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The present study was conducted to investigate the pattern of neuronal activation and corticotropin-releasing hormone (CRH) expression in fed, food deprived and refed lean (Fa/?) and obese (fa/fa) Zucker rats. The pattern of neuronal activation was studied by measuring the expression of the immediate-early gene c-fos. Expression of c-fos and CRH mRNA was determined by in situ hybridization histochemistry. In both lean and obese rats, one hour of refeeding led to a transient increase in c-fos mRNA levels which was detected in the paraventricular hypothalamic nucleus (PVH), the dorsomedial hypothalamic nucleus, the supraoptic nucleus, the paraventricular thalamic nucleus, the central nucleus of amygdala (CeA), the lateral and medial parabrachial nuclei, the nucleus of the solitary tract, and the area postrema. In addition, refeeding led to strong activation of the arginine-vasopressin neurons located in the magnocellular part of the PVH. Following 24 h of food deprivation, CRH expression in the parvocellular division of the PVH was significantly higher in obese rats compared to lean animals. During refeeding, PVH CRH mRNA levels in obese rats decreased to reach control values. The decrease in CRH expression in obese rats was accompanied by the alleviation of the hypercorticosteronemia that characterized obese Zucker rats. CRH mRNA levels in the central nucleus of the amygdala were significantly higher in lean rats than in obese animals, when the rats were fed ad libitum During food deprivation, CeA CRH mRNA levels decreased in lean rats and gradually returned to predeprivation values during refeeding. In refed obese rats, CeA levels of CRH mRNA were higher than those of ad libitum fed or food-deprived obese mutants. In the perifornical region of the lateral hypothalamic area (LHA), the expression of CRH mRNA rose significantly in response to refeeding in lean rats, but not in obese animals. Following the first hour of refeeding, the number of neurons expressing CRH mRNA in the LHA in lean rats almost doubled. The present results demonstrate that refeeding has a stimulating effect in obese Zucker rats in a pattern of activation similar to that seen in lean Fa/? rats. They also demonstrate differences in CRH expression between Fa/? and fa/fa rats after refeeding. The most apparent of these differences was seen in the lateral hypothalamus in which refeeding failed to up-regulate CRH expression in obese rats.

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.

The purpose of this study was to determine if there were differences in the expression of lipoprotein lipase (LPL) in African American (AA) and Caucasian (CA) women. LPL mRNA and protein levels were determined in subcutaneous and omental fat of lean and obese subject from the 2 races (4 groups; 12 to 15 subjects/group). LPL mRNA levels of lean AA were not different from the lean CA women in either fat depot. LPL mRNA levels in the subcutaneous fat of the obese AA were higher than those of CA women (1.3 +/- 0.1 v 0.86 +/- 0.06, P.05), but not different in omental fat. LPL mass in subcutaneous fat of lean AA was higher (0.95 +/- 0.09 v 0.64 +/- 0.06, P.05), but not different in omental fat from the CA women. LPL mass in subcutaneous and omental fat was not different in the 2 obese groups. Differences in the activity of LPL were evaluated by (1) measuring the increments of triglycerides (TG) at 2, 4, 6, and 8 hours after a fat-rich meal and (2) by measuring postheparin plasma lipolytic activity. Plasma TG levels in the lean AA were lower than those of the lean CA women at basal and at 2, 4, 6, and 8 hours postprandially. The increase in TG levels at 2 hours tended to be lower in the AA than the CA women, was significantly lower at 4 hours (24 +/- 5 v 45 +/- 7, P.05), and was not different 8 hours postprandially. No differences were observed in either the absolute or the incremental concentrations of TG in the obese groups. Postheparin plasma LPL activity was higher in the lean AA than the lean CA women (4.8 +/- 0.4 v 3.4 +/- 0.4, P.05), but not different in the obese groups. These results indicate that the lower TG concentrations in the lean AA women may be partly due to enhanced expression, activity, and intravascular availability of LPL. Furthermore, it appears that the racial differences in expression and function of LPL are attenuated with obesity., (Copyright 2002 by W.B. Saunders Company)

The aim of the present study was to assess whether the glucocorticoid corticosterone (Cort) modulates the effects of leptin on food intake and lipid deposition. Rats were subjected to a 6-day intracerebroventricular infusion of leptin and were either sham-adrenalectomized (Sham-ADX) or ADX and supplemented with 0 (C0), 40 (C40), or 80 mg (C80) of Cort. Investigation of potential peripheral sites of interaction of leptin and Cort included liver and plasma triglyceride (TG) content and lipoprotein lipase (LPL) activity in adipose and muscle tissues. The study confirmed the respective anorectic and orexigenic effects of leptin and Cort and revealed that the leptin-induced reduction in food intake was dampened by the high dose of Cort replacement. Such an interaction did not, however, extend to body and adipose tissue weights, which were lowered by leptin infusion independently of the Cort status. Leptin and ADX significantly reduced liver TG content and triglyceridemia, whereas Cort replacement significantly increased these variables. Central infusion of leptin also lowered plasma insulin levels, accompanied by a reduction in LPL activity of storage tissues (inguinal and epididymal white adipose tissue, 2- and 3-fold, respectively). In contrast, leptin infusion increased LPL activity in oxidative tissues (soleus and vastus lateralis muscles, 3- and 4-fold, respectively). Cort replacement prevented the ADX-induced fall in epididymal LPL activity but failed to do so in leptin-infused rats. The study demonstrates that, whereas the anorectic effect of leptin is dampened by high but physiological plasma levels of corticosterone, leptin can produce its effects on body weight, lipid transport and accumulation, and adipose and muscle LPL activity in the absence or presence of an intact hypothalamic-pituitary-adrenal axis.

Objective: This study examined the effects of topiramate (TPM), a novel neurotherapeutic agent reported to reduce body weight in humans, on the components of energy balance in female Zucker rats., Research Methods and Procedures: A 2 x 3 factorial experiment was performed in which two cohorts of Zucker rats differing in their phenotype (phenotype: lean, Fa/?; obese, fa/fa) were each divided into three groups defined by the dose of TPM administered (dose: TPM 0, vehicle; TPM 15, 15 mg/kg; TPM 60, 60 mg/kg)., Results: The reduction in body weight gain induced by TPM in both lean and obese rats reflected a decrease in total body energy gain, which was more evident in obese than in lean rats. Whereas TPM administration did not influence the intake of digestible energy in lean rats, it induced a reduction in food intake in obese animals. In lean, but not in obese rats, apparent energy expenditure (as calculated by the difference between energy intake and energy gain) was higher in rats treated with TPM than in animals administered the vehicle. The low dose of TPM decreased fat gain (with emphasis on subcutaneous fat) without affecting protein gain, whereas the high dose of the drug induced a reduction in both fat and protein gains. The effects of TPM on muscle and fat depot weights were representative of the global effects of TPM on whole body fat and protein gains. The calculated energetic efficiency (energy gain/energy intake) was decreased in both lean and obese rats after TPM treatment. TPM dose independently reduced hyperinsulinemia of obese rats, but it did not alter insulinemia of lean animals., Discussion: The present results provide sound evidence for the ability of TPM to reduce fat and energy gains through reducing energetic efficiency in both lean and obese Zucker rats.

Objective: The effects of lean fish on plasma lipoproteins, postheparin plasma lipolytic activities and sex hormones were examined in 11 normolipidemic male subjects., Methods: This study was a randomized crossover trial of two isoenergetic prudent-type diets, lean fish diet and beef, pork, veal, eggs and milk (nonfish) diet. Experimental diets provided approximately 11800 kJ--18% as proteins, 50% as carbohydrates, 32% as lipids [ratio of polyunsaturated to saturated fatty acids (P:S) of 1:1 compared with 0.5:1 in preexperimental diet], and 260 mg cholesterol/day., Results: Compared with the nonfish diet, the lean fish diet induced higher plasma total and LDL apolipoprotein (apo) B and apo B:apo A-1 ratio, indicating that the substitution of lean fish for beef, veal, pork, eggs and milk provides little benefits with regard to plasma apo B concentrations in a low-fat high P:S diet. Moreover, triglycerides:apo B and cholesterol:apo B ratios of VLDL were lower following the lean fish diet than the nonfish diet, suggesting the presence of smaller very low-density lipoprotein (VLDL) particles following the consumption of lean fish. Higher plasma concentrations of sex hormone-binding globulin (SHBG), HDL2 cholesterol and HDL2:HDL3 cholesterol ratio were found with the lean fish diet compared with the nonfish diet. Negative correlations between plasma postheparin lipoprotein lipase (LPL) activity and VLDL triglycerides (n = 11, r = -0.53, p = 0.02), and between plasma postheparin LPL activity and VLDL triglycerides:apo B ratio (n = 11, r = -0.64, p = 0.02) were also observed following the lean fish diet., Conclusion: These results suggest that the effects of substituting lean fish for beef, veal, pork, eggs and milk on plasma lipoproteins may be partly associated with variations in plasma sex hormone status and plasma LPL activity in normolipidemic men.

