Publications by authors named "Sona Kang"

31 Publications

Epigenetic regulation of inflammatory factors in adipose tissue.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 Nov 29;1866(11):159019. Epub 2021 Jul 29.

Nutritional Sciences and Toxicology Department, University of California Berkeley, Berkeley, CA 94720, United States of America. Electronic address:

Obesity is a strong risk factor for insulin resistance. Chronic low-grade tissue inflammation and systemic inflammation have been proposed as major mechanisms that promote insulin resistance in obesity. Adipose tissue has been recognized as a nexus between inflammation and metabolism, but how exactly inflammatory gene expression is orchestrated during the development of obesity is not well understood. Epigenetic modifications are defined as heritable changes in gene expression and cellular function without changes to the original DNA sequence. The major epigenetic mechanisms include DNA methylation, histone modification, noncoding RNAs, nucleopositioning/remodeling and chromatin reorganization. Epigenetic mechanisms provide a critical layer of gene regulation in response to environmental changes. Accumulating evidence supports that epigenetics plays a large role in the regulation of inflammatory genes in adipocytes and adipose-resident immune cell types. This review focuses on the association between adipose tissue inflammation in obesity and major epigenetic modifications.
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http://dx.doi.org/10.1016/j.bbalip.2021.159019DOI Listing
November 2021

A necessary role of DNMT3A in endurance exercise by suppressing ALDH1L1-mediated oxidative stress.

EMBO J 2021 May 13;40(9):e106491. Epub 2021 Apr 13.

Nutritional Sciences and Toxicology Department, University of California Berkeley, Berkeley, CA, USA.

Exercise can alter the skeletal muscle DNA methylome, yet little is known about the role of the DNA methylation machinery in exercise capacity. Here, we show that DNMT3A expression in oxidative red muscle increases greatly following a bout of endurance exercise. Muscle-specific Dnmt3a knockout mice have reduced tolerance to endurance exercise, accompanied by reduction in oxidative capacity and mitochondrial respiration. Moreover, Dnmt3a-deficient muscle overproduces reactive oxygen species (ROS), the major contributors to muscle dysfunction. Mechanistically, we show that DNMT3A suppresses the Aldh1l1 transcription by binding to its promoter region, altering its epigenetic profile. Forced expression of ALDH1L1 elevates NADPH levels, which results in overproduction of ROS by the action of NADPH oxidase complex, ultimately resulting in mitochondrial defects in myotubes. Thus, inhibition of ALDH1L1 pathway can rescue oxidative stress and mitochondrial dysfunction from Dnmt3a deficiency in myotubes. Finally, we show that in vivo knockdown of Aldh1l1 largely rescues exercise intolerance in Dnmt3a-deficient mice. Together, we establish that DNMT3A in skeletal muscle plays a pivotal role in endurance exercise by controlling intracellular oxidative stress.
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http://dx.doi.org/10.15252/embj.2020106491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090849PMC
May 2021

The role of striated muscle Pik3r1 in glucose and protein metabolism following chronic glucocorticoid exposure.

J Biol Chem 2021 Jan-Jun;296:100395. Epub 2021 Feb 7.

Metabolic Biology Graduate Program, University of California Berkeley, Berkeley, California, USA; Department of Nutritional Sciences & Toxicology, University of California Berkeley, Berkeley, California, USA; Endocrinology Graduate Program, University of California Berkeley, Berkeley, California, USA. Electronic address:

Chronic glucocorticoid exposure causes insulin resistance and muscle atrophy in skeletal muscle. We previously identified phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1) as a primary target gene of skeletal muscle glucocorticoid receptors involved in the glucocorticoid-mediated suppression of insulin action. However, the in vivo functions of Pik3r1 remain unclear. Here, we generated striated muscle-specific Pik3r1 knockout (MKO) mice and treated them with a dexamethasone (DEX), a synthetic glucocorticoid. Treating wildtype (WT) mice with DEX attenuated insulin activated Akt activity in liver, epididymal white adipose tissue, and gastrocnemius (GA) muscle. This DEX effect was diminished in GA muscle of MKO mice, therefore, resulting in improved glucose and insulin tolerance in DEX-treated MKO mice. Stable isotope labeling techniques revealed that in WT mice, DEX treatment decreased protein fractional synthesis rates in GA muscle. Furthermore, histology showed that in WT mice, DEX treatment reduced GA myotube diameters. In MKO mice, myotube diameters were smaller than in WT mice, and there were more fast oxidative fibers. Importantly, DEX failed to further reduce myotube diameters. Pik3r1 knockout also decreased basal protein synthesis rate (likely caused by lower 4E-BP1 phosphorylation at Thr37/Thr46) and curbed the ability of DEX to attenuate protein synthesis rate. Finally, the ability of DEX to inhibit eIF2α phosphorylation and insulin-induced 4E-BP1 phosphorylation was reduced in MKO mice. Taken together, these results demonstrate the role of Pik3r1 in glucocorticoid-mediated effects on glucose and protein metabolism in skeletal muscle.
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http://dx.doi.org/10.1016/j.jbc.2021.100395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010618PMC
September 2021

Adipose Tissue Malfunction Drives Metabolic Dysfunction in Alström Syndrome.

Authors:
Sona Kang

Diabetes 2021 02;70(2):323-325

Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA

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http://dx.doi.org/10.2337/dbi20-0041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881857PMC
February 2021

Insulin-sensitizing effects of vitamin D repletion mediated by adipocyte vitamin D receptor: Studies in humans and mice.

Mol Metab 2020 12 10;42:101095. Epub 2020 Oct 10.

Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address:

Objective: Adipose tissue inflammation and fibrosis appear to contribute to insulin resistance in obesity. Vitamin D receptor (Vdr) genes are expressed by adipocytes, macrophages, and fibroblasts, all of which could potentially play a role in adipose tissue inflammation and fibrosis. As vitamin D has been shown to have direct anti-inflammatory effects on adipocytes, we determined whether specific vitamin D receptor-mediated effects on adipocytes could impact adipose tissue inflammation and fibrosis and ultimately insulin resistance.

Methods: We examined the effects of repleting vitamin D in 25(OH)D-deficient, insulin resistant, overweight-to-obese human subjects (n = 19). A comprehensive assessment of whole-body insulin action was undertaken with stepped euglycemic (∼90 mg/dL) hyperinsulinemic clamp studies both before and after the administration of vitamin D or placebo. Adipose tissue fibrosis and inflammation were quantified by real-time rt-PCR and immunofluorescence in subcutaneous abdominal adipose tissue. To determine whether vitamin D's effects are mediated through adipocytes, we conducted hyperinsulinemic clamp studies (4 mU/kg/min) and adipose tissue analysis using an adipocyte-specific vitamin D receptor knockout (VDR-KO) mouse model (adiponectin-Cre + VDR+/fl) following high-fat diet feeding for 12 weeks.

Results: 25(OH)D repletion was associated with reductions in adipose tissue expression of pro-inflammatory and pro-fibrotic genes, decreased collagen immunofluorescence, and improved hepatic insulin sensitivity in humans. Worsening trends after six months on placebo suggest progressive metabolic effects of 25(OH)D deficiency. Ad-VDR-KO mice mirrored the vitamin D-deficient humans, displaying increased adipose tissue fibrosis and inflammation and hepatic insulin resistance.

Conclusions: These complementary human and rodent studies support a beneficial role of vitamin D repletion for improving hepatic insulin resistance and reducing adipose tissue inflammation and fibrosis in targeted individuals, likely via direct effects on adipocytes. These studies have far-reaching implications for understanding the role of adipocytes in mediating adipose tissue inflammation and fibrosis and ultimately impacting insulin sensitivity.
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http://dx.doi.org/10.1016/j.molmet.2020.101095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585951PMC
December 2020

TET1 is a beige adipocyte-selective epigenetic suppressor of thermogenesis.

Nat Commun 2020 08 27;11(1):4313. Epub 2020 Aug 27.

Nutritional Sciences and Toxicology Department, University of California Berkeley, Berkeley, CA, 94720, USA.

It has been suggested that beige fat thermogenesis is tightly controlled by epigenetic regulators that sense environmental cues such as temperature. Here, we report that subcutaneous adipose expression of the DNA demethylase TET1 is suppressed by cold and other stimulators of beige adipocyte thermogenesis. TET1 acts as an autonomous repressor of key thermogenic genes, including Ucp1 and Ppargc1a, in beige adipocytes. Adipose-selective Tet1 knockout mice generated by using Fabp4-Cre improves cold tolerance and increases energy expenditure and protects against diet-induced obesity and insulin resistance. Moreover, the suppressive role of TET1 in the thermogenic gene regulation of beige adipocytes is largely DNA demethylase-independent. Rather, TET1 coordinates with HDAC1 to mediate the epigenetic changes to suppress thermogenic gene transcription. Taken together, TET1 is a potent beige-selective epigenetic breaker of the thermogenic gene program. Our findings may lead to a therapeutic strategy to increase energy expenditure in obesity and related metabolic disorders.
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http://dx.doi.org/10.1038/s41467-020-18054-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453011PMC
August 2020

The Role of the Gut Microbiome in Energy Balance With a Focus on the Gut-Adipose Tissue Axis.

Authors:
Han Xiao Sona Kang

Front Genet 2020 7;11:297. Epub 2020 Apr 7.

Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, United States.

Obesity is a complex disease attributable to many factors including genetics and environmental influences. Growing evidence suggests that gut microbiota is a major contributing factor to the pathogenesis of obesity and other metabolic disorders. This article reviews the current understanding of the role of gut microbiota in the regulation of energy balance and the development of obesity, and how the microbiota communicates with host tissues, in particular adipose tissue. We discuss several external factors that interfere with the interplay between gut microbiota and host tissue metabolism, including cold exposure, diet regimens, and genetic manipulations. We also review the role of diet-derived metabolites that regulate thermogenesis and thus energy homeostasis. Among the gut microbial metabolites, we emphasize short-chain fatty acids, which could be utilized by the host as a direct energy source while regulating the appetite of the host through the gut-brain axis.
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http://dx.doi.org/10.3389/fgene.2020.00297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154186PMC
April 2020

The role of DNA methylation in thermogenic adipose biology.

Authors:
Han Xiao Sona Kang

Epigenetics 2019 09 4;14(9):837-843. Epub 2019 Jun 4.

a Department of Nutritional Sciences and Toxicology, UC Berkeley , Berkeley , CA , USA.

The two types of thermogenic fat cells, beige and brown adipocytes, play a significant role in regulating energy homeostasis. Their development and thermogenesis are tightly regulated by dynamic epigenetic mechanisms, which could potentially be targeted to treat metabolic disorders such as obesity. However, we are just beginning to catalog and understand these dynamic changes. In this review, we will discuss the current understanding of the role of DNA (de)methylation events in beige and brown adipose biology in order to highlight the holes in our knowledge and to point the way forward for future studies.
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http://dx.doi.org/10.1080/15592294.2019.1625670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691979PMC
September 2019

Functional Implications of DNA Methylation in Adipose Biology.

