Insulin resistance: an adaptation for weight maintenance.
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Body Weight↗
Biomedical subjects
R H Eckel
Publications and source records attributed to R H Eckel.
Characterization of a high affinity octamer transcription factor binding site in the human lipoprotein lipase promoter.
A high affinity octamer transcription factor (OTF-1) binding site has been identified and characterized at position--46 base pairs (bp) in the proximal human lipoprotein lipase (LPL) promoter. The affinity of the LPL OTF-1 binding site was approximately 15-fold greater than a consensus octamer sequence, ATTTGCAT, present at position--66 bp in the mouse Vk T1 promoter, and approximately 5-fold greater than the OTF-1 site present at position--49 bp in the human histone H2B promoter. Diethylpyrocarbonate interference assays have identified both 5' and 3' adenine nucleotides, which flank the core LPL ATTTGCAT sequence and interfere with OTF-1 binding when chemically modified. Introduction of mutations in either 5' or 3' flanking AT-rich sequences lowered the affinity of OTF-1 binding below the level observed with the wild-type LPL octamer oligomer. A double mutation in both flanking AT regions, however, greatly reduced the affinity of this site to levels similar to that observed with the mouse Vk T1 OTF site. An additional nuclear transcription factor, NF-Y, has been shown to bind to a functional CCAAT box motif located at -65 bp in the LPL promoter using specific alpha-NF-Y antisera. The observation of high affinity OTF-1 and NF-Y binding sites in a region of the proximal LPL promoter which is necessary for high levels of LPL transcription suggests that these sites with their associated proteins play important functional roles in the transcriptional activation of the LPL promoter during adipocyte differentiation.
3T3 Cells↗
Regional similarities in the metabolic regulation of adipose tissue lipoprotein lipase.
Seven normal weight and 10 obese women were studied to determine the relative activities of adipose tissue lipoprotein lipase (ATLPL) in the gluteal and abdominal subcutaneous adipose tissue depots, both in the fasting state and in response to a 6-hour insulin/glucose infusion. In normal weight women, fasting gluteal enzyme activity was greater than abdominal (P less than .02). In the obese group, fasting levels of ATLPL were higher in both the gluteal and abdominal depots than in the normal weight group, but similar between regions. The regulation of ATLPL by insulin/glucose was also similar between regions in each group. When both groups were considered together, there was a strong correlation between fasting ATLPL of both regions, and between the insulin responsiveness of gluteal ATLPL and abdominal ATLPL after a 6-hour infusion. Despite regional differences in fasting ATLPL in lean women, these studies indicate that the regulation of ATLPL by insulin/glucose is largely similar in at least these two subcutaneous adipose tissue depots.
Adipose Tissue↗
Determinants of total high density lipoprotein cholesterol and high density lipoprotein subfraction levels among Hispanic and non-Hispanic white persons with normal glucose tolerance: the San Luis Valley Diabetes Study.
Determinants of total high-density lipoprotein cholesterol (HDL-C) and HDL subfractions were assessed in Hispanic and non-Hispanic white persons (n = 932), aged 20-74 years, in the San Luis Valley, Colorado. Using multiple regression, BMI was negatively associated with HDL-C, HDL2-C, and HDL3-C in men and HDL-C and HDL3-C in women. Among females, current smokers had lower HDL-C and subfractions. Women on beta-blockers had lower HDL3-C levels. For both sexes, a positive association was observed between age and HDL-C and subfractions and physical activity with HDL-C and HDL3-C. Drinking alcohol (> or = 50 g/week) was associated with higher HDL-C and HDL3-C in both sexes and HDL2-C in women. The positive association of age and negative associations of the subscapular/triceps ratio and fasting insulin had consistent relationships with HDL-C, HDL2-C, and HDL3-C in men and women. Ethnicity was not significantly associated with HDL-C or subfractions after controlling for body fat distribution or fasting insulin.
Adrenergic beta-Antagonists↗
Dietary substitution of medium-chain triglycerides improves insulin-mediated glucose metabolism in NIDDM subjects.
