8 results on '"Harper, Mary-Ellen"'
Search Results
2. SGCG rs679482 Associates With Weight Loss Success in Response to an Intensively Supervised Outpatient Program
- Author
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Nikpay, Majid, primary, Lau, Paulina, additional, Soubeyrand, Sébastien, additional, Whytock, Katey L., additional, Beehler, Kaitlyn, additional, Pileggi, Chantal, additional, Ghosh, Sujoy, additional, Harper, Mary-Ellen, additional, Dent, Robert, additional, and McPherson, Ruth, additional
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- 2020
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3. The adipocyte-expressed forkhead transcription factor Foxc2 regulates metabolism through altered mitochondrial function
- Author
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Lidell, Martin E., Seifert, Erin L., Westergren, Rickard, Heglind, Mikael, Gowing, Adrienne, Sukonina, Valentina, Arani, Zahra, Itkonen, Paula, Wallin, Simonetta, Westberg, Fredrik, Fernandez-Rodriguez, Julia, Laakso, Markku, Nilsson, Tommy, Peng, Xiao-Rong, Harper, Mary-Ellen, and Enerback, Sven
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Adipose tissues -- Physiological aspects -- Genetic aspects -- Research ,Diabetes -- Genetic aspects -- Physiological aspects -- Development and progression -- Research ,Transcription factors -- Physiological aspects -- Research ,Health - Abstract
OBJECTIVE--Previous findings demonstrate that enhanced expression of the forkhead transcription factor Foxc2 in adipose tissue leads to a lean and insulin-sensitive phenotype. These findings prompted us to further investigate the role of Foxc2 in the regulation of genes of fundamental importance for metabolism and mitochondrial function. RESEARCH DESIGN AND METHODS--The effects of Foxc2 on expression of genes involved in mitochondriogenesis and mitochondrial function were assessed by quantitative real-time PCR. The potential of a direct transcriptional regulation of regulated genes was tested in promoter assays, and mitochondrial morphology was investigated by electron microscopy. Mitochondrial function was tested by measuring oxygen consumption and extracellular acidification rates as well as palmitate oxidation. RESULTS--Enhanced expression of FOXC2 in adipocytes or in cells with no endogenous Foxc2 expression induces mitochondriogenesis and an elongated mitochondrial morphology. Together with increased aerobic metabolic capacity, increased palmitate oxidation, and upregulation of genes encoding respiratory complexes and of brown fat-related genes, Foxc2 also specifically induces mitochondrial fusion genes in adipocytes. Among tested forkhead genes, Foxc2 is unique in its ability to trans-activate the nuclear-encoded mitochondrial transcription factor A (mtTFAf/Tfam) gene--a master regulator of mitochondrial biogenesis. In human adipose tissue the expression levels of mtTFA/Tfam and of fusion genes also correlate with that of Foxc2. CONCLUSIONS--We previously showed that a high-calorie diet and insulin induce Foxc2 in adipocytes; the current findings identify a previously unknown role for Foxc2 as an important metabo-regulator of mitochondrial morphology and metabolism. Diabetes 60:427-435, 2011, Mitochondrial number and activity are essential for many cellular functions such as ATP production through oxidative phosphorylation and biosynthesis of amino acids and lipids (1). Peroxisome proliferator-activated receptor γ coactivator-1 [...]
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- 2011
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4. Physiological increases in uncoupling protein 3 augment fatty acid oxidation and decrease reactive oxygen species production without uncoupling respiration in muscle cells
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MacLellan, J. Darcy, Gerrits, Martin F., Gowing, Adrienne, Smith, Peter J.S., Wheeler, Michael B., and Harper, Mary-Ellen
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Insulin resistance -- Analysis -- Risk factors ,Fatty acids -- Analysis ,Type 2 diabetes -- Risk factors -- Analysis ,Health ,Analysis ,Risk factors - Abstract
Decreased uncoupling protein (UCP)3 is associated with insulin resistance in muscle of pre-diabetic and diabetic individuals, but the function of UCP3 remains unclear. Our goal was to elucidate mechanisms underlying the negative correlation between UCP3 and insulin resistance in muscle. We determined effects of physiologic UCP3 overexpression on glucose and fatty acid oxidation and on mitochondrial uncoupling and reactive oxygen species (ROS) production in L6 muscle cells. An adenoviral construct caused a 2.2- to 2.5-fold increase in UCP3 protein. Palmitate oxidation was increased in muscle cells incubated under normoglycemic or hyperglycemic conditions, whereas adenoviral green fluorescent protein infection or chronic low doses of the uncoupler dinitrophenol had no effect. Increased UCP3 did not affect glucose oxidation, whereas dinitrophenol and insulin treatments caused increases. Basal oxygen consumption, assessed in situ using self-referencing microelectrodes, was not significantly affected, whereas dinitrophenol caused increases. Mitochondrial membrane potential was decreased by dinitrophenol but was not affected by increased UCP3 expression. Finally, mitochondrial ROS production decreased significantly with increased UCP3 expression. Results are consistent with UCP3 functioning to facilitate fatty acid oxidation and minimize ROS production. As impaired fatty acid metabolism and ROS handling are important precursors in muscular insulin resistance, UCP3 is an important therapeutic target in type 2 diabetes., Insulin resistance in muscle is a primary component of type 2 diabetes, a disease with a prevalence that is increasing at an alarming rate in modern society. The importance of [...]
