Centre de Recherche de l'Hôpital Laval et Centre de Recherche sur le Métabolisme Énergétique, Département d'Anatomie et Physiologie, Faculté de Médecine, Université Laval, Quebec, Canada G1K 7P4
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ABSTRACT |
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This study aimed to assess whether adipose lipoprotein lipase (LPL) becomes resistant to insulin in a nutritional model of resistance of glucose metabolism to insulin. Sprague-Dawley rats were fed for 4 wk chow or a purified high-sucrose, high-fat (HSHF) diet that induced overt insulin resistance. Rats were fasted for 24 h and then refed chow for 1, 3, or 6 h. The postprandial rise in insulinemia was similar in both dietary cohorts, whereas glycemia was higher in HSHF-fed than in chow-fed animals, indicating glucose intolerance and insulin resistance. In chow-fed rats, adipose LPL activity increased two- to fourfold postprandially, but only minimally (30%) in HSHF-fed rats. Muscle LPL decreased postprandially in HSHF-fed rats, suggesting intact sensitivity to insulin, but it increased in chow-fed animals. Peak postprandial triglyceridemia was higher (+70%) in insulin-resistant than in control rats. The postprandial rate of appearance of triglycerides in the circulation was similar in control and insulin-resistant rats, indicating that hypertriglyceridemia of the latter was the result of impaired clearance. These results demonstrate that adipose LPL becomes resistant to insulin in diet-induced IR and further suggest that, under certain nutritional conditions, modifications in adipose LPL modulation associated with insulin resistance, along with low muscle LPL, heightens postprandial hypertriglyceridemia through attenuated triglyceride clearance.
high-fat diet; insulin resistance; triglycerides
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INTRODUCTION |
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ELEVATED POSTPRANDIAL TRIGLYCERIDEMIA is considered to be a condition of high atherogenic potential (20, 38). It has been suggested that the modulation of plasma triglyceride (TG) levels after a meal may be more closely related to the rate of TG clearance than to that of TG secretion (9, 10, 28, 30). Lipoprotein lipase (LPL, EC 3.1.1.34) bound to the vascular endothelium of capillaries is the key enzyme responsible for the hydrolysis of circulating TG (36). Therefore, postprandial LPL activity is likely to be an important factor in the modulation of plasma TG levels after a meal (8).
The postprandial modulation of LPL activity is tissue specific (36). Meal intake increases LPL activity in adipose tissue by as yet incompletely defined posttranslational mechanisms (14), whereas it decreases enzyme activity in muscle (26). We (26) have recently shown that the rise in insulin was a necessary and sufficient determinant of the meal-induced changes in LPL in both adipose and muscle tissues.
Resistance of glucose metabolism to the action of insulin, a condition termed insulin resistance, is associated with abnormal rates of TG clearance in the postprandial state (10, 28). Muscle LPL activity appears to respond normally to food intake or insulin in obese and/or insulin-resistant rats (5, 15, 26, 29), suggesting that in this tissue, LPL does not become resistant to the action of insulin. On the other hand, impaired stimulation of adipose tissue LPL activity has been reported in insulin-resistant obese humans compared with lean subjects 4 h after ingestion of a high-carbohydrate meal (23) or 6 h after a euglycemic-hyperinsulinemic clamp (13). However, another study showed that adipose LPL activity was increased to the same extent in lean and obese insulin-resistant Zucker rats after an insulinogenic meal (2). Because of these considerations, whether adipose LPL modulation becomes resistant to the action of insulin during the postprandial state remains unclear. This issue could be critical to explain the higher circulating TG levels (11) and impaired TG clearance seen in insulin-resistant individuals during feeding (10, 28), particularly in the face of a persistent decrease in muscle LPL activity.
The present study was aimed at assessing the response of adipose tissue LPL to refeeding in 24-h fasted control insulin-sensitive rats and in animals rendered overweight and insulin resistant by chronic (4 wk) ingestion of a high-sucrose, high-fat (HSHF) diet. The diet has been shown by us (15) and others (16) to induce overt insulin resistance in rats. Although a 24-h fast is obviously not representative of habitual ingestive behavior, the length of fasting was chosen for its ability to reduce both insulinemia and adipose LPL activity of obese rats to that of control insulin-sensitive animals (27), since insulin levels remain higher in insulin-resistant than in normal rats after a shorter (overnight) fast (4, 15). This was deemed important since persistence of hyperinsulinemia in the fasted state may affect basal LPL activity and its ability to respond to a further postprandial increase in insulin. Finally, pelleted chow was given to both groups of rats during refeeding to allow comparison of the LPL response to a meal similar in size and nutrient composition.