This study aimed to dissociate the peripheral effects of adrenalectomy (ADX) on triglyceride (TG) metabolism from those it exerts centrally on energy intake and to determine the impact of diet composition therein. Rats were fed either rodent chow or a diet high in sucrose and fat (HSF) and were adrenalectomized or left intact and pair fed to the ADX animals. Liver TG content, an index of hepatic TG production, was not affected by ADX, but was increased twofold by the HSF diet. ADX decreased the rate of hepatic TG secretion by 41% in chow-fed but not in HSF-fed animals. Triglyceridemia and postheparin plasma lipase activities remained largely unchanged by treatments. ADX decreased insulinemia fivefold in chow-fed rats, but less so in HSF-fed animals. Likewise, subcutaneous and visceral adipose depots were 40-60% smaller in ADX than in intact pair-fed rats given chow, but the effect of ADX was dampened by consumption of the HSF diet. Although smaller, adipose tissues of ADX rats maintained a higher activity of lipoprotein lipase (LPL) than those of intact pair-fed rats, whereas muscle LPL was decreased. The study confirms that in the presence of reduced energy intake, corticosterone contributes to the maintenance of adipose stores and that the consequences of its absence tend to be attenuated when a high-energy diet is fed. The study further shows that, contrary to ad libitum feeding conditions, most determinants of TG metabolism, such as hepatic TG stores, triglyceridemia, postheparin plasma LPL, and adipose tissue LPL, are minimally affected by glucocorticoids when consumption of a high-energy diet is restricted, suggesting that glucocorticoids affect TG metabolism mostly indirectly through their central action on ingestive behavior.

This study was designed to assess the contribution of hyperinsulinemia to the maintenance of high adipose and low muscle lipoprotein lipase (LPL) activity in the obese Zucker fa/fa rat. Insulinemia in obese Zucker rats was reduced for 4 days with a single injection of low-dose streptozotocin (STZ). Saline-injected intact obese (obese-INT) and STZ-injected obese (obese-STZ) rats were compared with a lean Fa/? reference group. LPL activity was assessed after a 12-hour fast, with or without a 1-hour refeeding period. Fasting serum insulin levels were 17-fold higher in obese-INT versus lean rats and were reduced to 60% of obese-INT levels in obese-STZ animals. In the postprandial state, serum insulin levels remained low in obese-STZ rats and were similar to the values in lean animals, whereas insulinemia increased in the obese-INT group to 18-fold the levels in lean rats. Serum glucose, nonesterified fatty acid (NEFA), and triglyceride levels, which were higher in obese-INT versus lean rats, were further increased in the obese-STZ group. Tissue weights of obese rats were unaffected by STZ treatment. Fasting LPL specific activity was higher in white adipose tissue ([WAT] +87%) and brown adipose tissue ([BAT] +167%) of obese-INT versus lean rats. Reducing the insulinemia in obese-STZ rats reduced fasting enzyme activity to the levels in lean animals in both WAT and BAT. Insulinemia and adipose LPL activity were positively correlated in the fasted state. Acute food intake increased WAT LPL activity in lean animals, but not in obese animals. Soleus LPL activity was lower in obese-INT compared with lean rats and was further decreased in obese-STZ animals. Heart LPL was decreased only in obese-STZ rats compared with the lean group. LPL in muscle tissue was not correlated with insulinemia, but an inverse relationship was found between serum NEFA levels and enzyme activity. It is concluded that in the obese Zucker rat, hyperinsulinemia is responsible for the maintenance of elevated basal LPL activity in adipose tissue independently of fat mass, whereas muscle enzyme activity appears to be more strongly and inversely related to the availability or tissue utilization of lipid substrates.

The present study was conducted to verify whether experimental conditions such as obesity and food deprivation, which promote food intake and reduce thermogenesis, could modify the expression of the corticotropin-releasing hormone (CRH)-binding protein (BP) in the rat brain. In situ hybridization, histochemistry, and immunohistochemistry were used to assess the expression of CRH-BP in lean (Fa/?) and obese (fa/fa) Zucker rats that were fed ad libitum, food deprived for 24 h, or food deprived for 24 h and refed for 6 h. In both lean and obese rats, food deprivation led to a reduction in body weight that was accompanied by a reversible increase in plasma corticosterone levels. Food deprivation and, to a lesser degree, obesity induced the expression of CRH-BP mRNA in the dorsal part of the medial preoptic area (MPOA). This induction of the CRH-BP gene led to by food deprivation was confirmed by the appearance in the dorsal part of the MPOA of neurons immunoreactive to CRH-BP. Food deprivation (in particular) and obesity also increased the levels of CRH-BP mRNA in the basolateral amygdala (BLA). The enhanced CRH-BP expression in the MPOA and BLA in response to food deprivation was reversed by refeeding. In lean Fa/? rats, the CRH-BP mRNA level in the pituitary cells was significantly decreased after food deprivation and restored after refeeding. When food was provided ad libitum, the number of cells expressing CRH-BP in the anterior pituitary was significantly higher in lean rats than in obese animals. Food deprivation for 24 h decreased dramatically the number of pituitary cells expressing CRH-BP in lean rats. Altogether, the present results demonstrate that food deprivation and, to a lesser extent, obesity can selectively affect the expression of CRH-BP. Given both the inactivating effect of CRH-BP on the CRH system and the potential roles played by the MPOA and BLA in the thermogenic and anorectic effects of CRH, it can be argued that the induction of the CRH-BP gene in obesity and after food deprivation occurs as a mechanism to reduce energy expenditure and to stimulate food intake.

The involvement of glucocorticoids (GC) in the development of diet-induced obesity and in the concomitant adaptations of triglyceride (TG)-rich lipoprotein metabolism were examined. Rats were fed either rodent chow, which maintains a low lipid flux, or a diet high in sucrose and fat (HSF) that increases lipid flux, leading to metabolic perturbations similar to those that define the plurimetabolic syndrome in humans. The GC status was manipulated through adrenalectomy (ADX) and corticosterone (Cort) replacement. Compared with chow, the HSF diet increased energy intake (17%) and whole body (8%) and adipose tissue (80%) weights. The HSF diet also increased the acute postprandial rise in plasma insulin (4-fold) and TG (3-fold), fasting liver TG content (3-fold), triglyceridemia (54%), and adipose tissue lipoprotein lipase (LPL) activity (2-fold). ADX decreased energy intake and whole body and adipose tissue weights in both dietary cohorts, but more so in HSF-fed than in chow-fed animals. These ADX-induced effects were totally prevented by Cort replacement in rats fed chow, but only partially so in those fed the HSF diet in proportion to the degree of restoration of energy intake. In the chow-fed cohort, the above indexes of TG metabolism remained unaffected by the Cort status, whereas in the HSF-fed cohort, these variables were decreased by ADX to levels of chow-fed animals. Cort replacement in the HSF-fed animals restored indexes of TG metabolism to intact levels and reestablished the diet-related differences observed in intact animals. These findings indicate that GC modulate fasting TG metabolism only minimally when a diet that maintains a low lipid flux is fed. In contrast, their presence is a necessary condition for the development of diet-induced obesity and the concomitant alterations in insulin sensitivity and TG-rich lipoprotein metabolism.