Authors:
Xiang Ma Sona Kang

Diabetes 2019 05;68(5):871-878

Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA

The twin epidemics of obesity and type 2 diabetes (T2D) are a serious health, social, and economic issue. The dysregulation of adipose tissue biology is central to the development of these two metabolic disorders, as adipose tissue plays a pivotal role in regulating whole-body metabolism and energy homeostasis (1). Accumulating evidence indicates that multiple aspects of adipose biology are regulated, in part, by epigenetic mechanisms. The precise and comprehensive understanding of the epigenetic control of adipose tissue biology is crucial to identifying novel therapeutic interventions that target epigenetic issues. Here, we review the recent findings on DNA methylation events and machinery in regulating the developmental processes and metabolic function of adipocytes. We highlight the following points: ) DNA methylation is a key epigenetic regulator of adipose development and gene regulation, ) emerging evidence suggests that DNA methylation is involved in the transgenerational passage of obesity and other metabolic disorders, ) DNA methylation is involved in regulating the altered transcriptional landscape of dysfunctional adipose tissue, ) genome-wide studies reveal specific DNA methylation events that associate with obesity and T2D, and ) the enzymatic effectors of DNA methylation have physiological functions in adipose development and metabolic function.
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http://dx.doi.org/10.2337/dbi18-0057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477906PMC
May 2019

DNMT3a and TET2 in adipocyte insulin sensitivity.

Oncotarget 2018 Oct 19;9(82):35289-35290. Epub 2018 Oct 19.

Nutritional Sciences and Toxicology Department, UC Berkeley, Berkeley, CA, USA.

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http://dx.doi.org/10.18632/oncotarget.26246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219679PMC
October 2018

TET2 facilitates PPARγ agonist-mediated gene regulation and insulin sensitization in adipocytes.

Metabolism 2018 12 5;89:39-47. Epub 2018 Sep 5.

Department of Nutritional Sciences and Toxicology, UC Berkeley, Berkeley, CA 94720, USA. Electronic address:

Emerging evidence indicates that epigenetic mechanisms like DNA methylation directly contribute to metabolic regulation. For example, we previously demonstrated that de novo DNA methyltransferase Dnmt3a plays a causal role in the development of adipocyte insulin resistance. Recent studies suggest that DNA demethylation plays an important role in the developmental process of adipocytes. However, little is known about whether DNA demethylase ten-eleven translocation (TET) proteins regulate the metabolic functions of adipocytes.

Methods: The expression of Tet genes was assessed in the fractionated adipocytes of chow- and high fat diet-fed C57/Bl6 mice using qPCR and western blotting. The effect of Tet2 gain- or loss-of-function in fully mature 3T3-L1 adipocytes in the presence/absence of Rosiglitazone (Rosi) and TNF-α on insulin sensitivity was using the insulin-stimulated glucose uptake and insulin signaling assays. Gene expression and DNA methylation analyses of PPARγ target genes was performed in the same setting. In addition, PPARγ reporter assays, co-immunoprecipitation assays, PPARγ ChIP-PCR analyses were performed.

Results: We found that adipose expression of TET2, alone among its family members, was significantly reduced in diet-induced insulin resistance. TET2 gain-of-function was sufficient to promote insulin sensitivity while loss-of-function was necessary to facilitate insulin sensitization in response to the PPARγ agonist Rosiglitazone (Rosi) in cultured adipocytes. Consistent with this, TET2 was required for Rosi-dependent gene activation of certain PPARγ targets accompanied by changes in DNA demethylation at the promoter regions. Furthermore, TET2 was necessary to sustain PPARγ binding to target loci upon activation with Rosi via physical interaction with PPARγ.

Conclusions: Our data demonstrate that TET2 works as an epigenetic regulator of Rosi-mediated insulin sensitization and transcriptional regulation in adipocytes.
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http://dx.doi.org/10.1016/j.metabol.2018.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221917PMC
December 2018

Dnmt3a is an epigenetic mediator of adipose insulin resistance.

Elife 2017 11 1;6. Epub 2017 Nov 1.

Nutritional Sciences and Toxicology Department, University of California, Berkeley, Berkeley, United States.

Insulin resistance results from an intricate interaction between genetic make-up and environment, and thus may be orchestrated by epigenetic mechanisms like DNA methylation. Here, we demonstrate that DNA methyltransferase 3a (Dnmt3a) is both necessary and sufficient to mediate insulin resistance in cultured mouse and human adipocytes. Furthermore, adipose-specific Dnmt3a knock-out mice are protected from diet-induced insulin resistance and glucose intolerance without accompanying changes in adiposity. Unbiased gene profiling studies revealed as a key negatively regulated Dnmt3a target gene in adipocytes with concordant changes in DNA methylation at the promoter region. Consistent with this, Fgf21 can rescue Dnmt3a-mediated insulin resistance, and DNA methylation at the locus was elevated in human subjects with diabetes and correlated negatively with expression of in human adipose tissue. Taken together, our data demonstrate that adipose Dnmt3a is a novel epigenetic mediator of insulin resistance in vitro and in vivo.
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http://dx.doi.org/10.7554/eLife.30766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730374PMC
November 2017

Exploration of Underlying Mechanism of Anti-adipogenic Activity of Sulfuretin.

Biol Pharm Bull 2017 Sep 3;40(9):1366-1373. Epub 2017 Jun 3.

Wonkwang University, College of Pharmacy, Department of Oriental Pharmacy, and Wonkwang-Oriental Medicines Research Institute.

