Lipoprotein lipase activity and serum lipoproteins in untreated Type 2 (insulin-independent) diabetes associated with obesity

Summary Serum lipoproteins and the heparin-releasable lipoprotein lipase (LPL) activity of adipose tissue and skeletal muscle were measured in 36 untreated obese patients with Type 2 (insulin-independent) diabetes and the values were compared with those of non-diabetic subjects of similar age, sex and relative body weight. In diabetic men, the LPL activity of adipose tissue was significantly reduced when expressed per tissue weight or per fat cell (p<0.01). Diabetic females had slightly but not significantly lower LPL activity in adipose tissue than the non-diabetic females. The muscle LPL activity was similar in diabetic and non-diabetic subjects of both sexes. When the diabetic men were classified according to fasting blood glucose, the patients with high glucose levels had lower adipose tissue LPL activity than those with moderate hyperglycaemia. In both diabetic and non-diabetic subjects, there was a significant positive correlation between HDL cholesterol concentrations and adipose tissue LPL activity. It is concluded that Type 2 diabetes influences adipose tissue LPL activity and plasma lipoprotein concentrations and that this effect is superimposed on the similar changes produced by obesity alone.     

Glucose uptake and perfusion in subcutaneous and visceral adipose tissue during insulin stimulation in nonobese and obese humans

To elucidate the role of adipose tissue glucose uptake in whole-body metabolism, sc and visceral adipose tissue glucose uptake and perfusion were measured in 10 nonobese and 10 age-matched obese men with positron emission tomography using [(18)F]-2-fluoro-2-deoxy-D-glucose, and [(15)O]-labeled water during normoglycemic hyperinsulinemia. Whole-body and skeletal muscle glucose uptake rates per kilogram were lower in obese than in nonobese subjects (P < 0.01). Compared with nonobese, the obese subjects had 67% lower abdominal sc and 58% lower visceral adipose tissue glucose uptake per kilogram of fat. In both groups, insulin stimulated glucose uptake per kilogram fat was significantly higher in visceral fat depots than in sc regions (P < 0.01). Both sc and visceral adipose tissue blood flow expressed per kilogram and minute was impaired in the obese subjects, compared with the nonobese (P < 0.05). Fat masses measured with magnetic resonance images were higher in obese than in nonobese individuals. If regional glucose uptake rates were expressed as per total fat mass, total glucose uptake rates per depot were similar in obese and nonobese subjects and represented 4.1% of whole-body glucose uptake in obese and 2.6% in nonobese subjects (P < 0.02 between the groups). In conclusion, insulin-stimulated glucose uptake per kilogram fat is higher in visceral than in sc adipose tissue. Glucose uptake and blood flow in adipose tissue exhibit insulin resistance in obesity, but because of the larger fat mass, adipose tissue does not seem to contribute substantially to the reduced insulin stimulated whole-body glucose uptake in obesity.     

Developmental changes in adipose and muscle lipoprotein lipase activity in the atherosclerosis-prone JCR:LA-corpulent rat

