11 results on '"Fried, Susan K."'
Search Results
2. Adiporedoxin, an upstream regulator of ER oxidative folding and protein secretion in adipocytes
- Author
-
Jedrychowski, Mark P., Liu, Libin, Laflamme, Collette J., Karastergiou, Kalypso, Meshulam, Tova, Ding, Shi-Ying, Wu, Yuanyuan, Lee, Mi-Jeong, Gygi, Steven P., Fried, Susan K., and Pilch, Paul F.
- Subjects
Adipocyte ,Adipokine ,Protein secretion ,Endoplasmic reticulum ,Oxidoreductase ,Disulfide bond formation - Abstract
Objective: Adipocytes are robust protein secretors, most notably of adipokines, hormone-like polypeptides, which act in an endocrine and paracrine fashion to affect numerous physiological processes such as energy balance and insulin sensitivity. To understand how such proteins are assembled for secretion we describe the function of a novel endoplasmic reticulum oxidoreductase, adiporedoxin (Adrx). Methods: Adrx knockdown and overexpressing 3T3-L1 murine adipocyte cell lines and a knockout mouse model were used to assess the influence of Adrx on secreted proteins as well as the redox state of ER resident chaperones. The metabolic phenotypes of Adrx null mice were characterized and compared to WT mice. The correlation of Adrx levels BMI, adiponectin levels, and other inflammatory markers from adipose tissue of human subjects was also studied. Results: Adiporedoxin functions via a CXXC active site, and is upstream of protein disulfide isomerase whose direct function is disulfide bond formation, and ultimately protein secretion. Over and under expression of Adrx in vitro enhances and reduces, respectively, the secretion of the disulfide-bonded proteins including adiponectin and collagen isoforms. On a chow diet, Adrx null mice have normal body weights, and glucose tolerance, are moderately hyperinsulinemic, have reduced levels of circulating adiponectin and are virtually free of adipocyte fibrosis resulting in a complex phenotype tending towards insulin resistance. Adrx protein levels in human adipose tissue correlate positively with adiponectin levels and negatively with the inflammatory marker phospho-Jun kinase. Conclusion: These data support the notion that Adrx plays a critical role in adipocyte biology and in the regulation of mouse and human metabolism via its modulation of adipocyte protein secretion.
- Published
- 2015
- Full Text
- View/download PDF
3. Adipose 'neighborhoods' collaborate to maintain metabolic health.
- Author
-
Fried SK
- Subjects
- Humans, Adiposity, Subcutaneous Fat metabolism, Subcutaneous Fat pathology, Intra-Abdominal Fat metabolism, Intra-Abdominal Fat pathology, Obesity metabolism, Adipose Tissue pathology
- Abstract
Body fat is stored in anatomically distinct adipose depots that vary in their cell composition and play specialized roles in systemic metabolic homeostasis via secreted products. Their local effects on nearby tissues (e.g. the gut and visceral adipose tissues) are increasingly recognized and this local crosstalk is being elucidated. The major subcutaneous fat depots, abdominal and gluteal-femoral, exert opposite effects on the risk of metabolic disease. The pace of research into developmental, sex, and genetic determinants of human adipose depot growth and function is rapidly accelerating, providing insight into the pathogenesis of metabolic dysfunction in persons with obesity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