- Published
- 2005
5. Decreased mitochondrial proton leak and reduced expression of uncoupling protein 3 in skeletal muscle of obese diet-resistant women
- Author
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Harper, Mary-Ellen, Dent, Robert, Monemdjou, Shadi, Bezaire, Veronic, Van Wyck, Lloyd, Wells, George, Kavaslar, Gul Nihan, Gauthier, Andre, Tesson, Frederique, and McPherson, Ruth
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Gene expression -- Research -- Physiological aspects -- Health aspects ,Obesity -- Health aspects -- Research ,Striated muscle -- Physiological aspects -- Health aspects -- Research ,Protons -- Research -- Health aspects -- Physiological aspects ,Mitochondria -- Research -- Health aspects -- Physiological aspects ,Proteins -- Physiological aspects -- Health aspects -- Research ,Health ,Physiological aspects ,Research ,Health aspects - Abstract
Weight loss in response to caloric restriction is variable. Because skeletal muscle mitochondrial proton leak may account for a large proportion of resting metabolic rate, we compared proton leak in diet-resistant and diet-responsive overweight women and compared the expression and gene characteristics of uncoupling protein (UCP)2 and UCP3. Of 1,129 overweight women who completed the University of Ottawa Weight Management Clinic program, 353 met compliance criteria and were free of medical conditions that could affect weight loss. Subjects were ranked according to percent body weight loss during the first 6 weeks of a 900-kcal meal replacement protocol. The highest and lowest quintiles of weight loss were defined as diet responsive and diet resistant, respectively. After body weight had been stable for at least 10 weeks, 12 of 70 subjects from each group consented to muscle biopsy and blood sampling for determinations of proton leak, UCP mRNA expression, and genetic studies. Despite similar baseline weight and age, weight loss was 43% greater, mitochondrial proton leak-dependent (state 4) respiration was 51% higher (P = 0.0062), and expression of UCP3 mRNA abundance was 25% greater (P < 0.001) in diet-responsive than in diet-resistant subjects. There were no differences in UCP2 mRNA abundance. None of the known polymorphisms in UCP3 or its 5' flanking sequence were associated with weight loss or UCP3 mRNA abundance. Thus, proton leak and the expression of UCP3 correlate with weight loss success and may be candidates for pharmacological regulation of fat oxidation in obese diet-resistant subjects., At the Weight Management Program at the University of Ottawa, we have documented a 10-fold variation in the rate of weight loss in 353 highly compliant women on a standard [...]
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- 2002
6. Mice expressing human but not murine beta 3-adrenergic receptors under the control of human gene regulatory elements
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Ito, Moriko, Grujic, Danica, Abel, E. Dale, Vidal-Puig, Antonio, Susulic, Vedrana S., Lawitts, Joel, Harper, Mary-Ellen, Himms-Hagen, Jean, Strosberg, A. Donny, and Lowell, Bradford B.
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Beta adrenoceptors -- Genetic aspects ,Fat cells -- Genetic aspects ,Health ,Genetic aspects - Abstract
[Β.sub.3]-Adrenergic receptors (ARs) are expressed predominantly in adipose tissue, and [Β.sub.3]-selective agonists are effective anti-obesity drugs in rodents. Rodent and human [Β.sub.3]-ARs differ with respect to expression in white versus [...]
- Published
- 1998
7. rs679482 Associates With Weight Loss Success in Response to an Intensively Supervised Outpatient Program.