OBJECTIVE: To characterize the developmental changes in adipose and muscle lipoprotein lipase (LPL) activity in the atherosclerosis-prone JCR:LA-corpulent rat, and to test the hypothesis that tissue-specific abnormalities in LPL activity precede the establishment of obesity. DESIGN: Lean (+/?) and obese cp/cp male JCR:LA rats were studied at 4, 5 and 8 weeks of age, that is at the onset of obesity, and at a time when obesity is well established. Assessment was made of plasma variables related to glucose and lipid metabolism and of LPL activity in several adipose depots, skeletal muscles and the heart. RESULTS: At week 4, body weights were identical in both genotypes and began to diverge at week 5. Eight-week-old cp/cp rats weighed 35% more than their lean counterparts. Perirenal and epididymal adipose depot weights were also identical in both genotypes at week 4 and began to increase in cp/cp rats at week 5, whereas the subcutaneous depot of 4-week-old cp/cp rats was slightly enlarged. At week 4, the cp/cp rats were hyperinsulinemic (5-fold), hyperleptinemic (30-fold) and hypertriglyceridemic (3-fold) compared to their lean counterparts, and their liver contained twice as much triglyceride. The 4-week-old cp/cp rats displayed 2-7-fold higher LPL specific activity in the various adipose depots compared to lean rats, and enzyme activity remained higher in obese than in lean rats at all subsequent ages. In contrast, LPL activity in the vastus lateralis, gastrocnemius and heart muscles of 4-week-old obese rats was approximately half that observed in lean animals. CONCLUSION: Profound, persistent alterations in the tissue-specific modulation of LPL activity are established in the JCR:LA cp/cp rat prior to the development of frank obesity. The increase in adipose tissue LPL activity and its decrease in muscle tissues are likely to be related to the concomitant alterations in insulinemia and triglyceridemia, respectively. The pre-obesity, tissue-specific alterations in LPL activity may be considered as an integrated adaptation to increased lipid flux aimed at driving lipids toward storage sites and limiting their uptake by triglyceride-laden muscles.     

Contribution of hyperinsulinemia to modulation of lipoprotein lipase activity in the obese Zucker rat

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.     

Effects of caloric restriction on lipid metabolism in man: changes of tissue lipoprotein lipase activities and of serum lipoproteins.

Heparin-releasable lipoprotein lipase (LPL) activity was measured in biopsy samples of adipose tissue and skeletal muscle of 8 normal healthy females, first during an isocaloric diet and then after 2 and 7 days on a 400-kcal diet. In adipose tissue the LPL activity expressed per tissue weight fell to 38% and to 22% of the initial level after 2 and 7 days' caloric restriction, respectively. In skeletal muscle the LPL activity rose slightly after two days (+24%) but decreased to 49% of the initial value after seven days on diet. The estimated total body LPL activity decreased to 50% and to 20% of the baseline value after 2 and 7 days, respectively, but the relative contribution of skeletal muscle to the total LPL increased from 10 to 30%. The triglyceride and VLDL triglyceride concentrations were not significantly changed during the low calorie diet but the LDL triglyceride increased and the HDL cholesterol decreased significantly (P less than 0.01). It is concluded that substantial restriction of calorie intake results in a decrease of over-all triglyceride removal capacity but in an increase of the fraction removed by skeletal muscle. The decrease of HDL cholesterol is probably a consequence of the low turnover of exogenous and endogenous triglyceride-rich lipoproteins.     

The effect of the Ala12 allele of the peroxisome proliferator-activated receptor-gamma2 gene on skeletal muscle glucose uptake depends on obesity: a positron emission tomography study

CONTEXT: The Pro(12)Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 gene is associated with insulin sensitivity. Obesity is a major risk factor for insulin resistance, but the association of the Pro(12)Ala polymorphism with body weight has been controversial. Furthermore, obesity may modulate the effect of this polymorphism on insulin sensitivity. OBJECTIVE: The aim of our study was to investigate the effects of the Pro(12)Ala polymorphism on skeletal muscle and adipose tissue glucose uptake (GU) in nonobese and obese subjects. DESIGN: The design was a cross-sectional study. STUDY SUBJECTS: The rates of GU were investigated in 124 (72 nonobese and 52 obese; body mass index cutoff point, 27 kg/m(2)) healthy subjects with the euglycemic hyperinsulinemic clamp. Skeletal muscle and adipose tissue GU and skeletal muscle perfusion were measured using fluorine-18-labeled fluorodeoxyglucose, [(15)O]H(2)O, and positron emission tomography. RESULTS: The rates of skeletal muscle GU were higher in nonobese subjects carrying the Ala(12) allele than in subjects carrying the Pro(12)Pro genotype (P = 0.004), whereas no differences were found in skeletal muscle perfusion between the groups. In contrast, in obese subjects the rates of skeletal muscle GU did not differ between carriers of the Ala(12) allele and carriers of the Pro(12)Pro genotype. No difference in adipose tissue GU was found in either nonobese or obese subjects according to Pro(12)Ala polymorphism. CONCLUSIONS: We conclude that the Pro(12)Ala polymorphism modulates skeletal muscle GU differently in nonobese and obese subjects.     