This study evaluated the ability of alpha1-adrenergic blockade to interfere with the development of diet-induced hyperlipidemia and deterioration of insulin action. Diets having extremely divergent effects on glucose and lipid metabolism were contrasted. Rats were fed for 4 weeks either a nonpurified diet (chow) or a hyperlipidemic (HL) purified diet containing 40% energy as sucrose, 40% as fat, and 20% as casein. Half of each dietary cohort was given the alpha1-adrenergic antagonist prazosin (3 mg/kg/day in the food). Blood was collected in the fasted state (10 h after food removal) and 2 h after the intake of a meal. In the fasted state, plasma triacylglycerols (TGs) were higher in rats fed the HL diet than in those given chow and were not affected by long-term treatment with prazosin. Postprandially, plasma TG increased twofold in the chow-fed group, with or without long-term prazosin. In contrast, prazosin reduced by more than half the eightfold increase in TG that followed intake of the high-fat meal (Diet x Blocker interaction; p < 0.002) in the HL cohort. The HL-fed animals also displayed fasting hypercholesterolemia (+30%; p < 0.0001), which was prevented by long-term treatment with prazosin. Likewise, the 50% increase in plasma cholesterol that followed meal ingestion only in the HL cohort was blunted by the alpha1-blocker (Diet x Blocker interaction; p < 0.001). Long-term prazosin also abolished fasting hyperinsulinemia in the HL cohort, whereas it did not alter fasting insulin in chow-fed animals (Diet x Blocker interaction; p < 0.005). Measurement of postprandial lipoprotein lipase activity in several tissues did not suggest the involvement of changes in the absolute availability of the enzyme as a determinant of the hypotriacylglycerolemic action of the alpha1-blocker. Thus long-term alpha1-adrenergic blockade, with minimal effects in rats fed a hypolipidemic diet, strongly attenuates several of the fasting and postprandial alterations in plasma variables of lipid and glucose metabolism induced by an extremely lipogenic diet.

The objective of the present study was to determine the combined effects of dietary protein and carbohydrate sources on total body energy and protein and fat gains as well as on plasma insulin and glucose and tissue lipoprotein lipase activity in male Sprague-Dawley rats fed semipurified diets for 28 days. The diets varied in both protein and carbohydrate sources, namely, casein-cornstarch, casein-sucrose, soy protein isolate (SPI)-cornstarch, SPI-sucrose, cod protein-cornstarch, and cod protein-sucrose. When SPI was combined with cornstarch, lower total body energy and fat gains were observed compared with the combination of either casein and sucrose, casein and cornstarch, or SPI and sucrose. Plasma glucose and insulin concentrations in addition to total and metabolizable energy intake and body weight gain were lower in rats fed the SPI-cornstarch diet than in those fed the casein-sucrose diet. Feeding the SPI-cornstarch diet compared with feeding either the casein-cornstarch or the SPI-sucrose diet also caused lower plasma glucose concentrations and a concomitant trend (p = 0.06) to reduced energy intake and body weight gain. Therefore, the reducing effects of the SPI-cornstarch diet compared with the casein-cornstarch, the casein-sucrose, and the SPI-sucrose diets on body energy and fat gains may result from reductions in energy intake and in plasma glucose concentrations.

Sprague-Dawley rats were fed purified diets varying in both protein (20%) and lipid (11%) content for 28 d to verify the independent and interactive effects of dietary proteins and lipids on serum and hepatic lipids, and on tissue lipoprotein lipase (LPL) activity in both fasted and postprandial states. These diets consisted of either casein-menhaden oil, casein-coconut oil, soy protein-menhaden oil (SPMO), soy protein-coconut oil, cod protein-menhaden oil, or cod protein-coconut oil. A randomized 3 x 2 factorial design was used. A significant protein-lipid interaction was seen on serum triglyceride levels: menhaden oil, compared with coconut oil, induced a decrease in serum triglyceride levels when combined with soy protein but not when combined with cod protein and casein. The lower serum triglyceride concentrations observed in the SPMO-fed rats could be the result of decreased hepatic triglycerides when soy protein was compared with casein and when menhaden oil was compared with coconut oil. Total LPL activity in the heart was higher in menhaden oil-fed rats than in coconut oil-fed rats in the postprandial state. The higher LPL activity in the heart could, however, explain only 10% of the reduction of serum triglycerides, contributing slightly to the lowering effects of SPMO diet on serum triglycerides. Therefore, the present results indicate that dietary proteins can modulate the effects of fish oil on triglyceridemia in the rat, and that could be mainly related to specific alterations in hepatic lipid concentrations.

The present study was conducted to assess the effects of leptin on food intake and energy balance in the presence or absence of corticosterone. Three cohorts of C57BL/6 mice differing in their corticosterone status [nonadrenalectomized (intact), adrenalectomized (ADX), and ADX with corticosterone replacement] were infused with either saline or leptin at a dose of 150 microg . kg-1 . day-1. Throughout the study, mice had free access to both a high-starch and a high-fat diet. At the end of the experimental period, mice were decapitated and their carcasses were processed for the determination of energy, protein, and lipid contents. Leptin significantly reduced body gains in weight, fat, and energy, whereas corticosterone therapy significantly promoted all of these gains. Leptin and ADX significantly reduced food intake and gross energetic efficiency, whereas corticosterone therapy significantly increased these variables. The effects of leptin, ADX, and corticosterone on food intake were accounted for by changes in the intake of the high-fat diet. Leptin also attenuated the preference for fat that developed quickly in mice simultaneously exposed to the high-starch and high-fat regimen. Altogether, the results of this study 1) emphasize the abilities of leptin and corticosterone to, respectively, decrease and increase energy deposition and ingestion of fat, 2) do not substantiate any leptin-corticosterone interaction in the regulation of energy balance, and 3) demonstrate that leptin can produce its effect on energy and fat gains in the absence of an intact hypothalamic-pituitary-adrenal axis.

This study aimed to identify the metabolic steps involved in the acute hypotriglyceridemia brought about by increased energy expenditure (cold exposure) and to assess the causative involvement of some determinants of triglyceride (TG) metabolism as well as that of the beta-adrenergic pathway. Rats were kept at 24 degreesC or exposed to 10 degreesC for 3 h after acute administration of the beta-adrenergic antagonist propranolol (Prop) or vehicle. Cold exposure increased the rate of TG secretion (Triton WR1339 method) into the circulation by 50% (P < 0.0005), an effect that was blunted by Prop. The cold-induced increase in TG secretion was closely related to changes in circulating nonesterified fatty acid levels, but not with serum insulin concentrations. Despite an increase in TG secretion, serum TG levels after acute cold exposure fell to 50% (P < 0.002) of those measured at 24 degreesC, indicating that the lowering of serum TG was entirely due to an increase in their rate of intravascular hydrolysis. This was confirmed by observing a 70% increase (P < 0.002) in the rate of clearance of an exogenous TG emulsion in cold-exposed rats compared with those kept in the warm. Prop treatment before cold exposure decreased (approximately 30%, P < 0.005) the cold-induced stimulation of TG hydrolysis. The increased TG clearance rate in cold-exposed animals occurred in the absence of any change in the intravascular availability of lipoprotein lipase (LPL). In contrast, the activity of LPL displayed a tissue-specific response to cold exposure, being reduced by one-half in white adipose tissue (P < 0.0005) and increased in brown adipose tissue (130%, P < 0.0001) and the heart (50%, P < 0.001). These findings show that, in the postprandial state, an acute increase in energy expenditure induced by cold exposure results in a lowering of serum TG entirely due to an increase in their rate of intravascular hydrolysis and that serum TGs are lowered despite an increase in the rate of TG secretion into the circulation. More efficient TG hydrolysis occurs independently of the intravascular availability of LPL. The study further shows that the effects of cold exposure on serum TG concentration and their rates of secretion and clearance are in large part mediated by the beta-adrenergic pathway.

The present study was designed to evaluate the interaction of corticosterone (CORT) and female gonadal steroids on energy balance and lipid metabolism. To this end, a 2 x 4 factorial experiment was carried out in which two cohorts of rats differing in their ovary status [OV status: intact (INT) and ovariectomy (OVX)] were each divided into four groups defined by their CORT status [CORT status: nonadrenalectomized (non-ADX), ADX without CORT replacement (placebo subcutaneous pellet), ADX with low-dose CORT replacement, and ADX with high-dose CORT replacement]. After 3 wk of treatment and a 12-h fast, rats were killed and their carcasses analyzed for energy (lipid and protein) content. In addition, indexes of endogenous triglyceride (TRIG) production (liver TRIG content), transport into plasma (triglyceridemia), and incorporation into fat stores [lipoprotein lipase (LPL) activity in adipose tissue (AT)] were assessed. OV and CORT status interacted on body weight gain, total energy, and fat gains. The interactions arose from the fact that the twofold increase in these variables brought on by OVX was abolished by ADX and restored by CORT replacement. Although in ADX groups there was a dose-related restoration of total energy and fat gain by CORT replacement in both INT and OVX cohorts, the impact thereupon of OVX observed in the non-ADX group reappeared only in ADX animals receiving the high dose of CORT. Protein gain was increased by OVX solely in non-ADX rats, whereas the high dose of CORT prevented any net protein gain independently of the OV status. Consistent with treatment effects on total body fat gain, OVX resulted in an increase in liver TRIG content, AT weight, AT LPL activity, and plasma insulin. All these effects of OVX were abolished by ADX and restored by the high dose of CORT. Plasma TRIG were unaffected by OV status but were highly responsive to CORT status. All treatment effects were highly correlated with cumulative food intake. This study shows that the presence of CORT is required for OVX to exert its action on global energy balance and the concomitant, closely integrated adaptations of lipid metabolism.

