Publications by authors named "Hei Sook Sul"

65 Publications

Aging-dependent regulatory cells emerge in subcutaneous fat to inhibit adipogenesis.

Dev Cell 2021 Apr 9. Epub 2021 Apr 9.

Department of Nutritional Sciences & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Program, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address:

Adipose tissue mass and adiposity change throughout the lifespan. During aging, while visceral adipose tissue (VAT) tends to increase, peripheral subcutaneous adipose tissue (SAT) decreases significantly. Unlike VAT, which is linked to metabolic diseases, including type 2 diabetes, SAT has beneficial effects. However, the molecular details behind the aging-associated loss of SAT remain unclear. Here, by comparing scRNA-seq of total stromal vascular cells of SAT from young and aging mice, we identify an aging-dependent regulatory cell (ARC) population that emerges only in SAT of aged mice and humans. ARCs express adipose progenitor markers but lack adipogenic capacity; they secrete high levels of pro-inflammatory chemokines, including Ccl6, to inhibit proliferation and differentiation of neighboring adipose precursors. We also found Pu.1 to be a driving factor for ARC development. We identify an ARC population and its capacity to inhibit differentiation of neighboring adipose precursors, correlating with aging-associated loss of SAT.
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http://dx.doi.org/10.1016/j.devcel.2021.03.026DOI Listing
April 2021

Signaling Pathways Regulating Thermogenesis.

Front Endocrinol (Lausanne) 2021 26;12:595020. Epub 2021 Mar 26.

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

Obesity, an excess accumulation of white adipose tissue (WAT), has become a global epidemic and is associated with complex diseases, such as type 2 diabetes and cardiovascular diseases. Presently, there are no safe and effective therapeutic agents to treat obesity. In contrast to white adipocytes that store energy as triglycerides in unilocular lipid droplet, brown and brown-like or beige adipocytes utilize fatty acids (FAs) and glucose at a high rate mainly by uncoupling protein 1 (UCP1) action to uncouple mitochondrial proton gradient from ATP synthesis, dissipating energy as heat. Recent studies on the presence of brown or brown-like adipocytes in adult humans have revealed their potential as therapeutic targets in combating obesity. Classically, the main signaling pathway known to activate thermogenesis in adipocytes is β-adrenergic signaling, which is activated by norepinephrine in response to cold, leading to activation of the thermogenic program and browning. In addition to the β-adrenergic signaling, numerous other hormones and secreted factors have been reported to affect thermogenesis. In this review, we discuss several major pathways, β-adrenergic, insulin/IGF1, thyroid hormone and TGFβ family, which regulate thermogenesis and browning of WAT.
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http://dx.doi.org/10.3389/fendo.2021.595020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034539PMC
March 2021

Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes.

Elife 2020 10 27;9. Epub 2020 Oct 27.

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

Brown adipose tissue is a metabolically beneficial organ capable of dissipating chemical energy into heat, thereby increasing energy expenditure. Here, we identify Dot1l, the only known H3K79 methyltransferase, as an interacting partner of Zc3h10 that transcriptionally activates the promoter and other BAT genes. Through a direct interaction, Dot1l is recruited by Zc3h10 to the promoter regions of thermogenic genes to function as a coactivator by methylating H3K79. We also show that Dot1l is induced during brown fat cell differentiation and by cold exposure and that Dot1l and its H3K79 methyltransferase activity is required for thermogenic gene program. Furthermore, we demonstrate that Dot1l ablation in mice using -Cre prevents activation of and other target genes to reduce thermogenic capacity and energy expenditure, promoting adiposity. Hence, Dot1l plays a critical role in the thermogenic program and may present as a future target for obesity therapeutics.
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http://dx.doi.org/10.7554/eLife.59990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661038PMC
October 2020

Epigenetic dynamics of the thermogenic gene program of adipocytes.

Biochem J 2020 03;477(6):1137-1148

Department of Nutritional Sciences and Toxicology and Endocrinology Program, University of California, Berkeley, CA 94720, U.S.A.

Brown adipose tissue (BAT) is a metabolically beneficial organ capable of burning fat by dissipating chemical energy into heat, thereby increasing energy expenditure. Moreover, subcutaneous white adipose tissue can undergo so-called browning/beiging. The recent recognition of the presence of brown or beige adipocytes in human adults has attracted much attention to elucidate the molecular mechanism underlying the thermogenic adipose program. Many key transcriptional regulators critical for the thermogenic gene program centering on activating the UCP1 promoter, have been discovered. Thermogenic gene expression in brown adipocytes rely on co-ordinated actions of a multitude of transcription factors, including EBF2, PPARγ, Zfp516 and Zc3h10. These transcription factors probably integrate into a cohesive network for BAT gene program. Moreover, these transcription factors recruit epigenetic factors, such as LSD1 and MLL3/4, for specific histone signatures to establish the favorable chromatin landscape. In this review, we discuss advances made in understanding the molecular mechanism underlying the thermogenic gene program, particularly epigenetic regulation.
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http://dx.doi.org/10.1042/BCJ20190599DOI Listing
March 2020

Epigenetic Regulation of Hepatic Lipogenesis: Role in Hepatosteatosis and Diabetes.