Lipoprotein lipase activity of adipose tissue and skeletal muscle in insulin-deficient human diabetes

Summary We have previously shown that lipoprotein lipase (LPL) activity of tissues is an important determinant not only of plasma VLDL levels but also of HDL-cholesterol. Studies were designed to investigate whether the serum lipoprotein alterations in uncontrolled insulin-deficient diabetes can be accounted for by changes in LPL activity of tissues. The heparin-releasable LPL activity was determined from biopsy samples of adipose tissue and skeletal muscle in 16 patients with newly detected untreated insulin-deficient diabetes and in 16 age-, sex- and body weight-matched healthy control subjects. Repeat assays were carried out after the patients had been on insulin treatment for an average of two weeks and when the diabetes was well controlled. When untreated the patients had increased concentrations of triglycerides and cholesterol in whole serum and in VLDL and LDL while the HDL cholesterol level was lower than that of controls (p<0.01). The cholesterol/triglyceride ratio in each of the three lipoproteins was similar in patients and controls. While untreated the diabetic patients had significantly reduced mean LPL activity both in adipose tissue (average 34% of control mean, p<0.001) and in skeletal muscle (average 45% of control mean, p<0.05). In the whole group HDL-cholesterol was positively correlated with adipose tissue LPL activity (r=+0.58, p<0.001) while log serum total triglyceride and log VLDL-triglyceride showed significant negative correlations with LPL activity of both adipose tissue and skeletal muscle. After initiation of insulin treatment the LPL activity increased significantly (p<0.01) in both tissues but was still subnormal after 2 weeks. At the same time the VLDL and LDL concentrations had returned to normal while the HDL-cholesterol remained low. The results suggest that the increase of VLDL and LDL triglyceride and the decrease of HDL-cholesterol present in uncontrolled insulin-deficient diabetes are, at least partly, accounted for by decreased LPL activity of tissues. The restoration of tissue LPL and of serum HDL-cholesterol by insulin are relatively slow processes. The results are consistent with the hypothesis that HDL-cholesterol concentration is dependent on the efficiency of removal of triglyceride-rich lipoproteins from the circulation.     

Insulin sensitisation affects lipoprotein lipase transport in type 2 diabetes: role of adipose tissue and skeletal muscle in response to rosiglitazone

Aims/hypothesis Lipoprotein lipase (LPL) is produced by adipose tissue and skeletal muscle, but acts on plasma lipoproteins after being transported to endothelial binding sites. Insulin resistance is associated with decreased plasma LPL mass. We investigated the effects of insulin sensitisation on tissue-specific LPL expression and transport in patients with type 2 diabetes. Materials and methods Arterio-venous gradients of plasma LPL activity and mass across adipose tissue and skeletal muscle were measured in 16 type 2 diabetic patients in a double-blind, placebo-controlled, cross-over randomised trial of rosiglitazone. In vivo LPL rate of action was assessed by tissue-specific arterio-venous triglyceride concentration gradients. LPL mRNA was quantified in adipose tissue and skeletal muscle biopsies. Results Adipose tissue released large quantities of inactive LPL (p<0.001); skeletal muscle released small amounts of active LPL (p<0.01). Rosiglitazone increased adipose tissue release of LPL mass (+35%, p=0.04) and decreased the release of active LPL from skeletal muscle (−57%, p=0.03). Rosiglitazone increased adipose tissue and skeletal muscle LPL mRNA, but did not affect adipose tissue LPL rate of action or activity. Adipose tissue release of LPL mass correlated with systemic LPL mass concentrations (r=0.47, p=0.007), suggesting that the rate of adipose tissue release of LPL mass is a major determinant of systemic LPL mass concentrations. Conclusions/interpretation LPL transport from adipose tissue and skeletal muscle are regulated differently. In adipose tissue, rosiglitazone increases LPL mRNA abundance and LPL transport rate and possibly increases endothelial binding sites for LPL, but affects neither tissue LPL activity nor LPL rate of action.     