Dietary medium-chain triglycerides (MCT) may improve insulin-mediated glucose metabolism. To examine this possibility, 10 non-insulin-dependent diabetes mellitus (NIDDM) patients, 4 hypertriglyceridemic, and 6 normotriglyceridemic nondiabetic control subjects were examined with a 5-day cross-over design, in which the short-term metabolic effects of a 40% fat diet containing 77.5% of fat calories as MCT were compared with an isocaloric long-chain triglyceride-containing diet. In diabetic patients, MCT failed to alter fasting serum glucose concentrations but reduced preprandial glycemic excursions by 45% (F = 7.9, P less than 0.01). On MCT, the amount of glucose needed to maintain euglycemia during an intravenous insulin infusion was increased in diabetic subjects by 30%, in hypertriglyceridemic subjects by 30%, and in normotriglyceridemic control subjects by 17%. MCT increased mean +/- SE insulin-mediated glucose disposal (4.52 +/- 0.56 vs. 2.89 +/- 0.21 mg.kg-1.min-1; n = 3, P less than 0.05) but failed to alter basal glucose metabolism or insulin-mediated suppression of hepatic glucose output. Metabolic responses to MCT were observed independent of sulfonylurea therapy or severity of fasting hyperglycemia. No change in fasting serum insulin or triglyceride concentrations were seen with MCT administration. Although MCT increased mean fasting serum beta-hydroxybutyrate levels from 0.10 +/- 0.03 to 0.26 +/- 0.06 mM (P less than 0.05) in normotriglyceridemic nondiabetic subjects, no change was seen in diabetic patients. Thus, MCT-containing diets increased insulin-mediated glucose metabolism in both diabetic patients and nondiabetic subjects. In diabetic subjects, this effect appears to be mediated by increases in insulin-mediated glucose disposal.(ABSTRACT TRUNCATED AT 250 WORDS)
3-Hydroxybutyric Acid↗
Preheparin lipoprotein lipolytic activities: relationship to plasma lipoproteins and postheparin lipolytic activities.
To determine the putative metabolic relevance of preheparin versus postheparin lipoprotein lipases, the relationships of both pre- and postheparin lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) to plasma triglycerides, low density lipoprotein (LDL) cholesterol, and high density lipoprotein (HDL) cholesterol were determined in 93 men. Relationships of preheparin lipases to their respective postheparin lipases were also examined. Although relationships between the preheparin lipases and plasma triglycerides and HDL cholesterol were not apparent, both preheparin LPL (rs = 0.306, P = 0.0036) and HTGL (rs = 0.348, P = 0.0008) correlated with LDL cholesterol, a relationship not seen with either postheparin lipase. Both postheparin LPL (rs = 0.515, P = 0.0001) and postheparin HTGL (rs = -0.228, P = 0.0028), however, correlated with HDL cholesterol. In addition, postheparin LPL was inversely correlated with postheparin HTGL (rs = -0.363, P = 0.0003), whereas the relationship between preheparin LPL and preheparin HTGL was positive (rs = 0.228, P = 0.0009). Overall, these data point to differences between pre- and postheparin lipases in their relationships to lipoproteins, and one to another. The relationships of LDL cholesterol to both preheparin LPL and HTGL suggest that displacement of active forms of both lipases from their endothelial binding sites may mark triglyceride-rich lipoproteins or their remnants for metabolic pathways that lead to LDL.
Adult↗
Tissue-specific regulation of lipoprotein lipase activity by insulin/glucose in normal-weight humans.
Eight normal-weight subjects (four men, four women) were studied to determine the relative activities of lipoprotein lipase (LPL) in adipose tissue (ATLPL) and vastus lateralis skeletal muscle (SMLPL), both in the fasting state and in response to a 6-hour insulin/glucose infusion. Mean fasting levels of ATLPL and SMLPL were not statistically different. After 6 hours of insulin/glucose infusion, mean ATLPL activity was significantly greater than the fasting level (P less than .01), while mean SMLPL activity decreased from basal (P less than .05). These tissue-specific changes in LPL responsiveness (0 to 6 hours) were significantly different (P less than .01). No differences between men and women were observed. These divergent tissue-specific LPL responses to insulin/glucose would serve to direct lipoprotein triglyceride-derived fatty acids away from muscle and to adipose tissue for storage.
Adipose Tissue↗
Weight reduction increases adipose but decreases cardiac LPL in reduced-obese Zucker rats.
