Plasma leptin levels and triglyceride secretion rates in
VMH-lesioned obese rats: a role of adiposity
Asako
Suga1,2,
Tsutomu
Hirano1,
Shuji
Inoue2,
Masatomi
Tsuji1,
Toshimasa
Osaka2,
Yoshio
Namba2,
Masakazu
Miura3, and
Mitsuru
Adachi1
1 First Department of Internal
Medicine, Showa University School of Medicine,
2 Division of Geriatric Health and
Nutrition, National Institute of Health and Nutrition, and
3 Mitsubishi Kagaku Bio-Clinical
Laboratory, Tokyo 142-8666, Japan
 |
ABSTRACT |
To explore the role of adiposity on
hypertriglyceridemia associated with obesity, we examined the relation
between triglyceride secretion rate (TGSR) and plasma leptin, insulin,
or insulin resistance in ventromedial hypothalamus (VMH)-lesioned rats
in the dynamic and static phases (2 and 14 wk after lesions,
respectively). VMH-lesioned rats gained body weight (BW) at fivefold
higher rates in the dynamic phase compared with sham-operated control
(sham) rats, and BW gain reached a plateau in the static phase.
Parametrial fat pad mass was increased 2.5-fold in VMH-lesioned rats
compared with sham rats in both phases. Leptin levels were sixfold
higher in VMH-lesioned rats of the dynamic phase and even higher in the static phase. Insulin levels were twofold higher in VMH-lesioned rats
than in sham rats in both phases. In the dynamic phase,
VMH-lesioned rats had 2-fold higher plasma triglyceride (TG) levels and
2.6-fold higher TGSRs, whereas steady-state plasma glucose (SSPG)
values, an indicator of insulin resistance, were lower. SSPG values
became significantly higher in VMH-lesioned rats in the static phase, but TGSR was not further accelerated. TGSR was significantly associated with leptin, independent of insulin. Leptin was highly correlated with
BW, fat mass, and nonesterified fatty acids (NEFA). These results
suggest that adiposity itself plays a critical role in TGSR probably
through increased NEFA flux from enlarged adipose tissues. Insulin
resistance is not associated with the overproduction of TG in this
animal model for obesity.
hyperinsulinemia; insulin resistance; ventromedial hypothalamus
lesions
 |
INTRODUCTION |
IT IS WELL KNOWN that hypertriglyceridemia is
frequently accompanied by obesity in human beings, which is a risk
factor for coronary heart disease (9). The mechanisms for
hypertriglyceridemia associated with obesity are multifactorial. It has
been suggested that insulin resistance and/or hyperinsulinemia plays a
key role in stimulating very low density lipoprotein
(VLDL)-triglyceride (TG) secretion by the liver (2, 15, 23). However,
the role of hyperinsulinemia in the pathogenesis of VLDL-TG
overproduction remains controversial (24, 33). Short-term
administration of insulin suppresses VLDL-TG secretion in vivo (11,
26), and the addition of insulin to the medium also suppresses VLDL-TG secretion from cultured hepatocytes (14, 32). Chronic hyperinsulinemia induced by multiple injections of insulin stimulates the TG secretion rate (TGSR) in rats fed sucrose or fructose-rich diets (22, 34). The
feeding of sucrose or fructose, however, is known to cause insulin
resistance (21, 36, 40), and this, although not hyperinsulinemia, might
induce a rise in TGSR. Some authors have emphasized the role of insulin
resistance in VLDL secretion by the liver (1, 25, 35). According to
their hypothesis, insulin itself suppresses hepatic VLDL secretion, but
an inability of insulin action leads to a diminution of its inhibitory
power on this secretion, which results in VLDL hypersecretion (24, 25).