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MATERIALS AND METHODS |
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Animals and treatments. One hundred twenty male Sprague-Dawley rats initially weighing 175-200 g were purchased from Charles River Laboratories (St. Constant, Canada) and housed individually in stainless steel cages in a room kept at 23 ± 1°C with a 12:12-h light-dark cycle (lights on at 2000). The animals were cared for and handled in conformance with the Canadian Guide for the Care and Use of Laboratory Animals, and the protocols were approved by our institutional animal care committee. Rats had free access to tap water and a stock diet (Charles River Rodent Diet no. 5075; Ralston Products, Woodstock, ON, Canada). Two days after their arrival, one-half of the rats was given the ground stock diet (chow), whereas the other one-half was fed a purified diet consisting of 41% energy as carbohydrate, 39% as fat, and 20% as protein. The composition of the diet was the following (in g/100 g diet): 45.0 sucrose, 10.0 corn oil, 10.0 lard, 22.5 casein, 0.3 DL-methionine, 1.2 vitamin mix (Teklad no. 40060; Teklad Test Diets, Madison, WI), 5.5 mineral mix (AIN-76; ICN Biochemicals, Montreal, QC, Canada), and 5.5 fiber (Alphacel; ICN Biochemicals). This HSHF diet has been shown to rapidly induce insulin resistance in peripheral tissues, including adipose tissues and muscles (15, 16). A subgroup of 36 rats was used after 2 wk of feeding to perform euglycemic-hyperinsulinemic clamps (see below). Two weeks later (i.e., after a total period of 4 wk), the remaining 84 rats were killed 1 h after the beginning of the lighted period, either after a 24-h fast or after 1, 3, or 6 h of refeeding after 24 h of food deprivation. This period of fasting was chosen because of its ability to decrease both insulinemia and adipose LPL of insulin-resistant rats to levels observed in insulin-sensitive animals (4, 15, 27). During the refeeding period, both chow- and HSHF-fed rats were given pelleted rodent chow, since a preliminary study indicated that this procedure temporarily limited food intake of chow-fed rats to that of HSHF-fed rats, whose food intake was otherwise reduced because of the change in diet. This allowed comparison of changes in LPL activity independently of meal size and composition. Refeeding was not pursued beyond 6 h because of differences in food intake between dietary cohorts. The protocol also allowed comparison of groups at the same time of the circadian glucocorticoid rhythm. Rats were anesthetized with an intraperitoneal injection of 0.4 ml/kg of a ketamine (20 mg/ml)-xylazine (2.5 mg/ml) solution, and blood and tissues were harvested immediately thereafter (see below).
Euglycemic-hyperinsulinemic clamp.
Thirty-six rats were cannulated in the right jugular vein and left
carotid artery under isoflurane anesthesia. Two days after surgery,
food was removed at 2200. The next day, after a 12-h fast, nine rats
from each of the two dietary cohorts were infused for 2 h with the
carrier solution [0.1% albumin (fraction V, fatty acid free); Sigma,
St. Louis, MO] dissolved in 0.9% NaCl], whereas the remaining nine
animals from both dietary cohorts were subjected to a 2-h
euglycemic-hyperinsulinemic clamp. The clamp was performed essentially
as described by Kraegen et al. (18). Rats were allowed to
rest for 20 min after having been fitted for the infusions. Insulin
(150 mU/ml) dissolved in the carrier solution was infused at a rate of
4.1 mU · kg body wt1 · min
1
in the jugular vein. Every 5 min, 20 µl of blood were taken from the
carotid cannula to measure glycemia. The cannula was then flushed of
blood with 3% sodium citrate dissolved in 0.9% NaCl. A 25% glucose
solution dissolved in 0.9% NaCl was infused in the jugular vein from
the beginning of the clamp and was adjusted thereafter to maintain
glycemia near the fasting level. Sham infusions were performed
similarly, except that no insulin was present in the NaCl-albumin
solution and no glucose was infused. Blood was also collected before
and after the clamp and was kept on ice until centrifuged (1,500 g, 4°C, 15 min). The separated plasma was stored at
70°C until later insulin measurement.