Sulfuretin is a natural flavonoid found in the plant Rhus verniciflua STOKES. The plant has been traditionally used as medicinal agent for antiviral, cathartic, diaphoretic, anti-rheumatic and sedative activities in East Asia. In this study we isolated and identified sulfuretin from R. verniciflua and investigated its anti-adipogenic activity against 3T3-L1 preadipocytes cells. We evaluated the effects of sulfuretin on the adipogenic transcription factors like peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα), fatty acid synthase (FAS), Fabp4, adiponectin and zinc fingerprint protein (Zfp) 521 by gene expression (real-time QPCR) and Western blot analysis. Sulfuretin treatment at Day 0 and 2 showed significant reduction of lipid production in 3T3-L1 cells in concentration dependent manner. Gene expression analysis (real-time PCR) revealed that sulfuretin inhibited the both major adipogenic factors (C/EBPα, C/EBPβ and PPARγ) and minor adipogenic factors (sterol regulatory element-binding protein (SREBP1c), adiponectin, FAS, Fabp4, Zfp423, and Ebf1). Western blot analysis showed the increased expression of β-catenin and suppression of PPARγ after sulfuretin treatment. Overall, sulfuretin is a natural flavonoid having potent anti-adipogenic activity through the suppression of major adipogenic factors C/EBPα, C/EBPβ and PPARγ, which initiate adipogenesis.
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http://dx.doi.org/10.1248/bpb.b17-00049DOI Listing
September 2017

IRF3 promotes adipose inflammation and insulin resistance and represses browning.

J Clin Invest 2016 08 11;126(8):2839-54. Epub 2016 Jul 11.

The chronic inflammatory state that accompanies obesity is a major contributor to insulin resistance and other dysfunctional adaptations in adipose tissue. Cellular and secreted factors promote the inflammatory milieu of obesity, but the transcriptional pathways that drive these processes are not well described. Although the canonical inflammatory transcription factor NF-κB is considered to be the major driver of adipocyte inflammation, members of the interferon regulatory factor (IRF) family may also play a role in this process. Here, we determined that IRF3 expression is upregulated in the adipocytes of obese mice and humans. Signaling through TLR3 and TLR4, which lie upstream of IRF3, induced insulin resistance in murine adipocytes, while IRF3 knockdown prevented insulin resistance. Furthermore, improved insulin sensitivity in IRF3-deficient mice was associated with reductions in intra-adipose and systemic inflammation in the high fat-fed state, enhanced browning of subcutaneous fat, and increased adipose expression of GLUT4. Taken together, the data indicate that IRF3 is a major transcriptional regulator of adipose inflammation and is involved in maintaining systemic glucose and energy homeostasis.
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http://dx.doi.org/10.1172/JCI86080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966307PMC
August 2016

MicroRNA-181b Improves Glucose Homeostasis and Insulin Sensitivity by Regulating Endothelial Function in White Adipose Tissue.

Circ Res 2016 Mar 7;118(5):810-21. Epub 2016 Jan 7.

From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., J.L., N.B., A.K.W., B.I., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (J.L., D.L.); Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong SAR, China (Y.Z.); Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Center for Life Sciences, Beth Israel Deaconess Medical Center, Boston, MA (S.K.); and Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (N.M.H.).

Rationale: The pathogenesis of insulin resistance involves dysregulated gene expression and function in multiple cell types, including endothelial cells (ECs). Post-transcriptional mechanisms such as microRNA-mediated regulation of gene expression could affect insulin action by modulating EC function.

Objective: To determine whether microRNA-181b (miR-181b) affects the pathogenesis of insulin resistance by regulating EC function in white adipose tissue during obesity.

Methods And Results: MiR-181b expression was reduced in adipose tissue ECs of obese mice, and rescue of miR-181b expression improved glucose homeostasis and insulin sensitivity. Systemic intravenous delivery of miR-181b robustly accumulated in adipose tissue ECs, enhanced insulin-mediated Akt phosphorylation at Ser473, and reduced endothelial dysfunction, an effect that shifted macrophage polarization toward an M2 anti-inflammatory phenotype in epididymal white adipose tissue. These effects were associated with increased endothelial nitric oxide synthase and FoxO1 phosphorylation as well as nitric oxide activity in epididymal white adipose tissue. In contrast, miR-181b did not affect insulin-stimulated Akt phosphorylation in liver and skeletal muscle. Bioinformatics and gene profiling approaches revealed that Pleckstrin homology domain leucine-rich repeat protein phosphatase, a phosphatase that dephosphorylates Akt at Ser473, is a novel target of miR-181b. Knockdown of Pleckstrin homology domain leucine-rich repeat protein phosphatase increased Akt phosphorylation at Ser473 in ECs, and phenocopied miR-181b's effects on glucose homeostasis, insulin sensitivity, and inflammation of epididymal white adipose tissue in vivo. Finally, ECs from diabetic subjects exhibited increased Pleckstrin homology domain leucine-rich repeat protein phosphatase expression.

Conclusions: Our data underscore the importance of adipose tissue EC function in controlling the development of insulin resistance. Delivery of miR-181b or Pleckstrin homology domain leucine-rich repeat protein phosphatase inhibitors may represent a new therapeutic approach to ameliorate insulin resistance by improving adipose tissue endothelial Akt-endothelial nitric oxide synthase-nitric oxide signaling.
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http://dx.doi.org/10.1161/CIRCRESAHA.115.308166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779381PMC
March 2016

Nuclear Mechanisms of Insulin Resistance.