Bilateral lesions of the ventromedial nuclei in the hypothalamus (VMH)
can produce obesity in rats, and VMH-lesioned rats are frequently used
as a representative animal model of obesity (4, 29). Inoue et al. (19)
reported that VMH-lesioned obese rats have marked hypertriglyceridemia
due to increased TGSR and the limited capacity of TG uptake by adipose
tissues. The higher TGSR was closely associated with increased plasma
insulin levels (19). However, it remains obscure whether the
hyperinsulinemia directly stimulates hepatic TG production or,
alternatively, whether insulin resistance accompanied by obesity is
responsible. It is difficult to distinguish the influence of
hyperinsulinemia on TG metabolism from that of insulin resistance in
genetically transmitted animal models of obesity, because
hyperinsulinemia and insulin resistance usually develop simultaneously
(4). Unlike congenitally obese animals, VMH-lesioned obese rats have an
initial rapid period of weight gain (dynamic phase) followed by a
steady-state plateau of body weight (static phase) (4, 29). Previous
experiments have shown that plasma insulin concentrations are higher
soon after the creation of VMH lesions before development of massive obesity (4). If the lesioned rats have hyperinsulinemia without accompanying insulin resistance, we would be able to identify the role
of hyperinsulinemia in the hepatic TG secretion, apart from that of
insulin resistance.
The flux of excess nonesterified fatty acids (NEFA) from adipose tissue
into the circulation is an important abnormality in obesity (10). It is
reasonable to assume that NEFAs released from adipose tissue are
dependent on the amount of fat tissue and that the NEFA flux to the
liver stimulates VLDL-TG production in a dose-dependent manner.
However, there is only a poor understanding of the direct association
between adiposity and hepatic TG production, because hyperinsulinemia
or insulin resistance is concomitantly developed with the progression
of obesity (7). A recently discovered obese gene product, leptin (41),
is secreted by adipose cells and functions in the regulation of food
intake and energy expenditure (8). A number of clinical and
experimental data have revealed a marked correlation between the
circulating leptin level and an absolute or a relative fat mass in the
body (8, 13, 16, 31). Thus plasma leptin concentration can
quantitatively indicate the degree of adiposity in the whole body.
In the present study, we measured plasma leptin and insulin
concentrations and determined TGSR and insulin resistance in
VMH-lesioned obese rats in different phases of obesity and attempted to
define the role of adiposity per se in hepatic TG production,
independent of hyperinsulinemia or insulin resistance.
 |
MATERIALS AND METHODS |
Rats. Female Sprague-Dawley rats of
220-250 g in body weight (Japan SCL, Hamamatsu, Japan) were kept
in individual cages on a rotating 12:12-h light-dark cycle with free
access to both standard rat chow (Oriental Food, Tokyo, Japan) and
water. The animals were anesthetized by inhalation of isoflurane
(Forane, Dainabot, Osaka, Japan), and electrolytic bilateral VMH
lesions were produced by the method previously described (4, 19, 29).
Control animals received sham VMH lesions (no current passed through
the electrode). We designated the early phase of obesity (2 wk after creating VMH lesions) as the dynamic phase and the late phase of
obesity (14 wk after VMH lesions) as the static phase (4, 19, 29). On
the day of experiments, food was withdrawn at 9:00 AM and experiments
were carried out after a 5-h fast (9:00 AM to 2:00 PM). The parametrial
fat pad was removed and weighed immediately after the following kinetic studies.
Triglyceride secretion rate.
Triglyceride secretion rate (TGSR) was determined by measuring the
increase in plasma TG concentration after an intravenous injection of
Triton WR 1339 (Sigma, St. Louis, MO) (600 mg/kg body wt, 25% solution
in saline). Rats were anesthetized with pentobarbital sodium (0.4 mg/100 g body wt, Nembutal, Dainabot), and blood was collected
immediately before Triton WR 1339 injection and at 15, 30, and 60 min
thereafter. Plasma TG concentration was found to increase linearly
(r > 0.992) over the 60-min period in each rat. TGSR was calculated from the increment in TG concentration per minute multiplied by the plasma volume of rat and expressed in
milligrams per minute per 100 g body wt to adjust significant differences in body weight among groups. The validity of the Triton method for estimating TGSR has been described elsewhere (18, 39). A
majority of plasma TG (>90%) was recovered in the VLDL fraction
(density >1.006 g/ml) in both pre- and post-Triton plasmas. Therefore, the TGSR determined by the Triton WR 1339 method virtually implies the rate of hepatic VLDL-TG secretion (18). Because food was
withdrawn 5 h before the experiment, intestinal contribution to TGSR
would not be significant, if any (30).