Rate of appearance of TG in plasma. To determine the rate at which exogenous and endogenous TG appear in the circulation, an additional protocol was carried out with 40 rats fed long-term chow or the HSHF diet, fasted, and refed exactly as described above. Either in the fasted state (10 rats/dietary cohort) or 2.5 h into the chow-refeeding period (10 rats/group), after an initial blood sample (0.15 ml) was withdrawn through the venous catheter, rats were injected through the catheter with 300 mg/kg body wt of Triton WR-1339 (Sigma), a detergent that prevents intravascular TG catabolism (25). Blood samples (0.15 ml) were then taken 20, 40, and 60 min after the Triton injection. The rate of TG appearance in the circulation was determined from regression analysis of TG accumulation in plasma vs. time. The rate of TG appearance was calculated by multiplying the slope of the regression line by plasma volume estimated from body weight and was expressed as micromoles per minute.
Plasma and tissue sampling.
Immediately after the opening of the thoracic cage, blood was collected
by cardiac puncture and centrifuged (1,500 g, 15 min at
4°C), and the separated plasma was stored at 70°C until later biochemical measurements. Inguinal, epididymal, and retroperitoneal white adipose tissues (WAT) were excised, and ~50 mg from each tissue
were homogenized with all-glass tissue grinders (Kontes, Vineland, NJ).
Adipose tissue samples were homogenized in 1 ml of a solution
containing 0.25 mol/l sucrose, 1 mmol/l EDTA, 10 mmol/l
Tris · HCl, and 12 mmol/l deoxycholate, pH 7.4. Homogenates were centrifuged (12,000 g, 20 min at 4°C), and the
fraction between the upper fat layer and the bottom sediment was
removed, diluted with 4 vol of the homogenization solution without
deoxycholate, and stored at
70°C until LPL activity measurement.
LPL in tissue homogenates represents a pool of endothelium-bound and
active intracellular enzyme. The response of this total pool to various physiological conditions generally parallels that of the
heparin-releasable, endothelium-bound fraction, although not
necessarily in an identical extent (22).
Plasma determinations. Plasma glucose concentrations were measured by the glucose oxidase method with a Beckman glucose analyzer. Insulin was determined by RIA using a reagent kit from Linco Research (St. Charles, MO) with rat insulin as the standard. Plasma TG were measured by an enzymatic method using a reagent kit from Boehringer Mannheim (Montreal, QC, Canada) that allows correction for free glycerol. Plasma nonesterified fatty acids (NEFA) were also determined by an enzymatic colorimetric technique (Wako Pure Chemical Industries, Richmond, VA).
Tissue LPL activity. Thawed tissue homogenates (100 µl) were incubated under gentle agitation for 1 h at 28°C with 100 µl of a substrate mixture consisting of 0.2 mol/l Tris · HCl buffer, pH 8.6, that contained 10 MBq/l [carboxyl-14C]triolein (Amersham, Oakville, ON, Canada) and 2.52 mmol/l cold triolein emulsified in 50 g/l gum arabic, as well as 20 g/l fatty acid-free BSA, 10% human serum as a source of apolipoprotein C-II, and either 0.2 or 2 mol/l NaCl. Free oleate released by LPL was then separated from intact triolein and mixed with Universol (NEN, Montreal, QC, Canada), and sample radioactivity was determined in a scintillation counter. LPL activity was calculated by subtracting lipolytic activity determined in a final NaCl concentration of 1 mol/l (non-LPL activity) from total lipolytic activity measured in a final NaCl concentration of 0.1 mol/l. LPL activity was expressed as microunits (1 µU = 1 µmol NEFA released/h of incubation at 28°C). The interassay coefficient of variation was 4.1% and was determined using bovine skim milk as a standard source of LPL. Protein content of the tissue extracts was measured by the method of Lowry et al. (19). To account for diet-induced differences in tissue TG content, data are expressed as LPL activity per gram total tissue protein.