- Author
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Nikpay, Majid, Lau, Paulina, Soubeyrand, Sébastien, Whytock, Katey L., Beehler, Kaitlyn, Pileggi, Chantal, Ghosh, Sujoy, Harper, Mary-Ellen, Dent, Robert, and McPherson, Ruth
- Subjects
SKELETAL muscle ,ENERGY dissipation ,TRANSCRIPTION factors ,FACTOR analysis ,SIGNAL sampling - Abstract
Weight loss in response to energy restriction is highly variable, and identification of genetic contributors can provide insights into underlying biology. Leveraging 1000 Genomes imputed genotypes, we carried out genome-wide association study (GWAS) analysis in 551 unrelated obese subjects of European ancestry who participated in an intensively supervised weight loss program with replication of promising signals in an independent sample of 1,331 obese subjects who completed the program at a later date. By single nucleotide polymorphism-based and sib-pair analysis, we show that that weight loss is a heritable trait, with estimated heritability (h2 = 0.49) within the range reported for obesity. We find rs679482, intronic to SGCG (sarcoglycan γ), highly expressed in skeletal muscle, to concordantly associate with weight loss in discovery and replication samples reaching GWAS significance in the combined meta-analysis (β = -0.35, P = 1.7 × 10-12). Located in a region of open chromatin, rs679482 is predicted to bind DMRT2, and allele-specific transcription factor binding analysis indicates preferential binding of DMRT2 to rs679482-A. Concordantly, rs679482-A impairs native repressor activity and increases basal and DMRT2-mediated enhancer activity. These findings confirm that weight loss is a heritable trait and provide evidence by which a novel variant in SGCG, rs679482, leads to impaired diet response. [ABSTRACT FROM AUTHOR]
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- 2020
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8. Mice expressing human but not murine beta3-adrenergic receptors under the control of human gene regulatory elements.
- Author
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Ito, Moriko, Grujic, Danica, Abel, E. Dale, Vidal-Puig, Antonio, Susulic, Vedrana S., Lawitts, Joel, Harper, Mary-Ellen, Himms-Hagen, Jean, Strosberg, A. Donny, Lowell, Bradford B., Ito, M, Grujic, D, Abel, E D, Vidal-Puig, A, Susulic, V S, Lawitts, J, Harper, M E, Himms-Hagen, J, Strosberg, A D, and Lowell, B B
- Subjects
BETA adrenoceptors - Abstract
Beta-adrenergic receptors (ARs) are expressed predominantly in adipose tissue, and beta3-selective agonists are effective anti-obesity drugs in rodents. Rodent and human beta3-ARs differ with respect to expression in white versus brown adipocytes as well as their ability to be stimulated by beta3-AR-selective agonists. Humans express beta3-AR mRNA abundantly in brown but not white adipocytes, while rodents express beta3-AR mRNA abundantly in both sites. To determine the basis for this difference, we have transgenically introduced 74 kilobases (kb) of human beta3-AR genomic sequence into gene knockout mice lacking beta3-ARs. Importantly, human beta3-AR mRNA was expressed only in brown adipose tissue (BAT) of transgenic mice, with little or no expression being detected in white adipose tissue (WAT), liver, stomach, small intestine, skeletal muscle, and heart. This pattern of expression differed from that observed in mice bearing a murine beta3-AR genomic transgene in which beta3-AR mRNA was expressed in both WAT and BAT, but not in other sites. Furthermore, we have transgenically introduced smaller human constructs containing -14.5 and -0.6 kb of upstream sequence into beta3-AR gene knockout mice. Both -14.5 and -0.6 kb constructs were expressed in BAT but not WAT. Thus, human but not murine cis-regulatory elements direct beta3-AR gene expression preferentially to brown adipocytes. Identification of responsible cis-regulatory element(s) and relevant trans-acting factor(s) should provide insight into mechanisms controlling human beta3-AR gene expression. In addition, the beta3-AR agonist, CGP-12177, stimulated oxygen consumption in mice expressing human but not murine beta3-ARs by 91% compared with only 49% in control beta3-AR gene knockout mice, demonstrating that the human beta3-AR can functionally couple with energy expenditure. These "humanized" mice should assist us in the development of drugs that may become effective anti-obesity agents in humans. [ABSTRACT FROM AUTHOR]
- Published
- 1998
- Full Text
- View/download PDF
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