Steady-state plasma glucose method for evaluation of
insulin resistance. Insulin resistance in
the whole body was assessed by the steady-state plasma glucose (SSPG)
method originally developed by Reaven's laboratory (37, 40) and
modified by Harano et al. (17). Rats were anesthetized with
pentobarbital and then given a constant infusion of glucose (8 mg · kg
1 · min
1),
insulin (2.5 mU · kg
1 · min
1,
Humulin R, Eli Lilly-Shionogi, Osaka, Japan), and somatostatin (0.5 µg/min, Sigma) for 170 min through a cannula inserted into the right
jugular vein. Blood samples were collected before the infusion was
started and 150, 160, and 170 min after the infusion from a cannula
inserted into the femoral vein. Under these conditions, endogenous
insulin release was inhibited by somatostatin and SSPG was maintained
during the last 20 min of the infusion. The mean of 150-, 160-, and
170-min samples was used to determine the SSPG values. Because the SSPG
response is a direct reflection of the efficiency of insulin-mediated
glucose disposal, higher SSPG values imply proportionally greater
insulin resistance.
Intravenous glucose tolerance
test. The test involved in an injection of
a 0.5 g/ml glucose solution via the catheter at a 1 g/kg body wt dose.
Blood samples were collected before glucose injection and 5, 10, 30, and 60 min afterward. The blood was immediately centrifuged at 4°C,
and plasma was stored at
20°C until it was assayed.
Measurements. Plasma TG concentration
was determined by the enzyme method with a commercially available kit
(Triglyceride-G test, Wako Pure Pharmaceutical, Osaka, Japan). Plasma
glucose levels were determined by glucose oxidase method (Glucose
B-test, Wako Pure Pharmaceutical). Plasma NEFA concentration was
determined by the enzyme method with a commercially available kit
(NEFA-C test, Wako Pure Pharmaceutical). Immunoreactive insulin
concentrations were determined by a radioimmunoassay kit (no. RI-13K,
Linco Research, St. Charles, MO) standardized against rat insulin.
Plasma leptin concentrations were determined by a radioimmunoassay kit
(no. RL-83K, Linco Research) for specifically determining rat leptin.
Statistics. Data are expressed as mean ± standard deviation (SD). Statistical significance was assessed by
one-way ANOVA, and P < 0.05 was
accepted as a significant difference. The correlation coefficients
between two parameters were determined by Pearson's simple linear
regression analysis. In an attempt to evaluate the partial influence of
parameters on the TGSR, independent of plasma insulin level, multiple
regression analysis was performed with the TGSR as the dependent
variable, and insulin was entered as the independent variable. An
F value greater than four was accepted as indicating independent significance.
 |
RESULTS |
Profiles of sham-operated and VMH-lesioned
rats. Table 1 shows general
and metabolic characteristics of sham-operated and VMH-lesioned rats in
the dynamic phase and in the static phase. The food intake of rats with
bilateral VMH lesions increased significantly compared with that of
sham-operated rats 2 wk after the operations; however, the hyperphagia
in VMH-lesioned rats became less obvious in the static phase. In the
dynamic phase, the VMH-lesioned rats gained body weight at 5-fold
higher rates and had a 2.5-fold increased parametrial fat pad weight
compared with sham-operated rats. In the static phase, body weight gain
in VMH-lesioned rats reached a plateau, but the final body weight and
the parametrial fat pad weight were 1.3- and 2.6-fold greater than
those in sham-operated rats, respectively. In sham-operated animals,
body weight and fat pad weight were increased 1.3- and 2-fold 14 wk
after the operation compared with those at 2 wk, respectively.