Trends Cell Biol 2016 05 25;26(5):341-351. Epub 2016 Jan 25.

Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. Electronic address:

Insulin resistance is a sine qua non of type 2 diabetes and is associated with many other clinical conditions. Decades of research into mechanisms underlying insulin resistance have mostly focused on problems in insulin signal transduction and other mitochondrial and cytosolic pathways. By contrast, relatively little attention has been focused on transcriptional and epigenetic contributors to insulin resistance, despite strong evidence that such nuclear mechanisms play a major role in the etiopathogenesis of this condition. In this review, we summarize the evidence for nuclear mechanisms of insulin resistance, focusing on three transcription factors with a major impact on insulin action in liver, muscle, and fat.
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http://dx.doi.org/10.1016/j.tcb.2016.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4844850PMC
May 2016

Identification of nuclear hormone receptor pathways causing insulin resistance by transcriptional and epigenomic analysis.

Nat Cell Biol 2015 Jan 15;17(1):44-56. Epub 2014 Dec 15.

1] Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA [2] Broad Institute, Cambridge, Massachusetts 02142, USA [3] Harvard Medical School, Boston, Massachusetts 02215, USA.

Insulin resistance is a cardinal feature of Type 2 diabetes (T2D) and a frequent complication of multiple clinical conditions, including obesity, ageing and steroid use, among others. How such a panoply of insults can result in a common phenotype is incompletely understood. Furthermore, very little is known about the transcriptional and epigenetic basis of this disorder, despite evidence that such pathways are likely to play a fundamental role. Here, we compare cell autonomous models of insulin resistance induced by the cytokine tumour necrosis factor-α or by the steroid dexamethasone to construct detailed transcriptional and epigenomic maps associated with cellular insulin resistance. These data predict that the glucocorticoid receptor and vitamin D receptor are common mediators of insulin resistance, which we validate using gain- and loss-of-function studies. These studies define a common transcriptional and epigenomic signature in cellular insulin resistance enabling the identification of pathogenic mechanisms.
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http://dx.doi.org/10.1038/ncb3080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281178PMC
January 2015

IRF4 is a key thermogenic transcriptional partner of PGC-1α.

Cell 2014 Jul;158(1):69-83

Division of Endocrinology, Beth Israel Deaconess Medical Center and Department of Genetics, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA. Electronic address:

Brown fat can reduce obesity through the dissipation of calories as heat. Control of thermogenic gene expression occurs via the induction of various coactivators, most notably PGC-1α. In contrast, the transcription factor partner(s) of these cofactors are poorly described. Here, we identify interferon regulatory factor 4 (IRF4) as a dominant transcriptional effector of thermogenesis. IRF4 is induced by cold and cAMP in adipocytes and is sufficient to promote increased thermogenic gene expression, energy expenditure, and cold tolerance. Conversely, knockout of IRF4 in UCP1(+) cells causes reduced thermogenic gene expression and energy expenditure, obesity, and cold intolerance. IRF4 also induces the expression of PGC-1α and PRDM16 and interacts with PGC-1α, driving Ucp1 expression. Finally, cold, β-agonists, or forced expression of PGC-1α are unable to cause thermogenic gene expression in the absence of IRF4. These studies establish IRF4 as a transcriptional driver of a program of thermogenic gene expression and energy expenditure.
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http://dx.doi.org/10.1016/j.cell.2014.04.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116691PMC
July 2014

Adipocyte-specific transgenic and knockout models.

Methods Enzymol 2014 ;537:1-16

Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Adipose tissue plays a major role in metabolic homeostasis, which it coordinates through a number of local and systemic effectors. The burgeoning epidemic of metabolic disease, especially obesity and type 2 diabetes, has focused attention on the adipocyte. In this chapter, we review strategies for genetic overexpression and knockout of specific genes in adipose tissue. We also discuss these strategies in the context of different types of adipocytes, including brown, beige, and white fat cells.
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http://dx.doi.org/10.1016/B978-0-12-411619-1.00001-XDOI Listing
September 2014

Arterial territory-specific phosphorylated retinoblastoma protein species and CDK2 promote differences in the vascular smooth muscle cell response to mitogens.

Cell Cycle 2014 12;13(2):315-23. Epub 2013 Nov 12.

Department of Medicine; Beth Israel Deaconess Medical Center; Harvard Medical School; Boston, MA USA.

Despite recent advances in medical procedures, cardiovascular disease remains a clinical challenge and the leading cause of mortality in the western world. The condition causes progressive smooth muscle cell (SMC) dedifferentiation, proliferation, and migration that contribute to vascular restenosis. The incidence of disease of the internal mammary artery (IMA), however, is much lower than in nearly all other arteries. The etiology of this IMA disease resistance is not well understood. Here, using paired primary IMA and coronary artery SMCs, serum stimulation, siRNA knockdowns, and verifications in porcine vessels in vivo, we investigate the molecular mechanisms that could account for this increased disease resistance of internal mammary SMCs. We show that the residue-specific phosphorylation profile of the retinoblastoma tumor suppressor protein (Rb) appears to differ significantly between IMA and coronary artery SMCs in cultured human cells. We also report that the differential profile of Rb phosphorylation may follow as a consequence of differences in the content of cyclin-dependent kinase 2 (CDK2) and the CDK4 phosphorylation inhibitor p15. Finally, we present evidence that siRNA-mediated CDK2 knockdown alters the profile of Rb phosphorylation in coronary artery SMCs, as well as the proliferative response of these cells to mitogenic stimulation. The intrinsic functional and protein composition specificity of the SMCs population in the coronary artery may contribute to the increased prevalence of restenosis and atherosclerosis in the coronary arteries as compared with the internal mammary arteries.
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http://dx.doi.org/10.4161/cc.27056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906247PMC
November 2014

Early B-cell factor-1 (EBF1) is a key regulator of metabolic and inflammatory signaling pathways in mature adipocytes.