4. Rosiglitazone remodels the lipid droplet and britens human visceral and subcutaneous adipocytes ex vivo.
- Author
-
Lee MJ, Jash S, Jones JEC, Puri V, and Fried SK
- Subjects
- Adipocytes metabolism, Adipose Tissue metabolism, Adult, Aged, Female, Humans, Lipid Droplets metabolism, Male, Middle Aged, Oxidation-Reduction, Phenotype, Adipocytes drug effects, Adipose Tissue drug effects, Hypoglycemic Agents pharmacology, Lipid Droplets drug effects, Rosiglitazone pharmacology
- Abstract
Treatment with PPARγ agonists in vivo improves human adipocyte metabolism, but the cellular mechanisms and possible depot differences in responsiveness to their effects are poorly understood. To examine the ex vivo metabolic effects of rosiglitazone (Rosi), we cultured explants of human visceral (omental) and abdominal subcutaneous adipose tissues for 7 days. Rosi increased mRNA levels of transcriptional regulators of brite/beige adipocytes (PGC1α, PRDM16), triglyceride synthesis (GPAT3, DGAT1), and lipolysis (ATGL) similarly in adipose tissues from both depots. In parallel, Rosi increased key modulators of FA oxidation (UCP1, FABP3, PLIN5 protein), rates of FA oxidation, and protein levels of electron transport complexes, suggesting an enhanced respiratory capacity as confirmed in newly differentiated adipocytes. Rosi led to the formation of small lipid droplets (SLDs) around the adipocyte central lipid droplet; each SLD was decorated with redistributed mitochondria that colocalized with PLIN5. SLD maintenance required lipolysis and FA reesterification. Rosi thus coordinated a structural and metabolic remodeling in adipocytes from both visceral and subcutaneous depots that enhanced oxidative capacity. Selective targeting of these cellular mechanisms to improve adipocyte FA handling may provide a new approach to treat metabolic complications of obesity and diabetes., (Copyright © 2019 Lee et al.)
- Published
- 2019
- Full Text
- View/download PDF
5. GH administration decreases subcutaneous abdominal adipocyte size in men with abdominal obesity.
- Author
-
Bredella MA, Karastergiou K, Bos SA, Gerweck AV, Torriani M, Fried SK, and Miller KK
- Subjects
- Adult, Body Composition drug effects, Cell Size drug effects, Double-Blind Method, Humans, Male, Obesity, Abdominal pathology, Placebos, Adipocytes drug effects, Adipocytes pathology, Human Growth Hormone therapeutic use, Obesity, Abdominal drug therapy, Subcutaneous Fat, Abdominal drug effects, Subcutaneous Fat, Abdominal pathology
- Abstract
Objective: To investigate the effects of short-term GH administration on abdominal subcutaneous adipocyte size and CT attenuation in men with abdominal obesity., Design: 6-week, randomized, double-blind, placebo-controlled study of GH (starting dose 2μg/kg/d) vs placebo of 15 abdominally obese men (mean age: 34±6years; mean BMI: 37.7±6.1kg/m
2 , mean IGF-1 SDS: -1.9±0.5) who underwent abdominal subcutaneous adipose tissue (SAT) aspirations to determine adipocyte size, CTs for body composition and measures of glucose tolerance at baseline and 6weeks. GH dosing was titrated to target IGF-1 levels in the upper normal age-appropriate range., Results: GH administration decreased subcutaneous abdominal adipocyte size compared to placebo. Adipocyte size was positively associated with 120-min glucose and HOMA-IR and inversely associated with peak-stimulated GH and CT attenuation. CT attenuation of SAT was inversely associated with 120-min glucose and HOMA-IR and increased following GH administration., Conclusion: In men with abdominal obesity, subcutaneous abdominal adipocyte size is positively associated with measures of impaired glucose tolerance and administration of GH at doses that raise IGF-1 levels within the normal range, decreases abdominal subcutaneous adipocyte size, suggesting that GH administration improves the health of adipose tissue. Clinical trials number: NCT00131378., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