The present study was designed to evaluate the acute and chronic effects of the alpha 1-adrenergic antagonist prazosin (Praz) on glucose tolerance and on postprandial plasma glucose and insulin kinetics. Rats were fed a high sucrose diet for 3 weeks, to which Praz (3 mg/kg/day) was added or not. They were then accustomed to ingest a meal 1 h after a single intraperitoneal (i.p.) injection of saline or Praz (1 mg/kg). Plasma levels of glucose and insulin were recorded at various times after meal intake. In addition, a fasting intravenous glucose tolerance test (IVGTT) was performed. In the chronic control cohort, pre-IVGTT plasma glucose and insulin levels were slightly but significantly higher after acute Praz than after acute saline administration. Factorial analysis of variance (ANOVA) showed that the increase in plasma glucose and insulin after intravenous (i.v.) glucose administration was also slightly greater in the animals that received acute Praz than in their saline counterparts. In contrast, after chronic treatment with Praz, pre- and post-IVGTT plasma glucose and insulin concentrations were identical in groups acutely injected with saline or Praz. In the chronic control cohort, preprandial plasma glucose and insulin measured in a sample collected before acute injection of saline or Praz were similar in both groups. The postprandial increase in plasma glucose and insulin was potentiated by the acute administration of Praz. Fasting plasma glucose and insulin concentrations were also similar in both groups chronically treated with Praz, and acute administration of the blocker still potentiated the increase in plasma glucose and insulin that followed meal intake. Chronic treatment alone did not affect postprandial glucose and insulin concentrations, and acute injection of Praz had comparable effects whether rats were chronically treated with the blocker or not. Therefore, potentiation of the glucose and insulin response to meal intake by Praz persisted after chronic treatment but required the acute presence of the blocker. However, repeated exposure to acute bouts of postprandial hyperinsulinemia induced by Praz did not lead to deterioration of insulin sensitivity or of the capacity of the pancreas to secrete insulin, as suggested by a normal response of glucose and insulin to IVGTT.

The purpose of this study was to evaluate the consequences of the acarbose-induced attenuation of postprandial glycemia and insulinemia on plasma lipid concentrations and on tissue lipoprotein lipase (LPL) activity. Rats were fed a high-sucrose diet ad libitum for two weeks. On the day of the experiment, half of the animals were given a high-sucrose meal, whereas the other half were given acarbose (10 mg/kg body weight) mixed with the meal. Serum lipids and tissue LPL activity were assessed in samples collected one hour after meal intake. Glycemia was comparable in both groups, whereas serum insulin in acarbose-fed rats was half that of control animals. The main effects of acarbose on postprandial lipids consisted of a lowering of triacylglycerols (-50%) and non-high density lipoprotein cholesterol. LPL was not altered by acarbose in white and brown adipose tissues, but was higher in the heart (+33%). The effects of acarbose on postprandial serum lipids are consistent with a slower rate of de novo lipogenesis from carbohydrate precursors and a consequent lowering of very-low density lipoprotein secretion into the circulation. In addition, the acarbose-induced dampening of the postprandial excursion of insulin may have maintained higher LPL activity in the heart, which would be liable to participate in the hypotriacylglycerolemic action of the inhibitor.

A crossover study was conducted to examine the effects on plasma lipoprotein concentrations of substituting lean white fish (LWF) for beef, port, veal, eggs, and milk products (BPVEM) within prudent isoenergetic diets. Fourteen premenopausal women received 8784 kJ--20% as protein, 50% as carbohydrates, and 30% as lipids [ratio of polyunsaturated to monounsaturated to saturated fatty acids (P:M:S) of 1:1:1 compared with 0.4:1:1 in preexperimental diet]--and 260 mg cholesterol/d. After 4 wk, the BPVEM diet significantly reduced concentrations of plasma cholesterol, low-density-lipoprotein (LDL) cholesterol, high-density-lipoprotein (HDL) cholesterol, apolipoprotein B, HDL-apolipoprotein A-I, and LDL-apolipoprotein B (P<0.05) as well as plasma postheparin hepatic triacylglycerol lipase activity compared with the preexperimental diet. These effects are probably attributable to elevation of the P:M:S. These responses were not observed with the LWF diet, suggesting that fish protein in LWF maintains unchanged plasma cholesterol concentrations despite a high P:M:S. The LWF diet, compared with the preexperimental diet, reduced very-low-density-lipoprotein triacylglycerol (P<0.05) and also the ratio of LDL cholesterol to apolipoprotein B (P<0.05), revealing the presence of denser LDL particles. Compared with the BPVEM diet, the LWF diet induced lower concentrations of very-low-density-lipoprotein triacylglycerols (P<0.05) and higher concentrations of LDL triacylglycerol and LDL apolipoprotein B (P<0.05), which were not associated with any increase in lipoprotein lipase activity. These results suggest that LWF as a substitute for BPVEM in isoenergetic diets with an elevated P:S produces minimal improvement in the lipoprotein profile in premenopausal women.

A fragment of the human lipoprotein lipase (LPL) cDNA (405 bp, 5' terminal end) was cloned in an expression vector to produce a approximately 17 kDa fusion peptide and was used as antigen to produce a high titre anti-LPL monoclonal antibody (10C3 MAb). This antibody reacts with both native and denatured forms of LPL from different tissue and animal sources. Competition studies with heparin indicate that 10C3 MAb is specific for an epitope at a heparin binding site. The antibody does not inhibit LPL enzyme activity, indicating that the antigenic epitope is not situated within or in the proximity of the LPL catalytic region. With these characteristics, 10C3 MAb should prove to be a useful immunochemical tool in clinical as well as in fundamental investigations on the metabolism of triglyceride-rich lipoproteins and in studies on the functional anatomy of LPL.

The effects of the glucocorticoid receptor antagonist, RU-38486 (RU-486), and the mineralocorticoid receptor (MR) antagonist, RU-28318, on energy balance were investigated in a 2 [surgery: ovariectomy (OVX) and sham operation] x 3 (corticosteroid antagonist: placebo, RU-28318, RU-486) experimental design. Rats were treated for 28 days. Food intake and body weight were monitored throughout the treatment period. At the end of the treatment, rats were killed and their carcasses were analyzed for energy and nitrogen contents. Energy content was determined by adiabatic bomb calorimetry, whereas nitrogen was determined in 250-to 300-mg samples of dehydrated carcasses, with the use of the Kjeldahl procedure. The energy as protein was subtracted from total carcass energy to determine energy as fat. The gains in energy, fat, and protein were calculated by subtracting the values obtained at the end of the treatment period from initial values estimated from the body weights measured at the beginning of the experiment. A significant interaction effect of surgery and corticosteroid antagonist was observed on body energy gain, energetic efficiency, and fat gain. Whereas body energy gain, energetic efficiency, and fat gain were larger in OVX rats than in sham-operated animals treated with either placebo or RU-486, they were comparable in OVX and sham-operated rats treated with RU-28318. Surgery, but not corticosteroid antagonist, had a significant effect on digestible energy intake, energy expenditure, and protein gain. All these variables were higher in OVX rats than in sham-operated animals. Surgery also affected corticosterone levels and adrenal weight. Both of these variables were lower in OVX rats than in sham-operated animals. By demonstrating the ability of RU-28318 to attenuate the effects of OVX on energy balance, the present study provides evidence that MR occupation by corticosteroids facilitates the OVX-induced changes in energy balance.