VMH-lesioned rats had a 2-fold higher plasma TG concentration in the
dynamic phase and a 2.5-fold higher plasma TG concentration in the
static phase than those in respective controls. Plasma NEFA levels were significantly increased in VMH-lesioned rats in both phases compared with those in the respective control rats. Plasma insulin levels were
twofold higher in VMH-lesioned rats of the dynamic phase compared with
controls. These levels tended to be further increased in VMH-lesioned
rats of the static phase, but this figure did not reach statistical
significance. Plasma insulin levels were comparable between the control
rats of 2 wk and those of 14 wk after the sham operation. Plasma leptin
concentrations were sixfold higher in VMH-lesioned rats in the dynamic
phase, and the levels were further elevated in the static phase. In
sham-operated rats, plasma leptin levels were doubled 14 wk after the
operation compared with those at 2 wk.
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Table 1.
General and metabolic characteristics of sham-operated and
VMH-lesioned rats in different phases of obesity
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|
Correlation of plasma leptin concentrations with
adiposity. Plasma leptin levels were highly correlated
with body weight, parametrial fat pad weight, and percent fat pad (the
fat pad weight divided by body weight) in all rats (Fig.
1). The fat pad weight was significantly
correlated with body weight (n = 30, r = 0.830, P < 0.0001).

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Fig. 1.
Correlations of plasma leptin concentrations with body weight (BW),
parametrial fad pad weight, and percent fat pad. , VMH-lesioned rats
of dynamic phase; , sham-operated control rats 2 wk after operation;
, ventromedial hypothalamus (VMH)-lesioned rats of static phase;
, sham-operated control rats 14 wk after operation.
|
|
TGSR and insulin resistance. TGSRs in
VMH-lesioned rats were increased by 2.5-fold in the dynamic phase and
1.5-fold in the static phase compared with the respective sham-operated
controls (Fig. 2). In sham-operated rats,
the TGSR was increased twofold at 14 wk compared with that at 2 wk.
Although the TGSR increase was marked, SSPG values were not increased
in VMH-lesioned rats 2 wk after the creation of VMH lesions and, in
fact, were lower than those in sham-operated controls. SSPG values,
however, were substantially elevated in rats with VMH lesions of the
static phase. Despite the marked increase in SSPG values, the TGSRs in the static phase showed only a nonsignificant rise compared with those
in VMH-lesioned rats of the dynamic phase. Unlike VMH-lesioned rats,
SSPG values were not altered in control rats 2 or 14 wk after the sham
operation. In all animals, there was an excellent positive correlation
between plasma TG concentrations and TGSRs (r = 0.708, P < 0.0002, n = 22), indicating that an increase
in TG production causes hypertriglyceridemia.

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Fig. 2.
Triglyceride secretion rate (TGSR) and insulin resistance. TGSR was
determined by measuring increase in plasma triglyceride (TG)
concentration after an intravenous injection of Triton WR 1339 (600 mg/kg body wt). TGSR was calculated from the increment in TG
concentration/min × plasma volume and expressed in
mg · min 1 · 100 g body wt 1. Rats were given
a constant infusion of glucose (8 mg · kg 1 · min 1),
insulin (2.5 mU · kg 1 · min 1),
and somatostatin (0.5 µg/min) for 170 min, and an average
concentration of plasma glucose at 150-, 160-, and 170-min samples was
used to determine steady-state plasma glucose (SSPG) values, which
indicate insulin resistance. VMH-2W, VMH-lesioned rats of dynamic
phase; sham-2W, sham-operated control rats 2 wk after operation;
VMH-14W, VMH-lesioned rats of static phase; sham-14W, sham-operated
control rats 14 wk after operation. Data are means ± SD.