- Full Text
- View/download PDF
6. Low expression of the GILZ may contribute to adipose inflammation and altered adipokine production in human obesity.
- Author
-
Lee MJ, Yang RZ, Karastergiou K, Smith SR, Chang JR, Gong DW, and Fried SK
- Subjects
- Adipokines metabolism, Adipose Tissue metabolism, Adipose Tissue pathology, Adult, Biopsy, Dual Specificity Phosphatase 1 metabolism, Female, Gene Expression Regulation, Gene Knockdown Techniques, Humans, Inflammation metabolism, Inflammation pathology, Interleukin-6 metabolism, Leptin metabolism, MAP Kinase Signaling System genetics, Male, NF-kappa B genetics, NF-kappa B metabolism, Obesity metabolism, Obesity pathology, RNA, Messenger biosynthesis, Transcription Factor RelA genetics, Transcription Factor RelA metabolism, Transcription Factors biosynthesis, Tumor Necrosis Factor-alpha genetics, Inflammation genetics, Obesity genetics, Transcription Factors genetics, Tumor Necrosis Factor-alpha metabolism
- Abstract
The glucocorticoid-induced leucine zipper (GILZ), a primary target of glucocorticoids, is expressed in human adipocytes, but its importance in adipocyte function is unknown. Because TNFα is increased in obese adipose tissue and antagonizes a number of glucocorticoid actions, we investigated the interplay of these pathways. GILZ knockdown increased and GILZ overexpression decreased interleukin-6 (IL-6) and leptin mRNA and protein secretion. GILZ knockdown increased the magnitude of the glucocorticoid effect on leptin secretion, but did not affect the glucocorticoid suppression of IL-6. Although GILZ silencing decreased adiponectin mRNA levels, it did not affect the amount of adiponectin secreted. GILZ negatively modulated pro-inflammatory signaling pathways, blocking basal and TNFα-stimulated (1 h) p65 nuclear factor κB nuclear translocation and transcriptional activity by binding to p65 in the cytoplasm. GILZ silencing increased basal ERK1/2 and JNK phosphorylation, and decreased MAPK phosphatase-1 protein levels. Longer term TNFα (4 h or 24 h) treatment decreased GILZ expression in human adipocytes. Furthermore, adipose tissue GILZ mRNA levels were reduced in proportion to the degree of obesity and expression of inflammatory markers. Overall, these results suggest that GILZ antagonizes the pro-inflammatory effects of TNFα in human adipocytes, and its downregulation in obesity may contribute to adipose inflammation and dysregulated adipokine production, and thereby systemic metabolism., (Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2016
- Full Text
- View/download PDF
7. FSP27 and PLIN1 interaction promotes the formation of large lipid droplets in human adipocytes.
- Author
-
Grahn TH, Zhang Y, Lee MJ, Sommer AG, Mostoslavsky G, Fried SK, Greenberg AS, and Puri V
- Subjects
- Apoptosis Regulatory Proteins, Cells, Cultured, Humans, Lipolysis, Perilipin-1, Proteins genetics, Adipocytes metabolism, Carrier Proteins metabolism, Phosphoproteins metabolism, Proteins metabolism, Triglycerides metabolism
- Abstract
Human adipocytes express high levels of two distinct lipid droplet proteins, fat specific protein 27 (FSP27; also called CIDEC), a member of the CIDE family, and perilipin1 (PLIN1), a member of the PAT family. Both proteins play a role in fat metabolism in adipocytes, but how they interact is not known. Our present study demonstrates that FSP27 and PLIN1 co-localize and interact in cultured human primary adipocytes. We also found that the C-terminal domain of FSP27, aa 120-220, interacts with PLIN1. Individual expression of exogenous FSP27 or PLIN1 increased triglyceride content and decreased glycerol release (a measure of lipolysis), but co-expression of both proteins did not further increase triglyceride content or decrease lipolysis in human adipocytes. However, the combination of PLIN1 and FSP27 increased the average size of lipid droplets or caused the formation of unilocular adipocytes. Our data suggest that FSP27 interacts with PLIN1 to regulate lipid droplet size in human adipocytes in a concerted manner., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
8. Resistance to the antilipolytic effect of insulin in adipocytes of African-American compared to Caucasian postmenopausal women.