Lipoprotein lipase activity in adipose tissue and skeletal muscle of runners: relation to serum lipoproteins.

Physically well-trained people generally have lower VLDL-triglyceride and higher HDL-cholesterol levels than sedentary subjects. To examine the underlying mechanisms of this lipoprotein pattern, we measured the lipoprotein lipase (LPL) activity in needle biopsy specimens of adipose tissue and skeletal muscle of competitive runners and of body weight-matched, physically less-active controls. The active sportsmen were either sprinters, whose training program consisted mainly of athletics of short duration or long distance runners undergoing a strenuous endurance exercise program. In sprinters (all males) the serum lipid and lipoprotein concentrations did not differ significantly from those of controls and the mean LPL activities in muscle and adipose tissue were also similar in these two groups. The long distance runners (both sexes), on the other hand, had higher means levels of HDL-cholesterol than the respective controls. The LPL-activity of both adipose tissue (p less than 0.05) and skeletal muscle (p less than 0.01) was significantly higher in male long distance runners than in control males. Female runners had higher muscle LPL activity than controls (p less than 0.01) but in adipose tissue the difference in LPL activity was not significant. Rough estimates calculated for LPL activity present in whole body adipose tissue and skeletal muscle indicated that total LPL activity was 2.3 times higher in male long distance runners and 1.5 times higher in female long distance runners than in the respective controls. In combined groups of male runners and controls, there was a highly significant positive correlation between the serum HDL-cholesterol level and the LPL activity of adipose tissue expressed per tissue weight (r = +0.72, p less than 0.001) or per whole body fat (r = +0.62, p less than 0.001). The group means of HDL-cholesterol and adipose tissue LPL activity in the five cohorts studied (male sprinters, distance runners and controls and female distance runners and controls) were also positively correlated (r = +0.94). It is concluded that endurance training is associated with an adaptive increase of LPL activity not only in skeletal muscle but also in adipose tissue. These changes are not observed in sprinters who are trained by exercises of shorter duration. The high HDL-cholesterol levels of physically well-trained people are probably accounted for, at least partly, by the increased LPL activity and the concomitant rapid turnover or triglyceride-rich lipoproteins.     

TNFalpha expression of subcutaneous adipose tissue in obese and morbid obese females: relationship to adipocyte LPL activity and leptin synthesis

INTRODUCTION: Tumor necrosis factor (TNFalpha) has been invoked as an adipostat. Accordingly, the adipose tissue expression of TNFalpha has been shown to be proportional to the degree of adiposity. The regulatory role of TNFalpha in obesity may be controlled by several mechanisms. These include the inhibitory effect on LPL activity, the mediation on glucose homeostasis or the effect on leptin. To assess the role of TNFalpha in obesity we measured adipocyte TNFalpha expression in 96 females with a wide range of adiposity and with or without type 2 diabetes. We analysed the relationship between TNFalpha expression, adipocyte LPL activity, insulin resistance and leptin in this population. RESULTS: The TNFalpha and leptin expression of the adipose tissue in obese and morbid obese patients were significantly higher than in controls. Obese and morbid obese patients had slightly higher levels of LPL activity, but these differences were not significant. We observed a significant relationship between adipose TNFalpha expression and body mass index (r=0.35, P<0.001). TNFalpha expression was negatively related to LPL activity (r=-0.28, P<0.05) and positively related to leptin expression (r=0.35, P<0.001). CONCLUSION: Our results indicate that obese women, even those with morbid obesity, over-express TNFalpha in subcutaneous adipose tissue in proportion to the magnitude of the fat depot and independently of the presence of type 2 diabetes. The TNFalpha system may be a homeostatic mechanism that prevents further fat deposition by regulating LPL activity and leptin production.     