Statistical significance by one-way ANOVA at
P < 0.05: a, vs. sham control (2 wk); b, vs. sham control (14 wk); c, vs. VMH-lesioned rats of dynamic
phase.
|
|
Intravenous glucose tolerance
test. Basal plasma glucose levels were
identical in all groups of rats. These levels peaked 5 min after
glucose injection and then declined (Fig.
3). The levels after glucose load were
significantly higher in VMH-lesioned rats of the static phase compared
with their sham-operated counterparts, whereas such glucose intolerance
was not observed in VMH-lesioned rats of the dynamic phase.
VMH-lesioned rats in both phases showed a marked increase in insulin
response to glucose load compared with control rats. In VMH-lesioned
rats, the magnitude of the hyperinsulinemia was comparable between
animals in the two phases. Plasma NEFA levels before glucose injection
were significantly higher in VMH-lesioned rats in both the dynamic and
static phases compared with respective control rats. The levels in
these rats in the dynamic phase declined immediately after the glucose
injection, and then the difference in NEFA levels at the baseline
between VMH-lesioned and control rats disappeared. In the dynamic phase animals, plasma NEFA levels gradually rose from 10 min after the administration of the glucose, whereas in sham-operated rats, they
continued to decline for up to 60 min after the load. When the plasma
NEFA response was indicated as a percent change from the basal level,
the percent suppression of NEFA at 10 min postglucose load was
significantly larger in VMH-lesioned rats of the dynamic phase compared
with that in control rats. Plasma NEFA levels were higher in
VMH-lesioned rats of the static phase before and 30 and 60 min after
the glucose injection than those in their sham-operated counterparts.
The levels were almost normally suppressed in the early phase of the
intravenous glucose tolerance test (IVGTT) (up to 10 min), but the
suppression became weaker in the late phase (after 30 min).

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Fig. 3.
Responses of plasma glucose, immunoreactive insulin, and nonesterified
fatty acid (NEFA) in intravenous glucose tolerance test. Glucose
solution (0.5 g/ml) at the 1 g/kg body wt dose was injected into rats,
and blood samples were collected before injection and 5, 10, 30, and 60 min afterward. , VMH-lesioned rats of dynamic phase; ,
sham-operated control rats 2 wk after operation; , VMH-lesioned rats
of static phase; , sham-operated control rats 14 wk after operation.
Statistical significance (P < 0.05):
a, vs. sham control (2 wk); b, vs. sham control (14 wk); c, vs.
VMH-lesioned rats of dynamic phase.
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|
Correlations of TGSR with plasma insulin or
adiposity. As depicted in Fig.
4, TGSR was significantly related to both
plasma insulin and leptin concentrations. Multiple regression analysis (Table 2) revealed that leptin was
independently associated with TGSR when insulin was entered as an
independent variable. Body weight was substantially related to TGSR,
and this was independent of the association with insulin. TGSR was
weakly correlated with parametrial fat pad mass, but this correlation
was lost when insulin was entered as an independent variable.

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Fig. 4.
Correlations of TGSR with insulin and leptin. , VMH-lesioned rats of
dynamic phase (n = 5); ,
sham-operated control rats 2 wk after operation
(n = 6); , VMH-lesioned rats of
static phase (n = 5); ,
sham-operated control rats 14 wk after operation
(n = 6).
|
|
Correlations between adiposity, NEFA, and
insulin. Correlations between basal plasma levels of
NEFA, insulin, leptin, parametrial fat pad mass, and percent fat pad
(parametrial fat pad mass/body weight) are demonstrated in Table
3. Plasma NEFA levels were significantly
correlated with the fat pad mass, the percentage of that mass, and
plasma leptin and insulin levels. Plasma insulin was also significantly
correlated with these parameters related to adiposity.