- Author
-
Fried SK, Tittelbach T, Blumenthal J, Sreenivasan U, Robey L, Yi J, Khan S, Hollender C, Ryan AS, and Goldberg AP
- Subjects
- Abdominal Fat drug effects, Abdominal Fat metabolism, Adipocytes drug effects, Adult, Aged, Buttocks, Fatty Acids, Nonesterified metabolism, Female, Humans, Insulin pharmacology, Isoproterenol pharmacology, Middle Aged, Phenylisopropyladenosine pharmacology, Adipocytes metabolism, Black or African American, Insulin metabolism, Insulin Resistance ethnology, Lipolysis drug effects, Postmenopause metabolism, White People
- Abstract
High fatty acid (FA) flux is associated with systemic insulin resistance, and African-American (AA) women tend to be more insulin resistant. We assessed possible depot and race difference in the antilipolytic effect of insulin in adipocytes isolated from abdominal (Abd) and gluteal (Glt) subcutaneous (sc) adipose tissue of overweight, postmenopausal AA and Caucasian (C) women. Percent body fat, fasting insulin, visceral adiposity, and adipocyte size was higher in AA women. Disinhibited lipolysis (presence of adenosine deaminase) per unit adipocyte surface area was similar in Abd and Glt and in AA and C. However, rates of 'basal' [submaximal phenylisopropyl adenosine (PIA)-suppressed] and insulin-suppressed lipolysis were higher in Abd of AA compared with C women even after adjustment for percent fat and visceral fat area. The race difference in rates of PIA- and insulin-suppressed lipolysis in AA were correlated with their hyperinsulinemia, but AA race, independent of fasting insulin, was associated with lower responsiveness (percent suppression) to submaximal insulin concentrations, although sensitivity (ED50) was not affected. Overall, these data are consistent with the hypothesis that decreased responsiveness of Abd adipocytes to antilipolytic effectors may contribute to higher FA availability and thereby to racial differences in insulin resistance.
- Published
- 2010
- Full Text
- View/download PDF
9. Dietary L-arginine supplementation reduces white fat gain and enhances skeletal muscle and brown fat masses in diet-induced obese rats.
- Author
-
Jobgen W, Meininger CJ, Jobgen SC, Li P, Lee MJ, Smith SB, Spencer TE, Fried SK, and Wu G
- Subjects
- Adipose Tissue, Brown pathology, Amino Acids blood, Animals, Arginine administration & dosage, Blood Glucose analysis, Body Weight drug effects, Glucose Tolerance Test, Leptin blood, Male, Muscle, Skeletal pathology, Nitric Oxide blood, Organ Size drug effects, Rats, Rats, Sprague-Dawley, Adipose Tissue drug effects, Adipose Tissue, Brown drug effects, Arginine pharmacology, Diet, Dietary Supplements, Muscle, Skeletal drug effects, Obesity pathology
- Abstract
Previous studies showed that dietary L-arginine supplementation decreased white fat mass in genetically obese rats. This study tested the effectiveness of L-arginine in diet-induced obesity. Male Sprague-Dawley rats were fed for 15 wk a high-fat (HF) (40% energy) or low-fat (LF) (10% energy) diet beginning at 4 wk of age, resulting in 18% higher body weight gains and 74% higher weights of major white fat pads (retroperitoneal, epididymal, subcutaneous, and mesenteric adipose tissues) in HF than in LF fed rats. Starting at 19 wk of age, rats in each dietary group were supplemented for 12 wk with 1.51% L-arginine-HCl or 2.55% L-alanine (isonitrogenous control) (n = 8 per treatment) in drinking water and arginine groups were individually pair-fed to alanine controls. Despite similar energy intake, absolute weights of white fat pads increased by 98% in control rats over a 12-wk period but only by 35% in arginine-supplemented rats. The arginine treatment reduced the relative weights of white fat pads by 30% and enhanced those of soleus muscle by 13%, extensor digitorum longus muscle by 11%, and brown fat by 34% compared with control rats. Serum concentrations of insulin, adiponectin, growth hormone, corticosterone, triiodothyronine, and thyroxine did not differ between control and arginine-supplemented rats. However, arginine treatment resulted in lower serum concentrations of leptin, glucose, triglycerides, urea, glutamine, and branched-chain amino acids, higher serum concentrations of nitric-oxide metabolites, and improvement in glucose tolerance. Thus, dietary arginine supplementation shifts nutrient partitioning to promote muscle over fat gain and may provide a useful treatment for improving the metabolic profile and reducing body white fat in diet-induced obese rats.