The consequences of chronic ingestion of a high-carbohydrate (starch + glucose [HCHO]) and high-fat (lard + corn oil [HFAT]) diet on triglyceride metabolism and insulin sensitivity were evaluated in fasted and fed rats. Compared with their HFAT counterparts, animals fed the HCHO diet displayed fasting and postprandial hypertriglyceridemia that was apparent after 3 weeks of feeding and persisted after 6 weeks. It was determined that hypertriglyceridemia was due to oversecretion of triglycerides into the circulation. During fasting triglyceride accumulation in plasma after administration of Triton WR1339 was indeed twofold higher in HCHO than in HFAT rats, whereas the global capacity for intravascular triglyceride hydrolysis, as assessed by an intravenous fat tolerance test and measurement of postheparin plasma lipoprotein and hepatic lipase activities, was comparable in both dietary cohorts. The postprandial increase in triglycerides after a high-carbohydrate meal was larger in HCHO than in HFAT rats. A fasting intravenous glucose tolerance test (IVGTT) showed that HFAT animals displayed insulin resistance after 3 weeks of feeding, which worsened after 6 weeks of treatment. Thus, the HCHO diet elicited fasting and postprandial hypertriglyceridemia without impairment of insulin sensitivity as compared with the HFAT diet, whereas the latter brought about deterioration of the sensitivity of glucose metabolism to insulin without affecting triglyceridemia. From these studies and other animal models, it is suggested that rapid delivery of fatty acids to tissues from chylomicron-derived triglycerides leads to insulin insensitivity, while fatty acids may not be available to increase endogenous production of triglycerides because they are mainly oxidized. In contrast, dietary starch/glucose increases hepatic synthesis and secretion of triglycerides that result in hypertriglyceridemia, but the deleterious effects of glucose-fatty acid competition on insulin sensitivity are prevented because endogenously derived triglycerides are catabolized more slowly and glucose is available for oxidation. The present results support the concept that coexistence of hypertriglyceridemia and resistance of glucose metabolism to insulin may be frequent but not obligatory.

The following studies have been carried out to compare the effects of fish protein with other dietary proteins on plasma cholesterol and lipoproteins in animal models and in humans. In rabbits, fish protein has been shown to induce relatively variable effects compared to casein and soy protein on serum cholesterol depending in part on the origin of dietary lipids with which it is combined. In a protein-lipid interaction study, casein, soy or cod protein were combined with corn or coconut oil. Casein and soy protein in the presence of corn oil induced lower serum cholesterol levels despite its combination with either corn or coconut oil. This is in part due to serum high density lipoprotein (HDL) cholesterol concentrations, which were consistently higher with cod protein than with either casein or soy protein, regardless of the dietary lipid source. In rabbits, this rise in HDL cholesterol was associated with a decrease in very low density lipoprotein (VLDL) triglycerides and an increase in postheparin plasma lipoprotein lipase activity. The effects of lean white fish on plasma lipoproteins also have been investigated in post and premenopausal women fed a low-fat, high P/S (polyunsaturated/saturated fat) ratio diet. In postmenopausal women, lean white fish compared with other animal protein products induced higher concentrations of plasma cholesterol, LDL-apolipoprotein (apo) B and HDL cholesterol, mainly in the HDL3 fraction. In premenopausal women, lean white fish induced lower concentrations of VLDL triglycerides and higher concentrations of LDL-apoB in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to determine whether the postprandial modulation of lipoprotein lipase (LPL) activity was altered in rats with resistance of glucose metabolism to insulin action induced by a high-fat diet. Relationships between serum insulin and tissue LPL activity were established in rats chronically fed a high-carbohydrate or high-fat diet, and the effects of fasting and intake of meals of habitual and alternate composition were contrasted. The feeding paradigm did not result in the development of obesity. Global resistance of glucose metabolism to insulin brought about by chronic high-fat feeding was confirmed by an intravenous glucose tolerance test. Fasting serum glucose and insulin concentrations were similar in both cohorts, as was LPL activity in retroperitoneal and inguinal white adipose tissues (WAT), the heart, and soleus. A high-carbohydrate meal brought about higher postprandial insulinemia in the cohort chronically fed the high-fat diet. This was associated with larger changes in LPL activity, that is, an increase in inguinal WAT and in brown adipose tissue and a decrease in soleus, red vastus lateralis, and the heart. Thus the established postprandial modulation of LPL, presumably by insulin, was potentiated in the presence of hyperinsulinemia induced by chronic high-fat feeding despite the concomitant impairment of glucose metabolism.

A method is described for the determination of changes in gene expression by reverse transcription of the target mRNA followed by PCR amplification of the resulting cDNA (RT-PCR), using the lipoprotein lipase gene as the model system. Known proportions of human and rat adipose tissue homogenates are mixed and are processed together throughout the RT-PCR procedure so that the rat tissue serves as an internal standard for the measurement of human adipose tissue lipoprotein lipase (LPL) in all steps including RNA extraction, reverse transcription and PCR amplification. Taking advantage of the highly conserved sequence of the LPL gene across species, selected homologous regions of the human and rat genes are amplified using the same primer pair and resulting in the same lengths of amplified DNA fragments. The two amplified products are then separated from each other by making use of differences in the position of a restriction site in the two amplified DNA fragments. The method is simple, precise and reproducible and avoids construction of tailored nucleic acids for use as internal standards.

This study evaluated the respective and interactive effects of chronic dl-fenfluramine treatment, an anorectic serotoninergic agonist, and gonadectomy on lipoprotein lipase activity in adipose tissue and skeletal muscle. Male and female Sprague-Dawley rats were gonadectomised. These as well as intact animals were treated with dl-fenfluramine or a placebo for 28 days. Gonadectomy brought about an increase in final body weight of females (16-18%, P < 0.0001), but a decrease in that of male animals (9-13%, P < 0.001). These changes were proportional to those of food intake. The increase in body weight of gonadectomised female rats was paralleled by that of retroperitoneal adipose tissue and vastus lateralis muscle weights, whereas in male rats, gonadectomy diminished muscle weight only. Lipoprotein lipase activity was doubled (P < 0.0001) by gonadectomy in adipose tissue of female rats, but remained unaltered by the surgery in male animals. Enzyme activity in muscle was unaffected by gonadectomy in both genders. Treatment with dl-fenfluramine reduced weight gain in males and females, whether they had been gonadectomised or not. A concomitant reduction was observed in adipose tissue mass and lipoprotein lipase activity, which was reduced to 50-65% of the activity measured in placebo-treated animals (P < 0.01). The drug remained without effect on muscle weight and lipoprotein lipase activity in either gender. Thus removal of gonadal steroids had divergent effects on LPL activity with regard to gender and tissue. In addition, dl-fenfluramine treatment was followed by decreased enzyme activity in adipose tissue, but not in muscle, this pattern being independent of the nature or presence of gonadal steroids.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of the present study was to evaluate the role of insulin as a possible mediator of the hypotriacylglycerolemic effect of alpha 1-adrenergic blockade. To this end, determinants of triacylglycerol (TG) metabolism were measured in animals having normal postprandial fluctuations in insulin levels (intact rats) and in others having invariable insulin concentrations (insulin-depleted rats infused long-term with insulin-delivering minipumps). Postprandial changes in plasma TG level, TG secretion rate (TGSR), TG elimination rate (TGER), and lipoprotein lipase (LPL) activity of white (WAT) and brown (BAT) adipose tissues, vastus lateralis muscle (VLM), and heart were measured in animals acutely injected or not with the alpha 1-antagonist prazosin 1 hour before the intake of a high-sucrose, fat-free meal. In intact rats, postprandial increases in glucose and insulin levels were potentiated by administration of prazosin before meal intake. The postmeal increase of plasma TG level was abolished by prazosin in intact animals, whereas this effect was absent in animals with invariable insulin levels. Intact animals treated with prazosin displayed both a lower TGSR (P < .01) and a higher TGER (P < .01) than their saline-injected counterparts. In animals with invariable insulin, both TGSR and TGER remained unaffected by prazosin treatment. Prazosin treatment of intact animals did not affect LPL activity in WAT, but increased enzyme activity in BAT (P < .02). In insulin-infused animals, prazosin increased LPL activity in WAT (P < .02) and BAT (P < .03). alpha 1-Adrenergic blockade had no effect on LPL in VLM and heart. These results confirm that alpha 1-adrenergic blockade prevents the postprandial increase in plasma TG level that follows the ingestion of a high-sucrose meal both by decreasing TGSR and by increasing TGER. The findings also demonstrate that these effects of prazosin are indirect and that their occurrence requires the postprandial increase in circulating insulin levels.