J Biol Chem 2013 Dec 30;288(50):35925-39. Epub 2013 Oct 30.

From the Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215.

EBF1 plays a crucial role in early adipogenesis; however, despite high expression in mature adipocytes, its function in these cells is currently unknown. To identify direct and indirect EBF1 targets in fat, we undertook a combination of transcriptional profiling of EBF1-deficient adipocytes and genome-wide EBF1 location analysis. Our results indicate that many components of metabolic and inflammatory pathways are positively and directly regulated by EBF1, including PI3K/AKT, MAPK, and STAT1 signaling. Accordingly, we observed significant reduction of multiple signaling events in EBF1 knockdown cells as well as a reduction in insulin-stimulated glucose uptake and lipogenesis. Inflammatory signaling, gene expression, and secretion of inflammatory cytokines were also significantly affected by loss of EBF1 in adipocytes, although ChIP-sequencing results suggest that these actions are indirect. We also found that EBF1 occupies some 35,000 sites in adipocytes, most of which occur in enhancers. Significantly, comparison with three other published EBF1 ChIP-sequencing data sets in B-cells reveals both gene- and cell type-specific patterns of EBF1 binding. These results advance our understanding of the transcriptional mechanisms regulating signaling pathways in mature fat cells and indicate that EBF1 functions as a key integrator of signal transduction, inflammation, and metabolism.
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http://dx.doi.org/10.1074/jbc.M113.491936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3861642PMC
December 2013

Interferon regulatory factor 4 regulates obesity-induced inflammation through regulation of adipose tissue macrophage polarization.

Diabetes 2013 Oct 8;62(10):3394-403. Epub 2013 Jul 8.

Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Interferon regulatory factors (IRFs) play functionally diverse roles in the transcriptional regulation of the immune system. We have previously shown that several IRFs are regulators of adipogenesis and that IRF4 is a critical transcriptional regulator of adipocyte lipid handling. However, the functional role of IRF4 in adipose tissue macrophages (ATMs) remains unclear, despite high expression there. Here we show that IRF4 expression is regulated in primary macrophages and in ATMs of high-fat diet-induced obese mice. Irf4(-/-) macrophages produce higher levels of proinflammatory cytokines, including interleukin-1β and tumor necrosis factor-α, in response to fatty acids. In coculture experiments, IRF4 deletion in macrophages leads to reduced insulin signaling and glucose uptake in 3T3-L1 adipocytes. To determine the macrophage-specific function of IRF4 in the context of obesity, we generated myeloid cell-specific IRF4 knockout mice, which develop significant insulin resistance on a high-fat diet, despite no difference in adiposity. This phenotype is associated with increased expression of inflammatory genes and decreased insulin signaling in adipose tissue, skeletal muscle, and liver. Furthermore, Irf4(-/-) ATMs express markers suggestive of enhanced M1 polarization. These findings indicate that IRF4 is a negative regulator of inflammation in diet-induced obesity, in part through regulation of macrophage polarization.
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http://dx.doi.org/10.2337/db12-1327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781469PMC
October 2013

Regulation of early adipose commitment by Zfp521.

PLoS Biol 2012 27;10(11):e1001433. Epub 2012 Nov 27.

Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.

While there has been significant progress in determining the transcriptional cascade involved in terminal adipocyte differentiation, less is known about early events leading to lineage commitment and cell fate choice. It has been recently discovered that zinc finger protein 423 (Zfp423) is an early actor in adipose determination. Here, we show that a close paralog of Zfp423, Zfp521, acts as a key regulator of adipose commitment and differentiation in vitro and in vivo. Zfp521 exerts its actions by binding to early B cell factor 1 (Ebf1), a transcription factor required for the generation of adipocyte progenitors, and inhibiting the expression of Zfp423. Overexpression of Zfp521 in cells greatly inhibits adipogenic potential, whereas RNAi-mediated knock-down or genetic ablation of Zfp521 enhances differentiation. In addition, Zfp521⁻/⁻ embryos exhibit increased mass of interscapular brown adipose tissue and subcutaneous white adipocytes, a cell autonomous effect. Finally, Ebf1 participates in a negative feedback loop to repress Zfp521 as differentiation proceeds. Because Zfp521 is known to promote bone development, our results suggest that it acts as a critical switch in the commitment decision between the adipogenic and osteogenic lineages.
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http://dx.doi.org/10.1371/journal.pbio.1001433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507953PMC
April 2013

Mammalian stem cells reprogramming in response to terahertz radiation.

PLoS One 2010 Dec 31;5(12):e15806. Epub 2010 Dec 31.

Department of Medicine, Endocrinology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.

We report that extended exposure to broad-spectrum terahertz radiation results in specific changes in cellular functions that are closely related to DNA-directed gene transcription. Our gene chip survey of gene expression shows that whereas 89% of the protein coding genes in mouse stem cells do not respond to the applied terahertz radiation, certain genes are activated, while other are repressed. RT-PCR experiments with selected gene probes corresponding to transcripts in the three groups of genes detail the gene specific effect. The response was not only gene specific but also irradiation conditions dependent. Our findings suggest that the applied terahertz irradiation accelerates cell differentiation toward adipose phenotype by activating the transcription factor peroxisome proliferator-activated receptor gamma (PPARG). Finally, our molecular dynamics computer simulations indicate that the local breathing dynamics of the PPARG promoter DNA coincides with the gene specific response to the THz radiation. We propose that THz radiation is a potential tool for cellular reprogramming.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0015806PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3013123PMC
December 2010

Inhibitor of DNA binding 2 is a small molecule-inducible modulator of peroxisome proliferator-activated receptor-gamma expression and adipocyte differentiation.

