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D H Bessesen

Publications and source records attributed to D H Bessesen.

15 recordsLinked to original sources
PubMed2006

Nutritional upregulation of p85alpha expression is an early molecular manifestation of insulin resistance.

AIMS/HYPOTHESIS: We sought to define early molecular alterations associated with nutritionally induced insulin resistance in humans. METHODS: Insulin sensitivity was assessed using a hyperinsulinaemic-euglycaemic clamp in eight healthy women while on an isocaloric diet and after 3 days of overfeeding (50% above eucaloric diet). Expression of phosphatidylinositol (PI) 3-kinase subunits p85alpha and p110 was assessed and measurements were made of IRS-1-associated PI 3-kinase activity, tyrosine and serine phosphorylation of IRS-1, and serine and threonine phosphorylation of p70S6 kinase. Measurements were made in skeletal muscle biopsies obtained before and after overfeeding. RESULTS: Three days of overfeeding resulted in a reduction of insulin sensitivity accompanied by: (1) increased expression of skeletal muscle p85alpha; (2) an alteration in the ratio of p85alpha to p110; (3) a decrease in the amount of IRS-1-associated p110; and (4) a decrease in PI 3-kinase activity. Increases in expression of p85alpha and in the p85alpha:p110 ratio demonstrated a highly significant inverse correlation with insulin sensitivity, and changes in PI 3-kinase activity correlated with changes in insulin sensitivity. Tyrosine and serine phosphorylation of IRS-1 and serine and threonine phosphorylation of p70S6 kinase were unaffected by 3 days of overfeeding. CONCLUSIONS/INTERPRETATION: We identified a novel mechanism of nutritionally induced insulin resistance in healthy women of normal weight. We conclude that increased expression of p85alpha may be one of the earliest molecular alterations in the mechanism of the insulin resistance associated with overfeeding.

Adult↗
PubMed2001

The role of carbohydrates in insulin resistance.

Insulin resistance is a metabolic disorder that is increasing worldwide and is associated with some of the most common diseases affecting modern societies including diabetes, hypertension, obesity and coronary heart disease. Although pharmacologic approaches to managing insulin resistance are being advocated by some, public health approaches involving changes in diet and physical activity are attractive because of their lower cost and risk. We briefly summarize some new information on the mechanisms that mediate insulin's many biological actions and examine the effects of dietary carbohydrates on insulin sensitivity. Specifically, we summarize some of the information available on the effects of simple sugars, complex carbohydrates including fiber, slowly digested starch and the general concept of glycemic index. The available data support the idea that consumption of diets high in total carbohydrate does not adversely affect insulin sensitivity compared with high fat diets. Animal data suggest that simple sugars, in particular fructose, have adverse effects on insulin action, but adverse effects have not been shown conclusively in humans. Increased intake of dietary fiber appears to improve insulin action and may protect against the development of diabetes. The effects of diets with high or low glycemic index on insulin action are controversial at this time. For firm conclusions to be reached, future studies must be of reasonable duration, be in defined populations and compare the effects of relevant doses of nutrients on specific endpoints of insulin action.

Animals↗
PubMed2000

Disposition of dietary ethanol carbons in rats: effects of gender and nutritional status.

Dietary ethanol is an important contributor to total caloric intake and has been associated with gender-specific alterations in body weight and the risk for coronary heart disease. To understand the metabolic basis of these effects, it is important to first clarify the effects of gender and nutritional state on the metabolic fate of dietary ethanol. Tracer studies were therefore performed using 14C-labeled ethanol in fasted or fed male and female Sprague-Dawley rats (N = 64) previously unexposed to ethanol. 1-(14C)-ethanol (4.5 microCi) was mixed with unlabeled ethanol (for a total ethanol dose equal to 10% of total daily caloric intake) and a 3-kcal liquid meal and administered through gastric feeding tubes. 14CO2 production was measured over the subsequent 8 hours. The 14C content of skeletal muscle, liver, adipose tissue, gastrointestinal (GI) tract, brain, heart, kidney, and serum was determined at 4 time points following tracer administration (20 minutes and 3, 8, and 24 hours; n = 4 at each time point). Tracer content on a whole-body level was significantly greater in skeletal muscle compared with liver in all groups (1.32 +/- 0.02 x 10(6) v 0.27 +/- 0.02 x 10(6) dpm, P < .001). Skeletal muscle tracer content decreased rapidly after 3 hours, whereas liver tracer content remained fairly constant throughout the study period. Fed female rats were the exception, with a significant increase in the tracer content of total liver and liver lipid at 8 hours. The tracer content was higher in the lipid extracts in liver from fed rats compared with fasted rats (1.08 +/- 0.19 x 10(5) v 0.48 +/- 0.08 x 10(5) dpm, P = .002). While male rats exhibited a fairly constant tracer content in adipose tissue throughout the 24-hour period, female rats showed an increase in adipose tissue tracer content at 8 and 24 hours, with levels 3 to 4 times those of the male animals (5.91 +/- 1.42 x 10(4) v 1.55 +/- 0.42 x 10(4) dpm, P = .02). These results demonstrate that (1) skeletal muscle plays an important role in the metabolism of dietary ethanol, (2) the fed state appears to favor the conversion of ethanol-derived carbons to lipid, and (3) female rats have a greater propensity to convert ethanol-derived carbons to lipid and to store these carbons in adipose tissue.