Energy balance and lipid metabolism were investigated in transgenic mice bearing an antisense glucocorticoid receptor (GCR) gene construct that impairs the normal expression of the GCR gene. Food intake was recorded during the 15 days preceding decapitation of adult normal and transgenic mice, and feces were collected to derive the digestible energy intake. Body composition measurements consisted of the determination of energy, protein, and fat content of the carcass. Carcass energy was determined by bomb calorimetry, whereas carcass protein was measured by the Kjeldahl procedure. Energy expenditure was estimated from the continuous oxygen consumption (VO2) monitoring over a 24-h period. Lipoprotein lipase (LPL) activity was quantified in epididymal white adipose tissue (WAT), heart, and vastus lateralis muscle (VLM) by measuring the in vitro hydrolysis of labeled triolein in the presence of tissue homogenates. Norepinephrine (NE) content of both interscapular brown adipose tissue (BAT) and heart were determined by high-performance liquid chromatography (HPLC). Energy intake and expenditure were significantly lower in transgenic mice than in controls. Concurrently, both fat content and total energy of the carcasses were significantly higher in the transgenic animals. In comparison with normal mice, heart and VLM LPL activity was significantly reduced in transgenic mutants. There was no difference between groups in LPL activity in WAT. Finally, heart and BAT NE contents were lower in transgenic animals than in control mice. These results suggest that a defective GCR system may affect energy balance through increasing energetic efficiency, and they emphasize the modulatory effects of hypothalamic-pituitary-adrenal axis changes on muscle LPL activity.

The effect of the 5-hydroxytryptamine agonist D,L-fenfluramine on energy balance was investigated in male and female rats in order to detect a possible gender difference. Male and female rats, either gonadally intact or castrated, received a daily injection of the 5-hydroxytryptamine (5HT) agonist fenfluramine during 28 days. Body weight and food intake were monitored throughout the treatment period. At the end of the treatment, rats were decapitated and their carcasses were processed in order to determine the carcass contents of energy, fat and protein. Regardless of the gender of the rats, fenfluramine significantly delayed the gains in body weight, body energy and body fat in either castrated or gonadally intact rats. In female rats, castration accelerated body weight gain in rats injected with saline as well as in those treated with fenfluramine. Additionally, castrated female rats deposited more energy, fat and protein than gonadally intact rats. In contrast, castrated male rats, independently of whether they received saline or fenfluramine, gained less body weight and deposited less energy, fat and protein than non-castrated male rats. In conclusion, the results of this study show that D,L-fenfluramine is as effective in altering energy balance in male as it is in female rats.

The present studies evaluated the effect of prazosin, a selective alpha 1-adrenergic antagonist, on some metabolic determinants of triacylglycerol-rich lipoproteins. Plasma triacylglycerols (TG), TG secretion rate, TG removal rate, plasma insulin, and glucose were evaluated postprandially in animals fed a high-sucrose meal. In the fasted state plasma TG, glucose, and insulin concentrations were minimally affected by prazosin. There was a significant postprandial elevation in plasma TG levels that was larger after ingestion of a meal containing corn oil than after intake of a fat-free meal. Prazosin totally blunted the postprandial elevation in plasma TG independently of the presence (P < 0.004) or absence of dietary fat (P < 0.01). In the postprandial phase after ingestion of a fat-free, high-sucrose meal, prazosin decreased the rate of secretion of TG into the circulation (-54%, P < 0.0003) and accelerated twofold the clearance of an injected fat emulsion (P < 0.02). The postprandial elevations in plasma insulin and glucose were significantly potentiated by administration of prazosin before intake of the fat-free meal. These results indicate that prazosin prevented the postprandial elevation in plasma TG that followed the ingestion of a high-sucrose meal. The results also demonstrate that the alpha 1-blocker exerted its action both by decreasing TG secretion and by increasing the rate of removal of circulating TG.

The purpose of this study was to evaluate the effects of prazosin, an alpha-1 adrenergic antagonist, on determinants of triacylglycerol metabolism in rats fed chronically diets high in starch or sucrose. Hepatic triacylglycerol secretion rate (HTGSR), lipoprotein lipase in white and brown adipose tissues, red vastus lateralis muscle and heart, as well as serum triacylglycerol concentration, were assessed in the post-prandial state, after injection of prazosin or saline. Post-prandial triacylglycerolemia was higher in the sucrose-fed than in the starch-fed rats. After the injection of prazosin, triacylglycerol concentrations were decreased in both dietary groups. This effect was more marked in sucrose-fed than in starch-fed rats (diet x blocker interaction: P < 0.0003). HTGSR was higher in rats fed sucrose than in starch-fed rats (+49%, P < 0.01). Prazosin decreased HTGSR (-45%) in the sucrose-fed rats but not in animals fed starch. Lipoprotein lipase activities in brown adipose tissue, vastus lateralis muscle and heart in rats injected with prazosin were enhanced compared with those of the saline-treated rats, but no change was found in enzyme activity in white adipose tissue. This effect of prazosin was independent of the type of diet. These results suggest that prazosin reduced serum triacylglycerol concentrations after food ingestion at least partly by enhancing lipoprotein lipase activity in several tissues. In addition, the prazosin-induced decrease in HTGSR in sucrose-fed rats, which was absent in starch-fed animals, probably accounted for the greater magnitude of the hypotriacylglycerolemic effect of the blocker in animals given sucrose.

This study describes the consequences of sustained exposure to the nonspecific beta adrenergic agonist isoproterenol on the activity of lipoprotein lipase (LPL) in tissues that are sites for a large portion of the intravascular hydrolysis of triacylglycerols. Chronic exposure to isoproterenol was accomplished by means of osmotic pump infusion during four consecutive days, and assessment of the activity of LPL was performed at the end of the treatment. Four days of ISO infusion resulted in a large decrease in LPL activity of parametrial white adipose tissue, which declined to half of that found in the untreated group. In contrast, brown adipose tissue LPL activity was greatly increased (approximately threefold) by ISO treatment. The beta agonist raised LPL activity in red vastus lateralis muscle by a factor of four over control values, whereas heart enzyme activity was not significantly altered by the drug. These results demonstrate that catecholamines are part of the factors which determine the tissue specificity of LPL regulation. The tissue-specific changes in enzyme activity in response to isoproterenol, which are in very good agreement with the known metabolic actions of catecholamines in adipose and skeletal muscle tissues, attest to the key role of the enzyme in the partitioning of lipid substrates in situations of increased sympathetic activity.

This study evaluated the effects of beta 2-adrenoceptor stimulation on some determinants of triglyceride metabolism. Male Sprague-Dawley rats were injected twice daily with clenbuterol (30 micrograms.kg-1) for 7 days, or with an equivalent volume of vehicle. Serum triglycerides, hepatic triglyceride secretion rate, and lipoprotein lipase activity in white and brown adipose tissues as well as in red vastus lateralis muscle and heart were evaluated in the fasting state and following a fat-free, high-sucrose meal, 3 h after the last agonist injection. In rats killed in the fasting and postprandial states, clenbuterol reduced the mass of white adipose tissue (-25 and -12%, respectively; p < 0.02), whereas it increased the mass of vastus lateralis muscle (+11 and +7%; p < 0.002) and heart (+13 and %; p < 0.0001). In vehicle-injected animals, the fasting state was associated with lower lipoprotein lipase activity in white and brown adipose tissues, and higher enzyme activity in vastus lateralis and heart, compared with the postprandial state. Postprandially, treatment with clenbuterol reduced lipoprotein lipase activity in white adipose (-24%), whereas it increased enzyme activity in brown adipose (+107%) as well as in vastus lateralis (+35%). In fasted animals, no significant variation of enzyme activity in these tissues was observed following clenbuterol treatment, whereas in the heart, a decrease of lipoprotein lipase activity was observed (-22%). Clenbuterol lowered serum triglycerides significantly (-23%), but not their rate of secretion, whereas the agonist decreased the insulin to glucagon ratio only in the postprandial state.(ABSTRACT TRUNCATED AT 250 WORDS)