Lipoprotein lipase (LPL) activity and mRNA levels were measured in cardiac muscle and adipose tissue from lean, obese, and weight-stable reduced-obese Zucker rats, both fasted and 2 h after feeding. Fasting epididymal fat LPL activity was substantially higher in obese rats relative to lean rats [6.9 vs. 0.2 nmol free fatty acid (FFA).10(6) cells-1.min-1; P = 0.0001], and was higher still in reduced-obese rats (15.7 nmol FFA.10(6) cells-1.min-1; P = 0.002). Adipose tissue LPL increased with feeding in all three groups. In marked contrast, fasting cardiac muscle LPL was lower in obese rats relative to lean (28.8 vs. 38.5 nmol FFA.g-1.min-1; P = 0.0064) and was lower still in reduced-obese rats (14.5 nmol FFA.g-1.min-1; P = 0.0001). LPL mRNA levels increased in adipose tissue along with enzyme activity; however, the magnitude of the changes were relatively small, suggesting that the primary regulatory steps are posttranslational. Weight reduction studies were also carried out in Sprague-Dawley rats with similar results. These studies show that sustained weight reduction results in coordinate changes in tissue-specific LPL, favoring delivery of lipoprotein triglyceride fatty acids to adipose tissue relative to cardiac muscle and the restoration of energy stores.
Adipose Tissue↗
Relationship between habitual physical activity and insulin levels among nondiabetic men and women. San Luis Valley Diabetes Study.
OBJECTIVE: To determine whether higher levels of physical activity would be associated with lower fasting insulin and C-peptide levels in a free-living nondiabetic population. RESEARCH DESIGN AND METHODS: A cross-sectional study was conducted with a Hispanic and non-Hispanic white population of 442 men and 489 women with normal glucose tolerance (by World Health Organization criteria) in two rural Colorado counties. Total physical activity was assessed by a 7-day physical activity recall from which metabolic equivalents were estimated. Relationships between metabolic equivalents and fasting insulin and C-peptide were assessed while considering obesity, age, and other risk factors known to influence fasting insulin levels. RESULTS: Among all subjects, univariate analyses showed that higher activity levels were associated with lower mean fasting insulin and C-peptide levels (P less than or equal to 0.05). Multiple linear regression showed that higher activity was significantly associated with lower values of log fasting insulin and C-peptide levels in men only (P less than 0.001) independent of obesity, fat distribution, and age. Men in the highest tertile of activity had an adjusted mean fasting insulin level of 59.2 pM and fasting C-peptide level of 0.5 nM compared with a fasting insulin level of 72.7 pM and fasting C-peptide level of 0.6 mM for men in the lowest tertile of activity. The magnitude of the inverse association between activity and insulin was greatest in older rather than younger men. Physical activity was not associated with fasting insulin or C-peptide levels in women in the multivariate analyses. CONCLUSIONS: Based on cross-sectional data, we conclude that higher levels of habitual physical activity are associated with lower fasting insulin and C-peptide levels in Hispanic and non-Hispanic white men.
Adult↗
Levels of acylation stimulating protein in obese women before and after moderate weight loss.
Acylation stimulating protein (ASP) is a small (MW 14,000) basic (pI 9.0) protein which has only recently been purified from human plasma. Since ASP is the most potent known stimulant of triglyceride synthesis in human adipose tissue, the present study was designed to determine if plasma ASP was elevated in patients with moderate obesity, and if so, whether this level changed with weight loss. Fasting plasma ASP levels were determined by competitive ELISA immunoassay in 10 obese women before weight loss, immediately after weight loss, and 3 months after maintaining weight reduction. Their plasma ASP results were compared to 17 age and sex-matched lean controls. With weight loss, plasma ASP decreased significantly: 19.6 +/- 10.7 mg/dl before weight loss vs 15.0 +/- 9.5 mg/dl after weight loss vs 13.8 +/- 7.7 mg/dl 3 months after being weight stable, P less than 0.05 initial vs final value. Nevertheless, plasma ASP was significantly higher than the control value at all three times. Thus, before weight loss, the average ASP in the obese group was four times that in the control group (19.6 +/- 10.7 vs 5.1 +/- 3.6 mg/dl, P less than 0.0005) while even 3 months after weight loss, it remained almost three times above the control group (13.8 +/- 7.7 vs 5.1 +/- 3.6 mg/dl, P less than 0.0005). The data suggest, therefore, that an elevated plasma level of ASP is common in obesity, that the level of plasma ASP may reflect the fat cell mass present in an individual, and raises the possibilities that ASP may play a role in initiation or maintenance of the obese state.