Adipose Tissue↗
PubMed2000

Trafficking of dietary oleic, linolenic, and stearic acids in fasted or fed lean rats.

Increasing evidence supports the notion that there are significant differences in the health effects of diets enriched in saturated, as opposed to monounsaturated or polyunsaturated fat. However, the current understanding of how these types of fat differ in their handling by relevant tissues is incomplete. To examine the effects of fat type and nutritional status on the metabolic fate of dietary fat, we administered (14)C-labeled oleic, linolenic, or stearic acid with a small liquid meal to male Sprague-Dawley rats previously fasted for 15 h (fasted) or previously fed ad libitum (fed). (14)CO(2) production was measured for 8 h after tracer administration. The (14)C content of gastrointestinal tract, serum, liver, skeletal muscle (soleus, lateral, and medial gastrocnemius), and adipose tissue (omental, retroperitoneal, and epididymal) was measured at six time points (2, 4, 8, 24, and 48 h and 10 days) after tracer administration. Plasma levels of glucose, insulin, and triglyceride were also measured. Oxidation of stearic acid was significantly less than that of either linolenic or oleic acid in both the fed and fasted states. This reduction was in part explained by a greater retention of stearic acid within skeletal muscle and liver. Oxidation of oleate and stearate were significantly lower in the fed state than in the fasted state. In the fasted state, liver and skeletal muscle were quantitatively more important than adipose tissue in the uptake of dietary fat tracers during the immediate postprandial period. In contrast, adipose tissue was quantitatively more important than skeletal muscle or liver in the fed state. The movement of carbons derived from dietary fat between tissues is a complex time-dependent process, which varies in response to the type of fat ingested and the metabolic state of the organism.

Adipose Tissue↗
PubMed1998

Effects of sibutramine on resting metabolic rate and weight loss in overweight women.

Sibutramine, a monoamine re-uptake inhibitor, has recently been approved by the Food and Drug Administration as a weight loss agent. Sibutramine lowers bodyweight in rodents by reducing energy intake and increasing energy expenditure. Sibutramine facilitates weight loss in human subjects, but it is not clear whether it acts on energy intake, energy expenditure, or both. The present study was a randomized clinical trial designed to assess the effects of sibutramine (at 10 or 30 mg/day) on body weight and resting metabolic rate (RMR). Forty-four overweight women were randomized to 1) placebo (n=15); 2) sibutramine at 10 mg/day (n=15) or, 3) sibutramine at 30 mg/day (n=14). All subjects were instructed to consume a 1200 kcal/day diet for 8 weeks while receiving drug or placebo. RMR was assessed by indirect calorimetry at baseline, at 3 hours after the first dose of drug (or placebo), and at the end of the 8-week weight-loss period. Sibutramine reduced body weight-relative to placebo, but there was no difference between weight loss on the two sibutramine doses. No significant differences in RMR between sibutramine and placebo were seen, either 3-hour post dose or after the 8-week weight-loss period. After the weight loss period, all groups were taken off medication and kept weight stable for another 4 weeks. RMR was measured again and was not different among groups. That there was no change in RMR when sibutramine was stopped further suggests that the drug does not directly affect RMR. In summary, while sibutramine was shown to be an effective weight-loss agent over 8 weeks, we found no evidence that it increased RMR.

Adolescent↗
PubMed1998

Recently identified peptides involved in the regulation of body weight.

The application of molecular and genetic techniques to the study of body weight regulation have produced exciting new insights into the physiological systems governing energy expenditure, appetite, and metabolic signaling. A number of new peptides have been identified that play important roles in these regulatory systems. These include the hormone leptin, the short and long forms of the leptin receptor, uncoupling proteins, agouti protein, melanocortin receptor isoforms, melanin-concentrating hormone, and the proteins responsible for tub and fat, two monogenic mouse models of obesity. This article reviews some of the new insights gained from studies of these peptides. Although much of this new knowledge has come from studies of obesity, there may be implications for the clinical syndromes associated with weight loss. As more is learned about these systems, potential new targets for therapeutic intervention will likely become evident. These interventions may develop first as obesity treatments, but investigators and clinicians involved in the care of cachectic patients should follow these scientific developments as well.