Effect of diet on adipose tissue and skeletal muscle VLDL receptor and LPL: implications for obesity and hyperlipidemia

This study was designed to examine the effect of a high-fat (primarily saturated), refined-carbohydrate (sucrose) diet (HFS), which is known to induce obesity and hyperlipidemia, on adipose tissue and skeletal muscle lipoprotein lipase (LPL) and very-low density lipoprotein receptor (VLDL-R) protein expressions. Female Fischer rats were placed on either a HFS or a low-fat, complex-carbohydrate (LFCC) diet for 22 months beginning at 2 months of age. After 20 months, a subgroup of the HFS rats were switched to the LFCC diet for 2 months (HFS/LFCC). Body weight, feed efficiency, plasma total cholesterol, VLDL-C, low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) concentrations and LDL-C to high-density lipoprotein cholesterol ratio were all significantly raised by the HFS diet and improved by conversion to the LFCC diet. Adipose tissue heparin-releasable, extractable and total LPL activity expressed per cell were significantly increased in the HFS-fed group. However, LPL protein abundance normalized against total cellular protein was unchanged in the HFS group. This observation is consistent with the presence of adipose tissue hypertrophy. Skeletal muscle LPL protein abundance and heparin-releasable activity were reduced by the HFS diet and improved after switching to the LFCC diet. Both adipose tissue and skeletal muscle VLDL-R protein levels were significantly reduced by the HFS diet and increased after conversion to the LFCC diet. We conclude that an HFS diet induces changes in LPL and VLDL-R in a manner which favors shunting of dietary fat from skeletal muscle to adipose tissue and decreases TG-rich lipoprotein clearance contributing to increased plasma lipids and obesity. Conversion to a LFCC diet can ameliorate the dyslipidemia and tissue changes induced by long-term HFS diet consumption.     

Effect of sucrose overfeeding on brown adipose tissue lipogenesis and lipoprotein lipase activity in rats

During cold-induced nonshivering thermogenesis, interscapular brown adipose tissue (BAT) lipoprotein lipase (LPL) activity and lipogenesis are elevated. Because of the many similarities between cold- and diet-induced thermogenesis, we examined the effect of ad libitum access to a 32% sucrose solution on caloric intake, adiposity, and BAT enzyme activities in male rats. Daily caloric intakes of sucrose-fed animals were elevated by 20%-25%, and 8 wk of sucrose feeding doubled carcass fat content. This sucrose-feeding induced obesity was associated with increases in circulating triglyceride and insulin levels as well as increased retroperitoneal white adipose tissue LPL activity. However, the increased carcass lipid content accounted for less than half of the excess calories ingested by the sucrose-fed rats. Sucrose feeding stimulated in vivo lipogenesis in BAT and elevated BAT fatty acid synthetase and acetyl-CoA carboxylase activities but not LPL activity. These findings suggest that overeating enhances endogenous lipogenesis but not uptake of circulating triglyceride in BAT. Thus, both cold- and diet-induced thermogenesis increase BAT lipogenesis, while only cold-induced thermogenesis is associated with elevated LPL activity in BAT.     

Responsiveness to thyroid hormone and to ambient temperature underlies differences between brown adipose tissue and skeletal muscle thermogenesis in a mouse model of diet-induced obesity