 |
DISCUSSION |
In the present study, we demonstrated that insulin resistance was not
developed in VMH-lesioned rats of the dynamic phase despite marked
hyperinsulinemia. The lack of insulin resistance in this phase was
confirmed by a low SSPG value, a normal glucose response, and an
augmented NEFA suppression in the IVGTT. Thus we may conclude that
hyperinsulinemia seen in the early phase of obesity is not a
consequence of insulin resistance and that the elevated TGSR is
entirely dissociated with insulin resistance in this phase. Similarly
to other obese animals, insulin resistance was then developed in
VMH-lesioned rats 14 wk after the creation of VMH lesions when body
weight gain reached a plateau and obesity became the static state. In
this phase, development of insulin resistance was confirmed by a high
SSPG value, an impaired glucose tolerance, and a diminished NEFA
suppression in the IVGTT. However, the developed insulin resistance did
not accelerate TGSR further in VMH-lesioned rats. We previously
reported that treatment with pioglitazone, an enhancer of insulin
action, cannot suppress elevated TGSR in fructose-fed Wistar fatty
rats, although it markedly ameliorated severe insulin resistance in
these obese models (21). Taken together, these studies suggest that
insulin resistance might not be an obligate factor to produce a hepatic
overproduction of TG in rats with obesity.
The role of hyperinsulinemia in hepatic VLDL-TG production is
controversial (24, 33). In vivo works have demonstrated that chronic
hyperinsulinemia enhances the hepatic secretion rate of VLDL-TG (22,
28, 38), whereas acute hyperinsulinemia in vivo (11, 25, 26) or
short-term incubation of insulin with hepatocytes (14, 32) has shown
that the hepatic secretion rate of VLDL is decreased. The present study
confirmed the close correlation between plasma insulin and TGSR in
VMH-lesioned rats reported earlier by Inoue et al. (19). Plasma levels
of glucose and NEFA were not reduced in the face of increased plasma
insulin levels in VMH-lesioned obese rats. Therefore, insulin could
promote hepatic VLDL-TG production under an abundance of substrate
availability. The data of VMH-lesioned obese rats may provide strong
evidence demonstrating that hyperinsulinemia stimulates hepatic TG
production even without insulin resistance in vivo.
The weight-reduction action of leptin is thought to be mediated
primarily by signal transduction through the leptin receptors in the
hypothalamus (8). VMH-lesioned rats could not respond to substantially
higher leptin levels (31), suggesting that a key target for the
biological actions of leptin was destroyed by the production of VMH
lesions (20). Although the physiological significance of the
circulating leptin on extracerebral organs still remains unclear, it is
generally accepted that the plasma leptin concentrations well reflect
the amount of adipose tissue in the whole body (8, 13, 16, 31),
irrespective of subcutaneous or visceral obesity (13). With the use of
plasma leptin as an index of generalized adiposity, we examined whether
the hepatic overproduction of VLDL-TG is directly attributable to an
increase in adiposity. We found a substantial correlation between TGSR and plasma leptin level, an indicator of adiposity, and multiple regression analysis showed that this correlation was independent of
insulin. Recent studies have found that insulin increases both secretion and production of leptin by adipocytes and its circulating levels (3). Therefore, there is a possibility that insulin directly
elevates plasma leptin levels without affecting adiposity. Nevertheless, a significant association between TGSRs and the parametrial fat pad weight or body weight also supports the hypothesis that increased adiposity per se contributes significantly to hepatic TG
production. There is another possibility that the peripheral actions of
leptin may contribute to hypertriglyceridemia in VMH-lesioned rats.
Recently, Lopez-Soriano et al. (27) have shown that intravenous leptin
injection mildly elevates plasma TG concentration in mice. However,
they fail to observe a significant change in hepatic lipogenesis by
leptin administration. Therefore, further studies will be needed to
elucidate whether or not leptin can directly stimulate hepatic TG
secretion in rats.
