Bala Cynwyd
323 Llandrillo Rd
Bala Cynwyd, PA 19004
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Publications & Research

Dr. Grujic has contributed to 7 publications.
Title Hyperoxaluria is Reduced and Nephrocalcinosis Prevented with an Oxalate-degrading Enzyme in Mice with Hyperoxaluria.
Date April 2009
Journal American Journal of Nephrology

Hyperoxaluria is a major risk factor for recurrent urolithiasis and nephrocalcinosis. We tested an oral therapy with a crystalline, cross-linked formulation of oxalate-decarboxylase (OxDc-CLEC) on the reduction of urinary oxalate and decrease in the severity of kidney injury in two models: AGT1 knockout mice (AGT1KO) in which hyperoxaluria is the result of an Agxt gene deficiency, and in AGT1KO mice challenged with ethylene glycol (EG).

Title Uncoupling Protein-2 Negatively Regulates Insulin Secretion and is a Major Link Between Obesity, Beta Cell Dysfunction, and Type 2 Diabetes.
Date July 2001
Journal Cell

beta cells sense glucose through its metabolism and the resulting increase in ATP, which subsequently stimulates insulin secretion. Uncoupling protein-2 (UCP2) mediates mitochondrial proton leak, decreasing ATP production. In the present study, we assessed UCP2's role in regulating insulin secretion. UCP2-deficient mice had higher islet ATP levels and increased glucose-stimulated insulin secretion, establishing that UCP2 negatively regulates insulin secretion. Of pathophysiologic significance, UCP2 was markedly upregulated in islets of ob/ob mice, a model of obesity-induced diabetes. Importantly, ob/ob mice lacking UCP2 had restored first-phase insulin secretion, increased serum insulin levels, and greatly decreased levels of glycemia. These results establish UCP2 as a key component of beta cell glucose sensing, and as a critical link between obesity, beta cell dysfunction, and type 2 diabetes.

Title Expression of Human Alpha 2-adrenergic Receptors in Adipose Tissue of Beta 3-adrenergic Receptor-deficient Mice Promotes Diet-induced Obesity.
Date December 2000
Journal The Journal of Biological Chemistry

Catecholamines play an important role in controlling white adipose tissue function and development. beta- and alpha 2-adrenergic receptors (ARs) couple positively and negatively, respectively, to adenylyl cyclase and are co-expressed in human adipocytes. Previous studies have demonstrated increased adipocyte alpha 2/beta-AR balance in obesity, and it has been proposed that increased alpha 2-ARs in adipose tissue with or without decreased beta-ARs may contribute mechanistically to the development of increased fat mass. To critically test this hypothesis, adipocyte alpha 2/beta-AR balance was genetically manipulated in mice. Human alpha 2A-ARs were transgenically expressed in the adipose tissue of mice that were either homozygous (-/-) or heterozygous (+/-) for a disrupted beta 3-AR allele. Mice expressing alpha 2-ARs in fat, in the absence of beta 3-ARs (beta 3-AR -/- background), developed high fat diet-induced obesity. Strikingly, this effect was due entirely to adipocyte hyperplasia and required the presence of alpha2-ARs, the absence of beta 3-ARs, and a high fat diet. Of note, obese alpha 2-transgenic beta 3 -/- mice failed to develop insulin resistance, which may reflect the fact that expanded fat mass was due to adipocyte hyperplasia and not adipocyte hypertrophy. In summary, we have demonstrated that increased alpha 2/beta-AR balance in adipocytes promotes obesity by stimulating adipocyte hyperplasia. This study also demonstrates one way in which two genes (alpha 2 and beta 3-AR) and diet interact to influence fat mass.

Title Energy Metabolism in Uncoupling Protein 3 Gene Knockout Mice.
Date June 2000
Journal The Journal of Biological Chemistry

Uncoupling protein 3 (UCP3) is a member of the mitochondrial anion carrier superfamily. Based upon its high homology with UCP1 and its restricted tissue distribution to skeletal muscle and brown adipose tissue, UCP3 has been suggested to play important roles in regulating energy expenditure, body weight, and thermoregulation. Other postulated roles for UCP3 include regulation of fatty acid metabolism, adaptive responses to acute exercise and starvation, and prevention of reactive oxygen species (ROS) formation. To address these questions, we have generated mice lacking UCP3 (UCP3 knockout (KO) mice). Here, we provide evidence that skeletal muscle mitochondria lacking UCP3 are more coupled (i.e. increased state 3/state 4 ratio), indicating that UCP3 has uncoupling activity. In addition, production of ROS is increased in mitochondria lacking UCP3. This study demonstrates that UCP3 has uncoupling activity and that its absence may lead to increased production of ROS. Despite these effects on mitochondrial function, UCP3 does not seem to be required for body weight regulation, exercise tolerance, fatty acid oxidation, or cold-induced thermogenesis. The absence of such phenotypes in UCP3 KO mice could not be attributed to up-regulation of other UCP mRNAs. However, alternative compensatory mechanisms cannot be excluded. The consequence of increased mitochondrial coupling in UCP3 KO mice on metabolism and the possible role of yet unidentified compensatory mechanisms, remains to be determined.

