipose tissue (28)
], may also
play an important role in the relationship between obesity,
hypertension and hyperinsulinemia (the main components of syndrome X).
The hormonal control of AT synthesis and secretion from adipocytes has
been shown to be up-regulated with glucocorticoids and TNF-.
However, in vitro studies have shown that insulin exerts an inhibitory
effect on AT production (29)
. To examine the role of
increased FM on AT, we followed AT expression after 3 h of
hyperglycemia while maintaining plasma insulin concentration at basal
(using somatostatin infusion) in lean and obese rats. The relative
increase in AT expression was threefold in both groups (Fig. 3
); however, the obese rats had fourfold increased FM compared with
the lean group. Additionally, the obese rats also demonstrated
resistance to the inhibitory effect of insulin on AT expression when
examined in an hyperinsulinemic clamp. These findings demonstrate a
potential pathological link between fat and hypertension. Plasminogen
activator inhibitor-1 is also secreted from fat tissue
(30)
, is increased with obesity, is associated with
decreased fibrinolytic activity in the blood and is a risk factor for
acute coronary events in humans. In fact, moderate CR in elderly obese
subjects decreased plasminogen activator inhibitor-1 levels
dramatically (31)
. In addition to cytokines, complement
factors (D, C3, B) are also secreted by fat tissue and have a role in
controlling immune responses (32
,33)
. Newly developed
differentiating techniques have suggested the existence of numerous
other proteins with mRNA encoded in adipocytes and specific proteins
formed and secreted from the adipocytes that achieve physiologically
adequate plasma levels. For example, the protein designated Acrp30 is a
novel serum protein similar to c1q, is produced exclusively in
adipocytes, has plasma levels in ng/mL range, binds preferentially to
muscle, has a cytokine tertiary structure and is regulated both acutely
and chronically by insulin (34)
. Modulation of risk
factors for diseases, which are nutritionally regulated in fat tissue,
may play a role in the longevity of the fat-depleted CR animals.
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FOOTNOTES |
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2 Supported by grants from the National Institutes of Health (KO8-AG00639, R29-AG15003, RO1-AG18381 to N.B.), the Core laboratories of the Albert Einstein Diabetes Research and Training Center (DK 20541). N.B. is a recipient of the Paul Beeson Physician Faculty Scholar in Aging Award.
4 Abbreviations used: FM, fat mass; CR, caloric restriction; LBM, lean body mass; BMI, body mass index; VF, visceral fat; HGP, hepatic glucose production; AT, angiotensinogen.
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TOPABSTRACTINTRODUCTIONFM, CR and peripheral...CR affects hepatic insulin...Fat distribution with aging...Fat-derived peptides, their...REFERENCES |
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