How can adiposity contribute to the stimulation of hepatic TG
production? We presume that excess NEFA flux into the
liver from enlarged adipose tissues stimulates hepatic TG production. In IVGTT, plasma NEFA concentrations in baseline were increased in
VMH-lesioned rats in the dynamic phase, whereas the percent decline in
NEFAs was not suppressed but, rather, enhanced. These results
demonstrate that the resistance to the antilipolytic action of insulin
is not developed in the adipocytes in the dynamic phase, but the
increased NEFA concentrations at the baseline may simply reflect an
enlarged adipose tissue mass. Significant correlations between NEFA and
parametrial fat pad weight or plasma leptin concentrations support this
concept. Plasma NEFA levels were significantly higher in VMH-lesioned
rats 60 min after glucose injection in the dynamic phase, suggesting
that the NEFA is again released from the enlarged adipose tissues when
insulin levels fall and that its antilipolytic power is diminished. On
the other hand, the suppression of NEFA levels during the IVGTT was
significantly sluggish in these obese animals in the late phase of
obesity, suggesting that insulin resistance is developed on the
adipocytes and that both increased adiposity and insulin resistance
contribute to an increase in plasma NEFA concentration. NEFA may
stimulate hepatic VLDL secretion by the substrate availability (24) and
by the suppression of intracellular degradation of apoprotein B (12).
Clinical studies conducted by Lewis et al. (26) have demonstrated that
an acute hyperinsulinemia during euglycemic-hyperinsulinemic clamp
suppresses plasma NEFA concentrations and hepatic secretion of VLDL-TG.
The elevation of plasma NEFA levels by infusing an artificial TG
emulsion (Intralipid) and heparin diminished the suppressive effect of insulin on the VLDL production. These results suggest that acute insulin-induced suppression of hepatic TG production is to a great extent mediated by the lowering effect of insulin on plasma NEFA concentrations. In vitro experiments also have shown that NEFA directly
stimulates VLDL-TG secretion by cultured hepatocytes even in the
presence of an excess amount of insulin (5, 6). These clinical and
experimental observations suggest that NEFA plays a major role in
stimulating hepatic TG production. This production was stimulated in
VMH-lesioned rats with an increase in adiposity but was not further
accelerated in extremely fatty rats (the fat pad mass >9 g),
suggesting that the substrate availability (NEFA flux) is a saturable
process, and the hepatic TG secretion is not further accelerated over a
sufficient amount of NEFA.
In addition to the direct effect of insulin on hepatic TG production,
there is also a possibility that hyperinsulinemia is linked to the
increase in hepatic TG production by adiposity in these obese animals.
Insulin is the major hormone promoting TG storage in adipocytes and
increasing fat tissue mass. It is well recognized that hyperinsulinemia
plays a central role in developing obesity in VMH-lesioned rats (4). We
are able to confirm from this work a significant relationship between
plasma insulin level and parameters related to adiposity. Therefore,
adipose tissue may be another primary organ responsible for insulin
that leads to the hepatic overproduction of VLDL-TG. That is, insulin
increases adiposity through its TG storage and trophic actions on
adipocytes, and then, enlarged fat tissue mass increases NEFA outflux,
which finally results in increased VLDL-TG secretion by the liver.
In summary, our results suggest that adiposity itself is another major
contributor to the increase in hepatic TG production, independent of
hyperinsulinemia. Insulin resistance does not stimulate TG production
in this animal model for obesity.
 |
ACKNOWLEDGEMENTS |
This study was supported by the fund for Comprehensive Research on
Aging and Health (Japan).
 |
FOOTNOTES |
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: T. Hirano, First
Dept. of Internal Medicine, Showa Univ. School of Medicine,
1-5-8 Hatanodai Shinagawa-ku, Tokyo 142-8666, Japan
(E-mail: hirano{at}med.showa-u.ac.jp.).
Received 18 August 1998; accepted in final form 9 December 1998.
 |
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