Adult↗
Lipoprotein lipase in human milk: compartmentalization and effect of fasting, insulin, and glucose.
The object of this study was to investigate the effect of maternal metabolic state on the activity of lipoprotein lipase (LPL) in human milk. Although the total LPL activity in milk was not significantly affected by up to three cycles of freezing and thawing, the amount of LPL associated with the cream fraction of the milk increased from an average of less than 10% to about 70% after this treatment. The enzyme was relatively stable when the milk was stored on ice, losing activity at a rate of about 1% per hour. At 37 degrees C degradation was more rapid, about 7% per hour. When LPL activity was measured in samples taken at hourly intervals by breast pump, using oxytocin to achieve a complete letdown at each pumping, activity was found to double from the first to the third pumping. Thereafter the activity was stable under fasting conditions. Hyperglycemic and euglycemic, hyperinsulinemic glucose clamp protocols were used to evaluate the effects of glucose and insulin. Both high plasma glucose and high plasma insulin in the presence of normal glucose significantly increased LPL activity within 4 hours. We conclude that, like adipose, tissue LPL, mammary LPL is regulated by plasma insulin.
Adult↗
Distribution and source of lipoprotein lipase in mouse mammary gland.
During lactation lipoprotein lipase (LPL) is elevated in mammary tissue and depressed in adipose tissue to redirect lipids for incorporation into milk fat. The cellular origin of lipoprotein lipase in mammary tissue is thought to be the mammary epithelial cell which is the predominant cell type noticeable in the lactating gland; however, mammary adipocytes are also present. If lipoprotein lipase is produced by adipocytes in other sites of the body, then the question remains as to why mammary adipocytes have not been shown to produce lipoprotein lipase. In this study we present several lines of evidence that indicate that the mammary adipocyte is a source of LPL in the lactating mammary gland of mice. This evidence includes the absence of extracellular and intracellular lipoprotein lipase activity in two types of primary mammary epithelial cell cultures and a similarity in the changes of lipoprotein lipase activity in genital adipose tissue from nonpregnant mice and lactating mammary tissue to the nutritional state of the animal. Other evidence presented here includes strong localization of lipoprotein lipase protein and messenger RNA by fluorescence immunohistochemistry and in situ hybridization, respectively, to interstitial cells located between epithelial structures. We postulate that these interstitial cells are regressed, lipid-deleted mammary adipocytes.
Adipose Tissue↗
Urinary organic acid excretion during feeding of medium-chain or long-chain triglyceride diets in patients with non-insulin-dependent diabetes mellitus.
Medium-chain triglycerides (MCTs) are absorbed and metabolized differently from long-chain triglycerides (LCTs). Recent data indicate that MCTs may be useful as a dietary substitute in a variety of clinical disorders. The current studies were undertaken to characterize urinary organic acid excretion in patients with non-insulin-dependent diabetes mellitus during 4 d of an LCT or MCT diet. Urinary excretion of the dicarboxylic acids adipic, suberic, and 3-hydroxysebacic and the (omega-1) hydroxylation products 5-hydroxyhexanoic acid and 7-hydroxyoctanoic acid, was increased during MCT feeding as compared with LCT feeding. Urinary suberic and 7-hydroxyoctanoic acid excretions were increased 55- and 30-fold, respectively, during the MCT-substituted diet. Urinary organic acid profiles provide information on the fate of lipids during MCT feeding and may also be useful in assessing complicance during clinical trials employing MCT-substituted diets.
Caproates↗
Lipoprotein lipase gene expression in rat adipocytes is regulated by isoproterenol and insulin through different mechanisms.
Lipoprotein lipase (LPL) is highly regulated by catecholamines and insulin in adipocytes. Isoproterenol, a beta-adrenergic agonist, decreases LPL enzyme activity, whereas insulin increases LPL activity. We have isolated an 868-basepair rat LPL cDNA clone to assess hormone-mediated changes in LPL steady state mRNA levels and LPL gene transcription rates in adipocytes. Northern blot analysis of isoproterenol-treated (10(-6) M) adipocytes showed that LPL steady state mRNA decreased by 15 min. Nuclear run-on transcription assays in isoproterenol-treated cells indicated that LPL gene transcription was also decreased at 15 min compared to that in control cells. Conversely, insulin (6.7 x 10(-8) M) mediated an increase in LPL steady state mRNA in treated adipocytes, yet LPL gene transcription was not different from that in control cells. Thus, the isoproterenol-mediated decrease in LPL enzyme activity and steady state mRNA levels in adipocytes is associated with decreases in LPL gene transcription. Insulin, which does not affect LPL gene transcription, increases LPL enzyme activity and steady state mRNA levels. The effect of insulin on LPL mRNA is probably due to insulin-induced changes in mRNA stability.