Statistical analysis. Data are presented as means ± SE. The main and interactive effects of the chronic diet and time or nutritional status were analyzed by factorial ANOVA. When justified by the ANOVA analysis, differences between individual group means were then analyzed by Fisher's protected least squares difference test. Differences were considered statistically significant at P < 0.05.
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RESULTS |
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In the animals subjected to the hyperinsulinemic-euglycemic clamp,
HSHF-fed rats were hyperinsulinemic compared with their chow-fed
counterparts before the onset of the insulin infusion (1.9 ± 0.4 vs. 0.8 ± 0.1 nmol/l, P < 0.04), whereas
insulinemia, which was increased significantly by exogenous insulin
infusion, was comparable in both cohorts at the end of the 2-h infusion (3.6 ± 0.5 vs. 4.1 ± 0.1 nmol/l in HSHF- and chow-fed rats,
respectively). Preinfusion glucose levels were slightly higher in the
HSHF than in the chow-fed group (5.0 ± 0.2 vs. 4.3 ± 0.1 mmol/l, P < 0.003). Glycemia achieved during insulin
infusion was comparable in the chow- and HSHF-fed rats (average levels
between 60 and 120 min of infusion: 4.4 ± 0.2 and 4.6 ± 0.2 mmol/l, respectively). The variation in glycemia during the infusions
never exceeded 10%. The sham infusion did not alter plasma glycemia
(data not shown). The steady-state glucose infusion rate needed to
maintain euglycemia in the HSHF-fed rats was approximately one-half of
that in the chow cohort (average between 60 and 120 min: 14.2 ± 1.5 vs. 27.2 ± 1.4 mg · kg1 · min
1, P
< 0.0001, n = 8 and 7, respectively), indicating
frank whole body insulin resistance.
Compared with chow, chronic ingestion for 4 wk of the HSHF diet
resulted in larger increases in body weight (P < 0.004) and adipose tissue weight (P < 0.0001) for all
depots studied (Table 1), which reflected
the larger energy intake (average: 413 ± 11 vs. 258 ± 14 kJ/day, P < 0.0001), as previously reported (15, 21). Pelleted chow intake during refeeding after a 24-h fast was
similar in both chow- and HSHF-fed animals at all times during refeeding (Table 2).
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At the end of the fasting period, no difference in plasma insulin
(Fig. 1A), glucose (Fig.
1B), NEFA (Fig. 1C), or TG (Fig. 1D)
concentrations was observed between chow- and HSHF-fed rats. As
expected, food intake increased glycemia and insulinemia of both
groups. Despite similar plasma insulin concentrations, HSHF-fed rats
had higher levels of glucose than chow-fed animals at 3 and 6 h
after the beginning of the refeeding period (P < 0.0001), which indicates resistance of glucose metabolism to the action of insulin in the former group. The reduction in plasma NEFA was slower
in HSHF-fed animals than in chow-fed rats (P = 0.003 between groups at 1 h); however, NEFA concentrations had reached
ad libitum values (data not shown) from the 3rd h of refeeding in both
groups. Triglyceridemia was significantly higher in HSHF-fed rats than in controls at 3 h upon refeeding (P < 0.01).
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In the three adipose depots studied (inguinal, retroperitoneal, and
epididymal; Fig. 2, A,
B, and C, respectively), LPL activity was not
significantly different between the two dietary groups after the 24-h
fast. Refeeding increased LPL activity in all three depots in chow-fed
animals (P < 0.0001), which peaked at 3 h in the
inguinal and epididymal depots, and further increased at 6 h in
the retroperitoneal depot (P < 0.05). In HSHF-fed
animals, food intake brought about a slight increase in LPL activity
that did not reach beyond 30% over fasting values. Three hours into the refeeding period, LPL activity was at least twofold higher in
chow-fed than in HSHF-fed animals (P < 0.003 for all
depots studied), which coincided with the time point at which
triglyceridemia was higher in the HSHF-fed than in the chow-fed rats.
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The refeeding-induced changes in LPL activity in the soleus and vastus
lateralis muscles (VLM) are depicted in Fig.