Thyroid hormone accelerates energy expenditure (EE) and is critical for cold-induced thermogenesis. To define the metabolic role played by thyroid hormone in the dissipation of calories from diet, hypothyroid mice were studied for 60 d in a comprehensive lab animal monitoring system. Hypothyroidism decreased caloric intake and body fat while down-regulating genes in the skeletal muscle but not brown adipose tissue thermogenic programs, without affecting daily EE. Only at thermoneutrality (30 C) did hypothyroid mice exhibit slower rate of EE, indicating a metabolic response to hypothyroidism that depends on ambient temperature. A byproduct of this mechanism is that at room temperature (22 C), hypothyroid mice are protected against diet-induced obesity, i.e. only at thermoneutrality did hypothyroid mice become obese when placed on a high-fat diet (HFD). This is in contrast to euthyroid controls, which on a HFD gained more body weight and fat at any temperature while activating the brown adipose tissue and accelerating daily EE but not the skeletal muscle thermogenic program. In the liver of euthyroid controls, HFD caused an approximately 5-fold increase in triglyceride content and expression of key metabolic genes, whereas acclimatization to 30 C cut triglyceride content by half and normalized gene expression. However, in hypothyroid mice, HFD-induced changes in liver persisted at 30 C, resulting in marked liver steatosis. Acclimatization to thermoneutrality dramatically improves glucose homeostasis, but this was not affected by hypothyroidism. In conclusion, hypothyroid mice are metabolically sensitive to environmental temperature, constituting a mechanism that defines resistance to diet-induced obesity and hepatic lipid metabolism.     

Effects of hyperinsulinemia on lipoprotein lipase, angiopoietin-like protein 4, and glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 in subjects with and without type 2 diabetes mellitus

Our aims were to compare the systemic effects of insulin on lipoprotein lipase (LPL) in tissues from subjects with different degrees of insulin sensitivity. The effects of insulin on LPL during a 4-hour hyperinsulinemic, euglycemic clamp were studied in skeletal muscle, adipose tissue, and postheparin plasma from young healthy subjects (YS), older subjects with type 2 diabetes mellitus (DS), and older control subjects (CS). In addition, we studied the effects of insulin on the expression of 2 recently recognized candidate genes for control of LPL activity: angiopoietin-like protein 4 (ANGPTL4) and glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1. As an effect of insulin, LPL activity decreased by 20% to 25% in postheparin plasma and increased by 20% to 30% in adipose tissue in all groups. In YS, the levels of ANGPTL4 messenger RNA in adipose tissue decreased 3-fold during the clamp. In contrast, there was no significant change in DS or CS. Regression analysis showed that the ability of insulin to reduce the expression of ANGPTL4 was positively correlated with M-values and inversely correlated with factors linked to the metabolic syndrome. Expression of glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 tended to be higher in YS than in DS or CS, but the expression was not affected by insulin in any of the groups. Our data imply that the insulin-mediated regulation of LPL is not directly linked to the control of glucose turnover by insulin or to ANGPTL4 expression in adipose tissue or plasma. Interestingly, the response of ANGPTL4 expression in adipose tissue to insulin was severely blunted in both DS and CS.     

JTT-501, a new oral hypoglycemic agent, reverses hypertriglyceridemia in Zucker fatty and ventromedial hypothalamus-lesioned obese rats

JTT-501 is a new oral hypoglycemic agent that is reported to be effective in insulin-resistant diabetic animal models by improving insulin resistance. It also improves hypertriglyceridemia. We investigated the mechanism of the reversal of hypertriglyceridemia in two types of obese animals using JTT-501. In Zucker fatty obese rats, an animal model of genetic obesity, fasting plasma triglyceride and glucose significantly decreased after a single daily oral dose of JTT-501 (100 mg/kg) for 7 days. In ventromedial hypothalamus (VMH)-lesioned obese rats, an animal model of nongenetic obesity, fasting plasma triglycerides significantly decreased but fasting plasma glucose levels remained unchanged after treatment with this agent. In Sprague-Dawley (SD) rats, fasting plasma triglyceride and glucose levels remained unchanged. The JTT-501-treated Zucker fatty and VMH-lesioned obese rats showed a decrease in insulin, but it was not significant, while the treated SD rats showed a significant decrease in insulin. Postheparin plasma lipoprotein lipase (LPL) increased significantly in treated Zucker fatty obese and SD rats, but did not change in VMH-lesioned obese rats. The hepatic triglyceride secretion rate (TGSR) did not change in any species treated with JTT-501. There was a negative correlation between postheparin plasma LPL and plasma triglyceride levels in Zucker fatty obese rats, while no such correlation was observed in VMH-lesioned obese or SD rats. The fractional catabolic rate (FCR) for plasma triglyceride was increased significantly by JTT-501 in both Zucker fatty and VMH-lesioned obese rats. These results suggest that JTT-501 decreases plasma triglycerides mainly by increasing postheparin plasma LPL in Zucker fatty obese rats, while it ameliorates an impairment in the ability of adipose tissue to remove triglyceride from the circulation in VMH-lesioned obese rats.     