- Published
- 2009
- Full Text
- View/download PDF
10. Multilevel regulation of leptin storage, turnover, and secretion by feeding and insulin in rat adipose tissue.
- Author
-
Lee MJ and Fried SK
- Subjects
- Adipocytes metabolism, Adipose Tissue drug effects, Animals, Blotting, Northern methods, Body Weight, Chloroquine pharmacology, Cycloheximide pharmacology, Iodine Isotopes, Leptin genetics, Leupeptins pharmacology, Lysosomes metabolism, Male, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Rats, Wistar, Starvation, Sulfur Isotopes, Adipose Tissue metabolism, Insulin pharmacology, Leptin metabolism
- Abstract
The mechanisms of the increased serum leptin in response to feeding are poorly understood. Therefore, we used metabolic labeling to directly assess leptin biosynthesis, secretion, and turnover in adipose tissue from 14 h-starved compared with fed 12-14 week old rats. Starvation decreased serum leptin (-47 +/- 7%), adipose tissue leptin content (-32 +/- 5%), and leptin secretion during 3 h of incubation (-65 +/- 12%). Starvation did not affect leptin mRNA levels but decreased rates of leptin biosynthesis by tissue fragments, as determined by [(35)S]methionine/cysteine incorporation into immunoprecipitable leptin. Insulin in vitro did not acutely increase leptin biosynthesis or rates of (125)I-leptin degradation. Pulse-chase studies showed that in adipose tissue from fed but not starved rats, insulin accelerated the secretion of [(35)S]leptin by approximately 2-fold after 30 and 60 min of chase. Degradation of newly synthesized leptin was slower in adipose tissue of starved than fed rats (half-lives of 50 and 150 min, respectively). Inhibitor experiments showed that both lysosomes and proteosomes contributed to leptin degradation. In conclusion, feeding compared with starvation influences leptin production at multiple posttranscriptional levels: synthesis, tissue storage, turnover, and secretion. The insulin-stimulated release of leptin from a preformed intracellular leptin pool may contribute to increases in serum leptin levels after meals.
- Published
- 2006
- Full Text
- View/download PDF
11. Sugars, hypertriglyceridemia, and cardiovascular disease.
- Author
-
Fried SK and Rao SP
- Subjects
- Adult, Dose-Response Relationship, Drug, Female, Humans, Male, Obesity chemically induced, Cardiovascular Diseases chemically induced, Dietary Carbohydrates administration & dosage, Dietary Carbohydrates adverse effects, Dietary Carbohydrates metabolism, Hypertriglyceridemia chemically induced, Hypertriglyceridemia genetics, Hypertriglyceridemia metabolism
- Abstract
Short-term studies consistently show that raising the carbohydrate content of the diet increases serum triacylglycerol concentrations. As compared with starches, sugars (particularly sucrose and fructose) tend to increase serum triacylglycerol concentrations by approximately 60%. The magnitude of the effect depends on other aspects of the diet, including the total amount of carbohydrate and the types of fat, carbohydrate, and fiber, but definitive studies to describe the dose-response relations are not available. Longer-term studies show that some high-carbohydrate diets are not associated with increased fasting serum triacylgycerol concentrations. However, sedentary subjects with upper-body and visceral obesity who have the metabolic syndrome tend to be at higher risk for hypertriglyceridemia in response to high-sucrose and high-carbohydrate diets; moderate weight loss mitigates the effect. Hyperinsulinemia or insulin resistance may play a role in promoting higher rates of VLDL synthesis and hypertriglyceridemia in obesity, but the mechanisms remain unclear. The effect of fructose in promoting triacylglycerol synthesis is independent of insulinemia, however. In terms of the long-term effects of diets high in sugars on the risk of cardiovascular disease, available epidemiologic evidence indicates no association of sugars or total carbohydrate intake per se, but high dietary glycemic load is associated with higher serum triacylglycerol concentrations and greater risk of coronary heart disease in women. Studies are needed to delineate the independent effects of dietary sugars and glycemic load on serum triacylglycerol concentrations in lean and obese men and women and to determine whether the elevations in fasting and fed concentrations of serum triacylglycerol with high-carbohydrate and high-sugars diets are associated with increased risk of cardiovascular disease.
- Published
- 2003
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.