Title Regulation of Skeletal Muscle Ucp-2 and Ucp-3 Gene Expression by Exercise and Denervation.
Date March 1999
Journal The American Journal of Physiology

The factors that regulate gene expression of uncoupling proteins 2 and 3 (UCP-2 and UCP-3) in skeletal muscle are poorly understood, but both genes are clearly responsive to the metabolic state of the organism. Therefore, we tested the hypothesis that denervation and acute and/or chronic exercise (factors that profoundly affect metabolism) would alter UCP-2 and UCP-3 gene expression. For the denervation studies, the sciatic nerve of rat and mouse hindlimb was sectioned in one leg while the contralateral limb served as control. Northern blot analysis revealed that denervation was associated with a 331% increase (P < 0.001) in UCP-3 mRNA and a 200% increase (P < 0. 01) in UCP-2 mRNA levels in rat mixed gastrocnemius (MG) muscle. In contrast, denervation caused a 53% decrease (P < 0.001) in UCP-3 and a 63% increase (P < 0.01) in UCP-2 mRNA levels in mouse MG. After acute exercise (2-h treadmill running), rat UCP-3 mRNA levels were elevated (vs. sedentary control) 252% (P < 0.0001) in white gastrocnemius and 63% (P < 0.05) in red gastrocnemius muscles, whereas UCP-2 levels were unaffected. To a lesser extent, elevations in UCP-3 mRNA (22%; P < 0.01) and UCP-2 mRNA (55%; P < 0.01) levels were observed after acute exercise in the mouse MG. There were no changes in either UCP-2 or UCP-3 mRNA levels after chronic exercise (9 wk of wheel running). These results indicate that acute exercise and denervation regulate gene expression of skeletal muscle UCPs.

Title The Human Uncoupling Protein-3 Gene. Genomic Structure, Chromosomal Localization, and Genetic Basis for Short and Long Form Transcripts.
Date November 1997
Journal The Journal of Biological Chemistry

Uncoupling protein-3 (UCP3) is a recently identified candidate mediator of adaptive thermogenesis in humans. Unlike UCP1 and UCP2, UCP3 is expressed preferentially and at high levels in human skeletal muscle and exists as short and long form transcripts, UCP3S and UCP3L. UCP3S is predicted to encode a protein which lacks the last 37 C-terminal residues of UCP3L. In the present study, we have defined the intron-exon structure for the human UCP3 gene and determined that UCP3S is generated when a cleavage and polyadenylation signal (AATAAA) located in the last intron prematurely terminates message elongation. In addition we have mapped UCP3 to the distal segment of human chromosome 11q13 (between framework markers D11S916 and D11S911), adjacent to UCP2. Of note, UCP2 and UCP3 in both mice and humans colocalize in P1 and BAC genomic clones indicating that these two UCPs are located within 75-150 kilobases of each other and most likely resulted from a gene duplication event. Previous studies have noted that mouse UCP2 maps to a region of chromosome 7 which is coincident with three independently mapped quantitative trait loci for obesity. Our study shows that UCP3 is also coincident with these quantitative trait loci raising the possibility that abnormalities in UCP3 are responsible for obesity in these models.

Title Ucp3: an Uncoupling Protein Homologue Expressed Preferentially and Abundantly in Skeletal Muscle and Brown Adipose Tissue.
Date July 1997
Journal Biochemical and Biophysical Research Communications

Uncoupling proteins (UCPs) are inner mitochondrial membrane transporters which dissipate the proton gradient, releasing stored energy as heat. UCP1 is expressed exclusively in brown adipocytes while UCP2 is expressed widely. We now report the molecular cloning of a third uncoupling protein homologue, designated UCP3. At the amino acid level, hUCP3 is 71% identical to hUCP2 and 57% identical to hUCP1. UCP3 is distinguished from UCP1 and UCP2 by its abundant and preferential expression in skeletal muscle in humans, and brown adipose tissue and skeletal muscle in rodents. Since skeletal muscle and brown adipose tissue are believed to be important sites for regulated energy expenditure in humans and rodents, respectively, UCP3 may be an important mediator of adaptive thermogenesis. Since UCP3 is minimally expressed in human heart and other critical organs, it is a promising target for anti-obesity drug development aimed at increasing thermogenesis.

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