Regional differences in adipose tissue lipoprotein lipase activity in relation to body fat distribution and menopausal status in obese women

Adipose tissue lipoprotein lipase (LPL) activity was determined in the abdominal and femoral regions in 25 pre- and 25 post-menopausal obese women, matched for body mass index and fat distribution. LPL activity was not different in pre- and post-menopausal women. Regional differences of the same magnitude were observed in pre- and post-menopausal women with femoral obesity. Such differences were not found in women with abdominal obesity either pre- or post-menopausal. Furthermore the abdominal/femoral ratio of LPL activity was positively correlated (P less than 0.05) to waist/hip ratio, independently of age, body mass index, fat cell size ratio and menopausal status. These data indicate that in obese women the regional differences in LPL activity are related to body fat distribution. The menopausal status does not seem to be a sufficient and necessary condition to abolish the typical female regional differences in LPL activity in adipose tissue from obese women.     

Adipose triglyceride lipase gene expression in human visceral obesity.

In comparison to subcutaneous (SC) fat, visceral adipose tissue is more sensitive to catecholamine-induced lipolysis and less sensitive to the antilipolytic effects of insulin. Variation in the expression of lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) have been reported. We therefore hypothesized that expression of adipose triglyceride lipase (ATGL) is different in visceral and SC depot and investigated whether ATGL mRNA expression is related to obesity, fat distribution and insulin sensitivity. ATGL, LPL, and HSL mRNA expression was measured in 85 paired samples of omental and subcutaneous adipose tissue in normal glucose tolerant lean and obese individuals. In addition, we included a subgroup of obese (BMI >30 kg/m2) individuals with either impaired or preserved insulin sensitivity determined by euglycemic-hyperinsulinemic clamps. ATGL mRNA levels are significantly decreased in insulin resistant obese subjects. Independently of body fat mass, omental ATGL mRNA correlates with fasting insulin concentration, glucose uptake during the steady state of the clamp and HSL mRNA expression. In obese, but not in lean subjects, LPL and HSL mRNA expression was significantly higher in omental compared to SC fat. In both depots, HSL mRNA was significantly lower in obese individuals. Visceral HSL mRNA expression is closely related to adipocyte size and fasting plasma insulin concentrations, whereas visceral fat area significantly predicts visceral LPL mRNA expression. ATGL mRNA expression is not significantly different between omental and SC fat. HSL, but not ATGL mRNA expression is closely related to individual and regional differences in adipocyte size. Impaired insulin sensitivity was associated with decreased ATGL and HSL mRNA expression, independently of body fat mass and fat distribution.     

Spontaneous and experimental human obesity: effects of diet and adipose cell size on lipolysis and lipogenesis.