3. The postprandial excursion of soleus
LPL activity was relatively modest and did not reach significance
relative to fasting values. However, soleus LPL was consistently lower
in the HSHF- than in the chow-fed cohort, and significantly so at the
1- and 3-h time points. In the VLM, LPL activity increased
significantly after refeeding in the chow-fed, but not in the HSHF-fed
animals. As was the case for the soleus, VLM LPL tended to be lower in
the HSHF-fed than in the chow-fed rats at all time points postrefeeding
and was approximately fourfold lower 1 h after the onset of
refeeding.
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In the fasted state, the rate of TG appearance in the circulation
(essentially very low density lipoprotein from hepatic origin) was
identical in the two dietary cohorts (Fig.
4). As expected because of the
postprandial input of intestinal chylomicrons, the rate of TG
appearance increased by 30-50% during refeeding (P < 0.0002), without a significant effect of the
chronic diet.
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DISCUSSION |
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The present study demonstrates that, after 24 h of food deprivation, the short-term activation of adipose tissue LPL on refeeding is impaired in insulin-resistant rats and that an HSHF diet alters the postprandial modulation of LPL by insulin. The findings further support the notion that impairment of adipose LPL modulation in rats with diet-induced insulin resistance exacerbates postprandial hypertriglyceridemia through attenuated TG clearance.
The HSHF diet, which mimics to some extent the high-energy diets frequently consumed by many individuals, has been previously used by us (15) and others (31) to induce insulin resistance in rats. The sucrose component of the diet potentiates the deleterious effect of high-fat diets on insulin-stimulated glucose uptake (16, 17, 37). In rats fed the HSHF diet for 2 wk, preclamp hyperinsulinemia and glucose infusion rates during the clamp confirmed the well-established production by such diets of whole body insulin resistance of glucose metabolism (16, 17). Defective peripheral insulin-mediated glucose disposal in rats fed a high-fat diet for 3 wk has been localized to skeletal muscle, WAT, and the liver in studies performed with glucose tracers and an insulin infusion rate similar to that used herein (35).
The length of fasting (24 h) was chosen because of its ability to decrease both insulinemia and adipose LPL of insulin-resistant rats to levels observed in insulin-sensitive animals (27). In diet-induced insulin-resistant rats (15) and in obese Zucker rats (4), hyperinsulinemia persists after overnight (12-h) food deprivation, which was also demonstrated in the present study (see RESULTS). Although direct measurement of insulin sensitivity was not performed in rats fed during 4 wk, the higher postprandial glycemia in HSHF-fed rats, which was not caused by differences in acute food consumption, is an indication of glucose intolerance and insulin resistance and corroborates the clamp studies performed 2 wk earlier. The fact that refeeding chow to the HSHF rats resulted in hyperglycemia without hyperinsulinemia relative to chow-fed rats suggests a transient defect in insulin secretion. In fact, a recent study has reported a defect in glucose-induced insulin secretion by islets isolated from high-fat-fed rats (7). Such a secretory defect appears to be transient and may conceivably be specific to chow refeeding, because HSHF-fed rats are hyperinsulinemic compared with chow-fed rats when assessed after an overnight fast or after refeeding of their habitual (HSHF) diet (15). In the present refeeding paradigm, the fact that fasting and postprandial insulinemia were similar in both dietary cohorts throughout the refeeding period had the advantage of allowing assessment of the acute modulation of LPL in response to an identical insulin load.
The postprandial modulation of LPL is mediated by insulin (26). The rise in insulinemia upon feeding is a sufficient and necessary condition to stimulate LPL activity in WAT and to decrease it in muscle (26). In WAT, the increase in LPL activity is induced by as yet poorly understood mechanisms that do not involve changes in LPL mRNA or total mass during at least the first 8 h after food intake (1, 12, 14, 23, 24, 33). The activity of LPL assessed here therefore constitutes the major modulated variable in the present conditions. Such a modulation probably involves several steps, including the release of active LPL, activation of an inactive pool present in the fasted state (1, 6), and possibly a reduced rate of LPL degradation (3, 34). The present findings clearly demonstrate that, in diet-induced insulin resistance, the postprandial modulation of WAT LPL is impaired. Indeed, acute food intake resulted in a two- to fourfold increase in adipose LPL activity in chow-fed rats during the first 6 h of refeeding, as opposed to a small (<30%) elevation in animals chronically fed the HSHF diet. This diet-induced difference was observed despite similar increases in insulinemia during refeeding. Thus it can be concluded that insulin resistance brought about by chronic ingestion of an HSHF diet extends to LPL activation in WAT during the first hours of feeding.