Animals↗
PubMed1997

High saturated fat and low starch and fibre are associated with hyperinsulinaemia in a non-diabetic population: the San Luis Valley Diabetes Study.

A geographically based sample of 1069 Hispanic and non-Hispanic white persons aged 20-74 years, living in southern Colorado and who tested normal on an oral glucose tolerance test (World Health Organization criteria) were evaluated to determine associations of dietary factors with fasting serum insulin concentrations. Subjects were seen for up to three visits from 1984 to 1992. A 24-h diet recall and fasting insulin concentrations were collected at all visits. In longitudinal data analysis, lower age, female gender, Hispanic ethnicity, higher body mass index, higher waist circumference, and no vigorous activity were significantly related to higher fasting insulin concentrations. High total and saturated fat intake were associated with higher fasting insulin concentrations after adjusting for age, sex, ethnicity, body mass index, waist circumference, total energy intake and physical activity. Dietary fibre and starch intake were inversely associated with fasting insulin concentrations. No associations with fasting insulin concentrations were observed for monounsaturated fat, polyunsaturated fat, sucrose, glucose and fructose intake. Associations were similar in men and women and for active and inactive subjects, though associations of fibre and starch intake with insulin concentrations were strongest in lean subjects. These findings support animal studies and a limited number of human population studies which have suggested that increased saturated and total fat intake and decreased fibre and starch intake increase fasting insulin concentrations and may also increase insulin resistance. These findings, which relate habitual macronutrient consumption to hyperinsulinaemia in a large population, may have implications for studies attempting primary prevention of non-insulin-dependent diabetes mellitus.

Adult↗
PubMed1996

Associations between dietary factors and serum lipids by apolipoprotein E polymorphism.

A geographically based observational study of 852 nondiabetic Hispanic and non-Hispanic white persons in southern Colorado aged 20-74 y was conducted to determine whether diet-lipid associations were modified by the apolipoprotein E (apoE, protein; APOE, gene) polymorphism. Subjects were seen for up to three visits from 1984 to 1992. A 24-h diet recall was collected and fasting serum lipid concentrations were measured at all visits. In longitudinal-regression analyses, dietary factors were significantly associated with serum lipid concentrations in the directions expected based on the large amount of literature on this topic. The positive relation between dietary cholesterol and serum total and low-density-lipoprotein cholesterol was strongest in Hispanic subjects with the APOE*2 allele (E2/ 2,3/2 genotypes) and non-Hispanic white subjects with the APOE*3 allele (E3/3 genotype), and there was no association in subjects with the APOE*4 allele (E4/3, 4/4 genotypes) in either ethnic group. No other statistically significant differences in the relations between dietary factors and serum lipid concentrations by APOE polymorphism were identified. These findings suggest that the APOE polymorphism plays only a minor role in modifying the association between dietary factors and serum lipids.

Adult↗
PubMed1995

Dietary fat is shunted away from oxidation, toward storage in obese Zucker rats.

Previous measurements of lipoprotein lipase (LPL) activity in adipose tissue (ATLPL) of lean and obese Zucker rats have consistently documented increased activity in obese rats relative to lean. Since LPL is considered to be rate limiting for the delivery of triglyceride fatty acids (TGFA) to muscle and adipose tissue, these data have been used to suggest that the metabolic partitioning of TGFA favors storage over oxidation in obese rats. To document the partitioning of TGFA directly, the fate of 14C labeled oleic acid (42nmols) was fed to lean, obese, and obese Zucker rats fed a hypocaloric diet designed to chronically reduce weight 25% below that of obese controls (reduced-obese). The amount of 14C recovered in CO2 over 6 hours following ingestion was significantly less in obese rats compared to lean (0.45 +/- 0.06 vs. 0.88 +/- 0.09nmols, p = .0004) and less still in the reduced obese group (0.34 +/- 0.06nmols p = .00003). Six hours after ingestion, the quantity of label found in adipose tissue was significantly greater in the obese rats compared to lean (14.51 +/- 1.92 vs. 1.38 +/- 0.29nmols p < .00001), but was intermediate in the reduced-obese group (9.23 +/- 0.98nmols p = .0003). At 2.2 hours there was significantly more label in skeletal muscle of lean rats compared to either obese or reduced-obese (2.33 +/- 0.24; 1.35 +/- 0.04nmols p = .01; 1.41 +/- 0.27nm p = .02). However, at 6 hours these differences between groups were no longer present. These finding Indicate that dietary fat is shunted away from oxidation toward storage in obese Zucker rats. Additionally it appears that there may be a relative block in the oxidation of TGFA that is taken up by skeletal muscle in obese rats. Finally the relative normalization of this partitioning defect in reduced-obese rats is at variance with what was suggested by previous measurements of tissue specific levels of LPL, and suggests an enhanced recirculation of fatty acids from adipose tissue to muscle in reduced-obese rats. This could occur through increased delivery of non-esterified fatty acids (NEFA) to muscle as a result of an increase in net lipolysis.