Mol Endocrinol 2008 Sep 18;22(9):2038-48. Epub 2008 Jun 18.

Howard Hughes Medical Institute, University of California, Los Angeles, California 90095, USA.

We previously identified the small molecule harmine as a regulator of peroxisome proliferator activated-receptor gamma (PPARgamma) and adipocyte differentiation. In an effort to identify signaling pathways mediating harmine's effects, we performed transcriptional profiling of 3T3-F442A preadipocytes. Inhibitor of DNA biding 2 (Id2) was identified as a gene rapidly induced by harmine but not by PPARgamma agonists. Id2 is also induced in 3T3-L1 preadipocytes treated with dexamethasone, 3-isobutyl-1-methylxanthine, and insulin, suggesting that Id2 regulation is a common feature of the adipogenic program. Stable overexpression of Id2 in preadipocytes promotes expression of PPARgamma and enhances morphological differentiation and lipid accumulation. Conversely, small interfering RNA-mediated knockdown of Id2 antagonizes adipocyte differentiation. Mice lacking Id2 expression display reduced adiposity, and embryonic fibroblasts derived from these mice exhibit reduced PPARgamma expression and a diminished capacity for adipocyte differentiation. Finally, Id2 expression is elevated in adipose tissues of obese mice and humans. These results outline a role for Id2 in the modulation of PPARgamma expression and adipogenesis and underscore the utility of adipogenic small molecules as tools to dissect adipocyte biology.
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http://dx.doi.org/10.1210/me.2007-0454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2631374PMC
September 2008

Phosphorylation of CCAAT/enhancer-binding protein alpha regulates GLUT4 expression and glucose transport in adipocytes.

J Biol Chem 2008 Jun 11;283(26):18002-11. Epub 2008 Apr 11.

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109-0622, USA.

The transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha) is required during adipogenesis for development of insulin-stimulated glucose uptake. Modes for regulating this function of C/EBPalpha have yet to be determined. Phosphorylation of C/EBPalpha on Ser-21 has been implicated in the regulation of granulopoiesis and hepatic gene expression. To explore the role of Ser-21 phosphorylation on C/EBPalpha function during adipogenesis, we developed constructs in which Ser-21 was mutated to alanine (S21A) to model dephosphorylation. In two cell culture models deficient in endogenous C/EBPalpha, enforced expression of S21A-C/EBPalpha resulted in normal lipid accumulation and expression of many adipogenic markers. However, S21A-C/EBPalpha had impaired ability to activate the Glut4 promoter specifically, and S21A-C/EBPalpha expression resulted in diminished GLUT4 and adiponectin expression, as well as reduced insulin-stimulated glucose uptake. No defects in insulin signaling or GLUT4 vesicle trafficking were identified with S21A-C/EBPalpha expression, and when exogenous GLUT4 expression was enforced to normalize expression in S21A-C/EBPalpha cells, insulin-responsive glucose transport was reconstituted, suggesting that the primary defect was a deficit in GLUT4 levels. Mice in which endogenous C/EBPalpha was replaced with S21A-C/EBPalpha displayed reduced GLUT4 and adiponectin protein expression in epididymal adipose tissue and increased blood glucose compared with wild-type littermates. These results suggest that phosphorylation of C/EBPalpha on Ser-21 may regulate adipocyte gene expression and whole body glucose homeostasis.
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http://dx.doi.org/10.1074/jbc.M800419200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440616PMC
June 2008

Wnt signaling stimulates osteoblastogenesis of mesenchymal precursors by suppressing CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma.

J Biol Chem 2007 May 10;282(19):14515-24. Epub 2007 Mar 10.

Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, MI 48109-0622, USA.

Mesenchymal precursor cells have the potential to differentiate into several cell types, including adipocytes and osteoblasts. Activation of Wnt/beta-catenin signaling shifts mesenchymal cell fate toward osteoblastogenesis at the expense of adipogenesis; however, molecular mechanisms by which Wnt signaling alters mesenchymal cell fate have not been fully investigated. Our prior work indicates that multipotent precursors express adipogenic and osteoblastogenic transcription factors at physiological levels and that ectopic expression of Wnt10b in bipotential ST2 cells suppresses expression of CCAAT/enhancer-binding protein alpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma) and increases expression of Runx2, Dlx5, and osterix. Here, we demonstrate that transient activation of Wnt/beta-catenin signaling rapidly suppresses C/EBPalpha and PPARgamma, followed by activation of osteoblastogenic transcription factors. Enforced expression of C/EBPalpha or PPARgamma partially rescues lipid accumulation and decreases mineralization in ST2 cells expressing Wnt10b, suggesting that suppression of C/EBPalpha and PPARgamma is required for Wnt/beta-catenin to alter cell fate. Furthermore, knocking down expression of C/EBPalpha, PPARgamma, or both greatly reduces adipogenic potential and causes spontaneous osteoblastogenesis in ST2 cells and mouse embryonic fibroblasts, suggesting that Wnt signaling alters the fate of mesenchymal precursor cells primarily by suppressing C/EBPalpha and PPARgamma.
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http://dx.doi.org/10.1074/jbc.M700030200DOI Listing
May 2007

Wnt10b inhibits obesity in ob/ob and agouti mice.