Rabbits were fed purified diets consisting of casein (CA), fish protein (FP), and soy protein (SP) combined with MaxEpa oil (ME) or corn oil (CN) to determine the effects of dietary protein and lipid sources on serum total, lipoprotein, and hepatic lipid levels. Dietary proteins and lipids exerted significant (p < 0.05) separate effects on serum total cholesterol (TC) (p < 0.005), very-low-density lipoprotein cholesterol (VLDL-C) (p < 0.001), and high-density lipoprotein cholesterol (HDL-C) (p < 0.001), whereas only dietary proteins significantly affected low-density lipoprotein cholesterol (LDL-C) (p < 0.001) and the LDL-C/HDL-C ratio (p < 0.05). Hence, FP induced serum TC (233 mg/dl), VLDL-C (22 mg/dl), and LDL-C (151 mg/dl) intermediary to hypercholesterolemic CA (TC, 319 mg/dl; VLDL-C, 57 mg/dl; LDL-C, 204 mg/dl) and cholesterol-lowering SP (TC, 129 mg/dl; VLDL-C 19 mg/dl; LDL-C, 84 mg/dl). The twofold rise in HDL-C on feeding FP (35 mg/dl), compared with CA (20 mg/dl) and SP (16 mg/dl), resulted in a drop in LDL-C/HDL-C to a level similar to that of SP groups. The cholesterol-lowering action of ME (188 mg/dl), in contrast to CN (266 mg/dl), was reflected mainly in VLDL (ME, 15 mg/dl; CN, 50 mg/dl) but also in HDL (ME, 16 mg/dl; CN, 31 mg/dl) fractions. Compared with CN, the significant (p < 0.05) ME-induced rise in serum and VLDL triglycerides was accompanied by a significant (p < 0.001) drop in lipoprotein lipase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

To explore the pathways by which fish protein feeding influences HDL metabolism, postheparin plasma lipoprotein lipase and hepatic triglyceride lipase activities were measured in rabbits fed fish protein or soybean protein combined with corn oil or coconut oil in a 2 x 2 factorial arrangement. In addition to greater serum total and LDL-cholesterol concentrations, the elevated HDL cholesterol concentration caused by feeding fish protein, compared with soybean protein, was accompanied by lower VLDL triglycerides and parallel higher lipoprotein lipase activity in fish protein-fed rabbits. These results suggest an enhanced assembly of circulating HDL through promoted lipoprotein lipase activity in rabbits fed fish protein. Moreover, dietary proteins and lipids interacted with one another to alter HDL triglycerides and liver cholesterol concentrations. Diet-induced changes in lipoprotein lipase activity were, however, not related to insulinemia, which was unaltered by purified diet feeding. The present results suggest that fish protein may affect HDL metabolism through the modulation of lipoprotein lipase activity in rabbits.

The present studies were designed to verify whether preventing the rise in serum levels of nonesterified fatty acids (NEFA) by adrenergic blockade would interfere with the decrease in tissue lipoprotein lipase (LPL) activity caused by acute exercise in rats. Ninety minutes before being killed, male rats were injected intraperitoneally with either saline, the beta-adrenergic blocker propranolol (25 mg/kg body weight), or the alpha 2-adrenergic blocker yohimbine (3 mg/kg body weight). Half of each group was killed at rest and the other half immediately after a 1-h run on a treadmill. LPL was determined in white adipose tissue (WAT), heart, and red vastus lateralis muscle (VLM). Exercise enhanced serum levels of NEFA 50% over resting values in saline-injected rats. The latter increase was totally abolished in animals having received propranolol or yohimbine. The activity of LPL in WAT, heart, and red VLM was approximately 35% lower in exercised rats than in resting animals. Serum triacylglycerols were also reduced by the run. Neither propranolol nor yohimbine interfered with any of these reductions. Exercise did not change serum glucose levels in saline-injected rats but decreased it in those injected with propranolol or yohimbine. Serum insulin was unchanged by exercise and by the antagonists. These findings suggest that the beta- and alpha 2-adrenergic pathways, as well as the exercise-induced rise in serum levels of NEFA, are not responsible for the early reducing effect of a 1-h run on tissue LPL activity in untrained rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The present experiments were aimed at evaluating the acute effects of exercise on lipoprotein lipase (LPL) activity in untrained rats. The activity of LPL was measured in postheparin plasma (PHP) before and at various times after a 1-h run on a treadmill (22 m/min, O degrees grade). LPL in PHP was 50% below pre-exercise levels immediately and 3 h after the run but was increased 65% over resting levels 24 h postexercise. To further characterize the very early fall in LPL activity in response to exercise and to assess the possible involvement therein of the beta-adrenergic pathway, LPL in heart, vastus lateralis muscle (VLM), and white (WAT) and brown (BAT) adipose tissues was determined at rest and immediately after exercise in rats that were treated or not with nadolol (25 mg.kg-1.day-1 for 30 days). Immediately after 1 h of exercise, there was a reduction in total enzyme activity in WAT (40% below resting levels), BAT (-58%), VLM (-53%), and heart (-30%). Exercise reduced serum triacylglycerol levels (-64%) and doubled those of nonesterified fatty acids. beta-Adrenergic blockade did not affect any of these variables. Both exercise and nadolol lowered serum cholesterol levels by approximately 20%, but the effects were not additive. These results show that the global intravascular pool of LPL undergoes divergent, time-dependent alterations in response to a single bout of moderate exercise. The acute downregulation of postheparin plasma LPL immediately after exercise reflected a fall in the total enzyme pool of all tissues studied.(ABSTRACT TRUNCATED AT 250 WORDS)

The current study investigated the early response of some determinants of triacylglycerol (TG) metabolism to acute exercise in rats that were treated or not with the nonselective beta-adrenergic blocker, nadolol (25 mg.kg b.wt.-1.day-1 for 30 days). Measurements of hepatic TG secretion rate (HTGSR), postheparin plasma hepatic TG lipase (HTGL) activity, and that of lipoprotein lipase (LPL) in postheparin plasma, heart, vastus lateralis muscle (VLM), white (WAT) and brown (BAT) adipose tissues were carried out in untrained rats at rest or immediately after a 1 h run on treadmill (22 m.min-1, 0 degrees grade). All animals were in the fasted state. Exercise reduced serum TG levels (46% below resting levels) and doubled those of nonesterified fatty acids. HTGSR was enhanced (+28%) by exercise while HTGL activity was not modified. The decrease in postheparin plasma LPL activity (-24%) caused by exercise was consistent with a reduction in enzyme activity in WAT (-32%), BAT (-45%) and heart (-25%). One h of treadmill running did not influence LPL activity in VLM. beta-Adrenergic blockade did not affect any of the variables of lipid metabolism, except for a slight decrease in specific activity of LPL in the heart (-14%). This study demonstrates that absolute variations in HTGSR and in LPL activity cannot account for the acute fall in serum TG levels caused by moderate exercise, in fasted, untrained rats. In addition, these results show that the beta-adrenergic pathway is either not involved in, or not necessary for, the latter effects of exercise on TG metabolism.

Purified diets varying in dietary protein, namely casein (CA), soy protein (SP), fish protein (FP), and lipid origin (corn oil (CN), coconut oil (CO)) were fed to rabbits to evaluate the effects of protein and fat source, as well as protein-lipid interactions, on serum total, lipoprotein and hepatic lipid levels. Dietary proteins and lipids exerted a separate effect on serum total cholesterol (C), very low-density lipoprotein cholesterol (VLDL-C), and low-density lipoprotein cholesterol to high density lipoprotein cholesterol (LDL-C/HDL-C) ratio. Hence, CA increased serum cholesterol compared to SP, while coconut oil enhanced serum and VLDL-C, and decreased LDL-C/HDL-C compared to corn oil. Dietary proteins interacted with dietary lipids to modulate HDL-C levels. Thus, FP maintained a high level of HDL-C regardless of lipid origin, compared to CA and SP whose HDL-C levels were decreased by corn oil, compared to coconut oil. A dietary protein-lipid interaction was also observed in the regulation of liver cholesterol levels. Coconut oil, compared to corn oil, decreased liver cholesterol in rabbits fed FP, whereas hepatic cholesterol concentration was unaltered by dietary lipid source in CA- and SP-fed rabbits. These results demonstrate that dietary proteins act synergistically with dietary lipids to regulate cholesterol metabolism in the rabbit.