Adipose Tissue↗
PubMed1995

Trafficking of dietary fat in lean rats.

Despite increasing interest in the role that fuel partitioning plays in determining body composition, the relative importance of oxidative versus storage pathways in the clearance of dietary fat remains unclear. A widely held view is that the primary destination of chylomicron triglyceride fatty acids (TGFA) is adipose tissue, and the primary source of lipid fuel for skeletal muscle is non-esterified fatty acids (NEFA). An alternate view is that muscle, not adipose tissue, is the primary site of TGFA clearance. This view is supported by estimates of the total lipoprotein lipase content of muscle and adipose tissue. To directly study the partitioning of dietary fat between oxidation and storage, 14C-labeled oleic acid was fed to Sprague Dawley rats and its metabolic rate followed over 30 days. Two hours after ingestion, more than 3.5 times as much label was found in skeletal muscle tissue (2.42 +/- 0.45 nmols) and CO2 (0.25 +/- 0.01 nmols) than was found in adipose tissue (0.71 +/- 0.14 nmols). Intramuscular triglyceride was the lipid class most extensively labeled. After skeletal muscle, liver was the next most important site of TGFA clearance. Surprisingly a substantial quantity of label remained associated with the GI tract even 24 hours after ingestion. Between 2 and 10 days following ingestion there was a net decline in the 14C content of muscle, liver and GI tract, associated with a net rise in the 14C content of adipose tissue. These findings demonstrate: 1) the importance of skeletal muscle and liver in whole organism TGFA clearance, 2) the importance of intramuscular partitioning of lipid fuels between direct oxidation and storage as TG, 3) the potentially important role of the GI tract in the delivery of dietary fat to the circulation 10-24 hours following ingestion, and 4) the stability of adipose tissue as a storage site. The complex nature of the tissue-specific clearance of TGFA over time is perhaps better described by the term "trafficking" than by the more commonly used term "partitioning." Future studies of TGFA clearance combined with sampling of relevant tissues over time will provide insight into the specific roles that abnormalities in liver, muscle and adipose tissue TGFA metabolism play in the development of hypertriglyceridemic disorders and states of increased or reduced body weight.

Adipose Tissue↗
PubMed1993

Spinal cord of the rat contains more lipoprotein lipase than other brain regions.

Lipoprotein lipase (LPL) is important for the delivery of triglyceride fatty acids (TGFA) to a variety of tissues. We have used measurements of heparin-releasable LPL activity, immunohistochemistry, in situ hybridization, and Northern analysis to more fully characterize the location of LPL within the entire central nervous system (CNS) of the rat. Surprisingly, the levels of LPL activity and mRNA in the caudal spinal cord were 5- to 10-times higher than those found in any other area of the brain, levels similar to those found in adipose tissue or skeletal muscle. A number of cell types including neurons in the hippocampus, Purkinje cells of the cerebellum, and cells deep within the cortex were identified as sources of LPL mRNA. LPL protein was found within many vascular structures throughout the CNS, and within Purkinje cells. The strongest immunostaining was around nerve rootlets associated with the caudal spinal cord. Feeding studies were carried out with [14C]oleic acid to see whether CNS LPL functioned in the uptake of TGFA. These studies demonstrated uptake of chylomicron triglyceride fatty acids throughout the CNS. The localization of LPL within these structures suggests that the uptake of triglyceride fatty acids is an integral part of normal lipid metabolism of the central nervous system and may be important in regulating feeding behavior and/or maintaining normal neuronal function.

Animals↗
PubMed1991

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↗
PubMed1991

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↗
PubMedDate not supplied

Overexpression and purification of transcriptionally competent CREB from a recombinant baculovirus.

Signal transduction and viral stimulatory pathways converge ultimately at the level of transcriptional activation to influence the expression of a variety of cellular genes in response to environmental stimuli and developmental signals. Recent studies have implicated the cyclic AMP-responsive element-binding protein (CREB) to be involved in mediating transcriptional activation in response to multiple varied stimuli, including (1) stimulation of the protein kinase A signal transduction pathway; (2) membrane depolarization and increases in intracellular calcium; and (3) viral induced gene expression. In order to study the structure and functional mechanisms of CREB actions in these systems, full-length CREB-327 was expressed in Spodoptera frugiperda (Sf9) cells with the baculovirus expression vector system. The expressed CREB, which is phosphorylated and localized in the nucleus, is capable of enhancing the transcription of a reporter gene containing the CRE sequence in a cell-free transcription assay. Approximately 12.5 mg of purified CREB per liter of infected Sf9 cell culture can be obtained. These large amounts of purified protein will facilitate studies of the structure and functions of this important transcriptional regulatory protein.

Animals↗