Despite the association between chronic hyperinsulinemia and high adipose LPL activity in obesity-associated insulin resistance, which suggests an intact responsiveness of LPL to insulin, a few previous studies have indirectly suggested that LPL may become insulin resistant under acute conditions. In overnight-fasted humans, the dose-response curve of adipose tissue LPL to insulin infusion was shown to be shifted to higher insulin concentrations in obese subjects compared with lean individuals (13). Also, the stimulation of LPL activity measured 4 h after an insulinogenic meal was partially blunted in obese men compared with their lean counterparts (23). In addition, we have recently shown that the postprandial activation of adipose LPL is delayed in obese Zucker rats despite frank postprandial hyperinsulinemia (27). Finally, stimulation of adipose LPL activity in older, less insulin-sensitive guinea pigs relies on slow mRNA changes, whereas that of young animals occurs rapidly (~1 h) after food intake (32). The present findings extend these studies with the novel finding that a defect in the acute feeding-induced activation of adipose LPL develops in rats chronically fed a diet that deteriorates insulin action on glucose metabolism. The results also demonstrate that, although transient, this defect persists for several hours after the onset of feeding.
The postprandial hypertriglyceridemia that was observed in the HSHF-fed
rats was the result of impaired clearance. Indeed, in response to the
intake of the same amount of chow, both dietary cohorts displayed the
same rate of appearance of TG in the circulation. In the present study,
muscle LPL most likely contributed to such an impaired clearance, as
its availability was lower postprandially in HSHF-fed than in chow-fed
rats. In fact, muscle LPL was decreased upon refeeding in
insulin-resistant rats, much as it normally is after a shorter period
(12 h) of fasting in insulin-sensitive rats (26),
suggesting maintenance of the sensitivity of muscle LPL to insulin. In
animals chronically fed chow, muscle LPL was increased postprandially,
rather than decreased. We have shown in lean and obese Zucker rats that
such an increase is mediated by the -adrenergic system, which is
activated upon refeeding after 24 h of fasting in
insulin-sensitive, but not in insulin-resistant, rats (27)
and which overwhelms insulin action. In the present study, this
resulted in a lower muscle LPL activity in insulin-resistant compared
with insulin-sensitive animals, which most likely contributed to
impaired TG clearance.
In two of the three depots studied, the largest differences in LPL activation between insulin-resistant and insulin-sensitive animals were observed 3 h after the beginning of food intake, which coincided in time with higher postprandial triglyceridemia in the insulin-resistant group. It is very likely that, in the face of an increasing input of exogenous TG, the impaired stimulation of adipose LPL by insulin during the feeding period exacerbated postprandial triglyceridemia through attenuated clearance. Such a possibility is supported by arteriovenous perfusion studies in insulin-resistant obese humans, in which lower TG clearance rates by WAT were associated with heightened postprandial triglyceridemia (10, 28).
In conclusion, this study demonstrates that WAT LPL becomes resistant to the stimulatory action of insulin during refeeding in rats with diet-induced insulin resistance of glucose metabolism. The findings also strongly support the notion that, under certain nutritional conditions such as refeeding after prolonged fasting, impairment of adipose LPL modulation associated with insulin resistance, together with maintenance of the reduction in muscle LPL activity, exacerbates postprandial hypertriglyceridemia through attenuated TG clearance.
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ACKNOWLEDGEMENTS |
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This study was supported by a grant from the Canadian Institutes of Health Research. F. Picard was a recipient of a Ph.D. fellowship from the Canadian Institutes of Health Research.
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FOOTNOTES |
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Address for reprint requests and other correspondence: Y. Deshaies, Dept. of Anatomy & Physiology, School of Medicine, Laval Univ., Quebec, QC, Canada G1K 7P4 (E-mail: yves.deshaies{at}phs.ulaval.ca).
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. Section 1734 solely to indicate this fact.
10.1152/ajpendo.00307.2001
Received 10 June 2001; accepted in final form 28 September 2001.
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