Diabetes 2007 Feb;56(2):295-303

Department of Molecular and Integrative Physiology, University of Michigan, 1301 E. Catherine Drive, Ann Arbor, MI 48109-0622, USA.

The Wnt family of secreted signaling molecules has profound effects on diverse developmental processes, including the fate of mesenchymal progenitors. While activation of Wnt signaling blocks adipogenesis, inhibition of endogenous Wnt/beta-catenin signaling by Wnt10b promotes spontaneous preadipocyte differentiation. Transgenic mice with expression of Wnt10b from the FABP4 promoter (FABP4-Wnt10b) have less adipose tissue when maintained on a normal chow diet and are resistant to diet-induced obesity. Here we demonstrate that FABP4-Wnt10b mice largely avert weight gain and metabolic abnormalities associated with genetic obesity. FABP4-Wnt10b mice do not gain significant body weight on the ob/ob background, and at 8 weeks of age, they have an approximately 70% reduction in visceral and subcutaneous adipose tissues compared with ob/ob mice. Similarly, on the lethal yellow agouti (A(y)) background, FABP4-Wnt10b mice have 50-70% less adipose tissue weight and circulating leptin at 5 months of age. Wnt10b-Ay mice are more glucose tolerant and insulin sensitive than A(y) controls, perhaps due to reduced expression and circulation of resistin. Reduced expression of inflammatory cytokines may also contribute to improved glucose homeostasis.
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http://dx.doi.org/10.2337/db06-1339DOI Listing
February 2007

Role of Wnts in prostate cancer bone metastases.

J Cell Biochem 2006 Mar;97(4):661-72

Department of Urology, The University of Michigan, Ann Arbor, Michigan, USA.

Prostate cancer (CaP) is unique among all cancers in that when it metastasizes to bone, it typically forms osteoblastic lesions (characterized by increased bone production). CaP cells produce many factors, including Wnts that are implicated in tumor-induced osteoblastic activity. In this prospectus, we describe our research on Wnt and the CaP bone phenotype. Wnts are cysteine-rich glycoproteins that mediate bone development in the embryo and promote bone production in the adult. Wnts have been shown to have autocrine tumor effects, such as enhancing proliferation and protecting against apoptosis. In addition, we have recently identified that CaP-produced Wnts act in a paracrine fashion to induce osteoblastic activity in CaP bone metastases. In addition to Wnts, CaP cells express the soluble Wnt inhibitor dickkopf-1 (DKK-1). It appears that DKK-1 production occurs early in the development of skeletal metastases, which results in masking of osteogenic Wnts, thus favoring osteolysis at the metastatic site. As metastases progress, DKK-1 expression decreases allowing for unmasking of Wnt's osteoblastic activity and ultimately resulting in osteosclerosis at the metastatic site. We believe that DKK-1 is one of the switches that transitions the CaP bone metastasis activity from osteolytic to osteoblastic. Wnt/DKK-1 activity fits a model of CaP-induced bone remodeling occurring in a continuum composed of an osteolytic phase, mediated by receptor activator of NFkB ligand (RANKL), parathyroid hormone-related protein (PTHRP) and DKK-1; a transitional phase, where environmental alterations promote expression of osteoblastic factors (Wnts) and decreases osteolytic factors (i.e., DKK-1); and an osteoblastic phase, in which tumor growth-associated hypoxia results in production of vascular endothelial growth factor and endothelin-1, which have osteoblastic activity. This model suggests that targeting both osteolytic activity and osteoblastic activity will provide efficacy for therapy of CaP bone metastases.
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http://dx.doi.org/10.1002/jcb.20735DOI Listing
March 2006

Effects of Wnt signaling on brown adipocyte differentiation and metabolism mediated by PGC-1alpha.

Mol Cell Biol 2005 Feb;25(4):1272-82

Department of Molecular and Integrative Physiology, University of Michigan Medical School, 1301 E. Catherine Rd., Ann Arbor, MI 48109-0622, USA.

Activation of canonical Wnt signaling inhibits brown adipogenesis of cultured cells by impeding induction of PPARgamma and C/EBPalpha. Although enforced expression of these adipogenic transcription factors restores lipid accumulation and expression of FABP4 in Wnt-expressing cells, additional expression of PGC-1alpha is required for activation of uncoupling protein 1 (UCP1). Wnt10b blocks brown adipose tissue development and expression of UCP1 when expressed from the fatty acid binding protein 4 promoter, even when mice are administered a beta3-agonist. In differentiated brown adipocytes, activation of Wnt signaling suppresses expression of UCP1 through repression of PGC-1alpha. Consistent with these in vitro observations, UCP1-Wnt10b transgenic mice, which express Wnt10b in interscapular tissue, lack functional brown adipose tissue. While interscapular tissue of UCP1-Wnt10b mice lacks expression of PGC-1alpha and UCP1, the presence of unilocular lipid droplets and expression of white adipocyte genes suggest conversion of brown adipose tissue to white. Reciprocal expression of Wnt10b with UCP1 and PGC-1alpha in interscapular tissue from cold-challenged or genetically obese mice provides further evidence for regulation of brown adipocyte metabolism by Wnt signaling. Taken together, these data suggest that activation of canonical Wnt signaling early in differentiation blocks brown adipogenesis, whereas activating Wnt signaling in mature brown adipocytes stimulates their conversion to white adipocytes.
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http://dx.doi.org/10.1128/MCB.25.4.1272-1282.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC548004PMC
February 2005
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