Adipose Tissue↗
Dextran sulfate is poorly absorbed after oral administration.
STUDY OBJECTIVE: To determine whether dextran sulfate (molecular weight, 7000 to 8000 daltons; 17% to 20% sulfur), a synthetic heparin analogue with anti-human immunodeficiency virus (HIV) activity in vitro, is absorbed after oral administration. DESIGN: Open-label, single-center study in two parts. The first part was a bioavailability study in which six subjects received a single 1800-mg oral dose and a single 225- or 300-mg intravenous dose. The second part was a study of the dose-response relation between dextran sulfate and total plasma lipolytic activity in which twelve subjects were given a single infusion of either 0.05, 0.5, 5, or 50 mg of dextran sulfate. SUBJECTS: Eighteen healthy volunteers. MEASUREMENTS AND MAIN RESULTS: In the bioavailability study, plasma and urine dextran-sulfate concentrations were measured by a competitive binding assay after each dose. In addition, two bioassays were used to assess plasma concentrations: plasma lipolytic activity and activated partial thromboplastin time (APTT). After the oral dose, plasma concentrations were not measurable with the competitive binding assay (lower limit of sensitivity, 1 microgram/mL); less than 0.5% of the dose was recovered in the urine, the APTT did not increase, and the median increase in the plasma lipolytic activity was only twofold (maximum increase, 11-fold). In contrast, after the intravenous dose of 225 mg, peak plasma concentrations by competitive binding assay were 26 to 35 micrograms/mL (median, 28 micrograms/mL); 25% to 29% (median, 25%) of the dose was recovered in the urine; the APTT increased to 3.5 to 9.2 times the baseline value (median increase, 6.9 times), and the plasma lipolytic activity increased by 185 to 548 times the baseline value (median increase, 438 times). In the dose-response study, intravenous doses as low as 0.5 mg produced significant increases in the plasma lipolytic activity. There was a steep dose-response curve between 0.5 and 50 mg. CONCLUSION: Dextran sulfate is very poorly absorbed after oral administration.
Administration, Oral↗
Lipoprotein lipase. A multifunctional enzyme relevant to common metabolic diseases.
Lipoprotein lipase is an important regulator of lipid and lipoprotein metabolism. It also contributes to the lipid and energy metabolism of different tissues in varying ways. Although the synthesis, manner of secretion, and mechanism of endothelial binding of lipoprotein lipase appear similar in all tissues, the factors that control gene expression and posttranslational events related to processing vary from tissue to tissue. The actual molecular events that determine this tissue specificity are not yet understood. In the future, however, it may be possible to stimulate or inhibit the activity of lipoprotein lipase in specific tissues and to alter metabolic processes so as to improve the quality and length of life in patients with metabolic diseases such as hypertriglyceridemia, HDL2 deficiency, and obesity.
Humans↗
Microvascular endothelial cell cultures from human omental adipose tissue.
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Adipose Tissue↗
Hypocaloric feeding in obese women: metabolic effects of medium-chain triglyceride substitution.
Medium-chain (MCT) and long-chain (LCT) triglyceride diets were compared during and after 4 or 12 wk of hypocaloric feeding in obese women to determine the effects on weight loss, ketones, nitrogen balance, and insulin action. After a base-line euglycemic clamp, two groups ingested an 800-kcal/d liquid diet with 30% of calories as LCT (group 1) or 6% of calories as LCT and 24% as MCT (group 2). Rate and amount of weight loss, serum ketones, and N balance were not different between groups. However, the subjects in group 2 (MCT) demonstrated an increase in glucose requirement to maintain euglycemia during the clamp after weight loss (delta 0.18 +/- 0.13 mmol.m-2.min-1) whereas subjects in group 1 (LCT) had a diminished requirement (delta -0.12 +/- 0.10, p = 0.036). Thus, an 800-kcal diet containing 24% of calories as MCT is safe and enhances insulin action but fails to increase the rate or amount of weight loss.
Adult↗