We examined the hypothesis that adipose tissue from lean and obese subjects might provide different internal signals in response to changes in stored calories. Adipose tissue was obtained before weight gain in nonobese subjects and after weight gain in five of the same individuals. Adipose tissue was removed before and after weight loss in seven obese patients. Two isocaloric diets were fed to both groups for 2–3 wk each; one diet was high in carbohydrate, and the other contained a low carbohydrate content. Incorporation of radioactivity from pyruvate into fatty acids in vitro was lower with the low-carbohydrate diet than with the high-carbohydrate diet. It was also significantly reduced after weight gain in the nonobese subjects but was not significantly altered in the obese. There were no significant effects of diet or weight gain on the enzymatic activities in the nonobese subjects. The large fat cells from both groups of subjects had an increased sensitivity to the lipolytic effects of isoproterenol as compared with the smaller fat cells. Variations in carbohydrate intake had no effect on the lipolytic response to isoproterenol. The dose response of fat cells to dibutyryl-cyclic-3′,5′-AMP did not change after weight gain in the nonobese males, but was significantly reduced on both levels of carbohydrate after weight loss in the obese (i.e., when studying the smaller fat cells). These studies suggest that differences in the metabolism of adipose tissue between obese and lean subjects persist when differences in the size of fat cells and caloric intake are controlled.     

Hemodynamic and metabolic responses to interstitial angiotensin II in normal weight and obese men

OBJECTIVE: The expression of the AT1 receptor in adipose tissue is not decreased or even increased in obese subjects despite systemic activation of the renin-angiotensin system. Therefore, we hypothesized that peripheral tissues of obese subjects are hypersensitive to angiotensin (Ang) II. METHODS: We characterized the effect of locally applied Ang II in skeletal muscle and subcutaneous adipose tissue of healthy non-obese (n = 12) and obese (n = 11) men using the microdialysis technique. Tissues were perfused with Ringer's solution + ethanol and incremental doses of Ang II (0.01, 0.1 and 1 micromol/l). Dialysate ethanol, glycerol, glucose, lactate, and pyruvate concentrations were measured to assess changes in blood flow (ethanol dilution technique), lipolysis and glycolysis, respectively. RESULTS: In adipose tissue, basal ethanol ratio was significantly higher and dialysate metabolite concentrations were significantly lower in obese versus non-obese men. In muscle, basal dialysate glycerol was significantly higher in obese versus non-obese men. Ang II elicited small increases in ethanol ratio and decreases in dialysate glucose in adipose tissue and skeletal muscle in both non-obese and obese men. Dialysate lactate increased significantly in both tissues of obese, but not non-obese men. Dialysate glycerol increased in adipose tissue of non-obese (+ 40%) but not of obese and remained almost unchanged in muscle of both groups. CONCLUSIONS: Interstitially applied Ang II elicits subtle changes in tissue perfusion and metabolism. However, we did not find a major increase in interstitial Ang II responsiveness in obese men.     

Postheparin plasma lipase activities in obesity: failure to increase with adipose organ enlargement

Published studies have shown that overproduction of very low density lipoproteins is a major factor leading to hypertiglyceridemia in obesity. Few systematic studies of triglyceride removal or postheparin lipoprotein lipase activity (LPLA) in obesity have appeared. We have examined heparin-released lipoprotein triglyceride hydrolase activities in 12 lean and 12 obese age- and sex-matched volunteers after overnight fasting. Heparin doses were calculated to compensate for the disproportionality between body mass and plasma volume in obesity. Triglyceride hydrolase activities of hepatic (HTGLA) and extrahepatic (LPLA) origin were distinguished by in vitro inhibition of LPLA with protamine sulfate. Incremental heparin doses were given to each subject to determine lipase activities under conditions of maximal release and to define sensitivity to heparin-facilitated lipase release. Maximal postheparin LPLA and HTGLA (u/ml plasma or u/total plasma vol) were similar in lean and obese individuals despite a nearly three-fold increase in calculated adipose tissue mass in the obese. Since adipose tissue LPLA has been reported to increase in proportion to adipocyte size, the lack of difference in maximal postheparin LPLA was expected. There was an inverse correlation between plasma triglyceride concentration and LPLA/kg adipose tissue. These empirical observations may reflect relatively decreased heparin-releaseable (functional) LPLA in relation to adipose organ mass in obese subjects. The mechanism of this relationship has not been established.