The effects of norepinephrine and insulin on thermogenesis were investigated in adipocytes isolated from brown adipose tissue (BAT) of obese non-diabetic LA/N-cp rats (obese LA), obese diabetic SHR/N-cp rats (obese SHR), and their corresponding lean controls. The maximal calorigenic response (Vmax) and the sensitivity [50% effective concentration (EC50)] to norepinephrine (1 microM) were markedly reduced in brown adipocytes from obese SHR rats compared with their lean controls (3- to 4-fold decrease in the Vmax and 50% increase in the EC50 value). In the same cells, there was a similar decrease in the respiratory response to dibutyryl adenosine 3',5'-cyclic monophosphate, indicating the presence of a major postreceptor defect. Remarkably, total BAT cytochrome oxidase activity (an index of cellular mitochondrial content) was also diminished three to four times in obese SHR rats, suggesting that a reduced BAT mitochondrial content is responsible for the decreased thermogenesis. Ultrastructural studies revealed that the cytoplasm of brown adipocytes from obese SHR rats contained a large lipid droplet, numerous tiny droplets, and few atypical mitochondria with loosely packed cristae. Adipocytes from obese SHR rats were also characterized by a significant resistance to the antithermogenic effect of insulin but not to that of the nonmetabolizable adenosine analogue N6-phenylisopropyl adenosine. In contrast, all the above biochemical parameters were normal in obese LA rats. These results demonstrate that the marked insulin resistance in BAT of obese SHR rats is associated with a decreased responsiveness and sensitivity to norepinephrine, indicating the presence of receptor and postreceptor defects. It is suggested that insulin resistance and/or diabetes in SHR/N-cp rats lead to a decreased mitochondriogenesis in BAT, which results in a reduced thermogenic capacity, thereby contributing to the development of obesity.

The activity of lipoprotein lipase was measured in white and brown adipose tissues, red vastus lateralis muscle, and heart of rats that have been insulin deficient (streptozotocin, 75 mg.kg-1) for 2 weeks, and that have then received implants of insulin-delivering minipumps (17 U.kg-1.day-1) for 1 or 4 days. Normal glycemia was restored in insulin-deficient animals after 4 days of insulin treatment. Hypertriglyceridemia, but not hypercholesterolemia, was reversed after 4 days of insulin infusion. After 2 weeks of insulin deficiency, fasting lipoprotein lipase activity was lowered in all tissues studied. In white adipose tissue, lipoprotein lipase decreased to 50% of control values. After a single day of insulin infusion, even if tissue weight has not yet been greatly affected, total activity was completely restored to control levels. Enzyme activity in brown adipose tissue was also depressed in deficient animals, and insulin infusion was followed by a slow recovery of activity, to a level intermediate between those of control and insulin-deficient groups. Insulin status had milder effects on lipoprotein lipase activity in vastus lateralis muscle than in the adipose tissues. Deficient rats displayed 60% less activity than controls, and 4 days of hormone infusion only partially restored enzyme activity. There was a large loss of lipoprotein lipase in the heart following 2 weeks of insulin depletion, which was not counteracted by hormone infusion. Thus the speed and extent of recovery of lipoprotein lipase activity following hormone replacement in insulin-deficient animals varied widely among tissues. These findings suggest that insulin is part of the factors that determine the tissue specificity of lipoprotein lipase regulation.

This study was designed to assess the individual and interactive effects of types of dietary carbohydrate and of chronic alpha 1-adrenergic blockade on some of the determinants of triacylglycerol metabolism in the rat. Specifically, dietary starch and sucrose were given chronically, with or without prazosin mixed with the diet. Serum lipid concentrations and the activity of lipoprotein lipase in several tissues were evaluated 3 h after a voluntary meal consisting of a diet that has been consumed chronically. Postprandial serum triacylglycerol levels were significantly higher (88%, P less than 0.05) after the ingestion of a meal high in sucrose than after a meal high in starch. Prazosin interacted significantly with dietary carbohydrates (P less than 0.03), in that the blocker did not affect triacylglycerol levels in starch-fed rats but greatly diminished their concentration in sucrose-fed animals. Postprandial measurement of lipoprotein lipase in epididymal white adipose tissue, brown adipose tissue, and vastus lateralis muscle showed that enzyme activity in these specific tissues was not affected by the type of dietary carbohydrate. Prazosin significantly decreased lipoprotein lipase activity in brown adipose tissue regardless of the diet, but it did not affect enzyme activity in the other tissues evaluated. These findings demonstrate that the influence of alpha 1-adrenergic blockade on triacylglycerol metabolism can be modulated by dietary components. They further suggest that, in the postprandial state, prazosin did not affect triacylglycerol concentrations by modulating total tissue activity of lipoprotein lipase, at least in the organs that were probed in this study.

Male Sprague Dawley rats were fed cholesterol-free or cholesterol-enriched purified diets containing 15% protein during 3 weeks. Three animal proteins and 6 plant proteins were used in the diets. Results indicated no specific effect of dietary proteins on serum cholesterol related to their animal or plant origin. Dietary proteins were also subjected to a pepsin-pancreatin in vitro digestion. Significant positive correlations were observed between serum cholesterol of rats fed cholesterol-enriched diets, and the tyrosine content of digestion products. This correlation was higher than that observed with intact dietary proteins. A following study showed that tyrosine supplementation may increase plasma cholesterol when diets contain a protein from which tyrosine is slowly released during enzymatic hydrolysis, indicating a relationship between the availability of dietary amino acids during digestion and plasma cholesterol. It has also been shown that this tyrosine effect was not mediated through plasma thyroid hormones.

This study was conducted to determine serum lipid levels and the activity of lipoprotein lipase in epididymal white adipose tissue of rats undergoing exercise training. During the 8-week period of treatment, one group of rats was kept sedentary and the remaining animals were exercise trained either continually (1 h of daily treadmill running) or intermittently (alternate weeks of daily running and inactivity). Exercise training, either continual or intermittent, decreased postprandial serum total and high-density lipoprotein cholesterol concentrations, which returned to sedentary levels in the intermittently trained animals following a week of rest. Lipoprotein lipase activity in whole epididymal adipose pad was lower in rats trained continually than in the sedentary group at the end of the treatment. The intermittent training program elicited large fluctuations in both the specific (per milligram of protein) and total (per tissue) activity of lipoprotein lipase in white adipose tissue. During rest periods, enzyme activity rose to levels that were higher than those of sedentary rats, whereas lipase activity was below that of sedentary animals following a week of running. In the last exercise--rest cycle, body weight gain of the intermittently trained rats was nearly abolished during the week of running, but it increased above that of sedentary animals during weeks of rest. The present results suggest that the modulation of lipoprotein lipase activity in white adipose tissue is one of the adaptations that take place to accommodate the fluctuations in the rate of energy deposition that occur in the rat during an intermittent training program.

This study was designed to evaluate the effect of guar gum on the postprandial increase in plasma lipids, insulin and lipoprotein lipase (LPL) activity in white adipose tissue (WAT). Male rats were given ad libitum access to purified diets containing either no fiber or 5% guar gum for 3 wk. The animals were killed at various times after a meal (10% of daily ad libitum intake of their respective diets). Consumption of guar gum resulted in smaller final body weight (-7%, P less than 0.05) and ad libitum food intake (-10%, P less than 0.05). The difference in epididymal WAT weight induced by the concomitant diet was relatively larger (-29%, P less than 0.05) than that of whole body weight. Although no difference was seen in fasting plasma total and high density lipoprotein cholesterol levels between dietary groups, the postprandial increase in these variables was larger in the animals given the fiber-free meal than in those receiving the fiber-supplemented meal (P less than 0.01). Guar also attenuated the postprandial rise in plasma triacylglycerols. The presence of fiber in the meal reduced the postprandial increase in plasma insulin (P less than 0.01). The meal-induced rise in LPL activity of WAT was significantly smaller (P less than 0.02) in the animals fed the diet containing fiber than in those receiving the fiber-free diet. Thus, guar gum altered the activity of LPL in WAT, an effect that may be related to the insulin response to this dietary component.(ABSTRACT TRUNCATED AT 250 WORDS)

A family with X-linked recessive microcephaly is reported. As patients there were found 8 men or boys respectively out of 3 generations, all of them being related by their mentally healthy mothers. Besides microcephaly the patients showed growth retardation and obesity. Some of them, in addition, had various anomalies as inguinal or umbilical hernias, cryptorchism, tapering fingers, contractures, deeply rooted thumbs and club-feet. There were no hints for a metabolic defect or a chromosomal aberration. The dermatoglyphics could be investigated in 5 patients and showed in all of them a shifting of the axial triradius into the distal position t'. Comparing the own findings with case reports on X-linked microcephalies, the above mentioned family was found not to correspond to any of these observations. It is assumed that in this family, a new disease has occurred which until now has not yet been described, so that the X-linked microcephalies seem to be a heterogenous group of disease from the genetic point of view.