Diabetes 2020 04;69(4):525-531

Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, CA

Hepatosteatosis, which is frequently associated with development of metabolic syndrome and insulin resistance, manifests when triglyceride (TG) input in the liver is greater than TG output, resulting in the excess accumulation of TG. Dysregulation of lipogenesis therefore has the potential to increase lipid accumulation in the liver, leading to insulin resistance and type 2 diabetes. Recently, efforts have been made to examine the epigenetic regulation of metabolism by histone-modifying enzymes that alter chromatin accessibility for activation or repression of transcription. For regulation of lipogenic gene transcription, various known lipogenic transcription factors, such as USF1, ChREBP, and LXR, interact with and recruit specific histone modifiers, directing specificity toward lipogenesis. Alteration or impairment of the functions of these histone modifiers can lead to dysregulation of lipogenesis and thus hepatosteatosis leading to insulin resistance and type 2 diabetes.
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http://dx.doi.org/10.2337/dbi18-0032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085244PMC
April 2020

Histone demethylase JMJD1C is phosphorylated by mTOR to activate de novo lipogenesis.

Nat Commun 2020 02 7;11(1):796. Epub 2020 Feb 7.

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

Fatty acid and triglyceride synthesis increases greatly in response to feeding and insulin. This lipogenic induction involves coordinate transcriptional activation of various enzymes in lipogenic pathway, including fatty acid synthase and glycerol-3-phosphate acyltransferase. Here, we show that JMJD1C is a specific histone demethylase for lipogenic gene transcription in liver. In response to feeding/insulin, JMJD1C is phosphorylated at T505 by mTOR complex to allow direct interaction with USF-1 for recruitment to lipogenic promoter regions. Thus, by demethylating H3K9me2, JMJD1C alters chromatin accessibility to allow transcription. Consequently, JMJD1C promotes lipogenesis in vivo to increase hepatic and plasma triglyceride levels, showing its role in metabolic adaption for activation of the lipogenic program in response to feeding/insulin, and its contribution to development of hepatosteatosis resulting in insulin resistance.
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http://dx.doi.org/10.1038/s41467-020-14617-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005700PMC
February 2020

Aifm2, a NADH Oxidase, Supports Robust Glycolysis and Is Required for Cold- and Diet-Induced Thermogenesis.

Mol Cell 2020 02 14;77(3):600-617.e4. Epub 2020 Jan 14.

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

Brown adipose tissue (BAT) is highly metabolically active tissue that dissipates energy via UCP1 as heat, and BAT mass is correlated negatively with obesity. The presence of BAT/BAT-like tissue in humans renders BAT as an attractive target against obesity and insulin resistance. Here, we identify Aifm2, a NADH oxidoreductase domain containing flavoprotein, as a lipid droplet (LD)-associated protein highly enriched in BAT. Aifm2 is induced by cold as well as by diet. Upon cold or β-adrenergic stimulation, Aifm2 associates with the outer side of the mitochondrial inner membrane. As a unique BAT-specific first mammalian NDE (external NADH dehydrogenase)-like enzyme, Aifm2 oxidizes NADH to maintain high cytosolic NAD levels in supporting robust glycolysis and to transfer electrons to the electron transport chain (ETC) for fueling thermogenesis. Aifm2 in BAT and subcutaneous white adipose tissue (WAT) promotes oxygen consumption, uncoupled respiration, and heat production during cold- and diet-induced thermogenesis. Aifm2, thus, can ameliorate diet-induced obesity and insulin resistance.
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http://dx.doi.org/10.1016/j.molcel.2019.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031813PMC
February 2020

Zc3h10 Acts as a Transcription Factor and Is Phosphorylated to Activate the Thermogenic Program.

Cell Rep 2019 11;29(9):2621-2633.e4

Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Program, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address:

Brown adipose tissue harbors UCP1 to dissipate chemical energy as heat. However, the transcriptional network that governs the thermogenic gene program is incompletely understood. Zc3h10, a CCCH-type zinc finger protein, has recently been reported to bind RNA. However, we report here that Zc3h10 functions as a transcription factor to activate UCP1 not through the enhancer region, but by binding to a far upstream region of the UCP1 promoter. Upon sympathetic stimulation, Zc3h10 is phosphorylated at S126 by p38 mitogen-activated protein kinase (MAPK) to increase binding to the distal region of the UCP1 promoter. Zc3h10, as well as mutant Zc3h10, which cannot bind RNA, enhances thermogenic capacity and energy expenditure, protecting mice from diet-induced obesity. Conversely, Zc3h10 ablation in UCP1 cells in mice impairs thermogenic capacity and lowers oxygen consumption, leading to weight gain. Hence, Zc3h10 plays a critical role in the thermogenic gene program and may present future targets for obesity therapeutics.
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http://dx.doi.org/10.1016/j.celrep.2019.10.099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911170PMC
November 2019

PDGFRα stromal adipocyte progenitors transition into epithelial cells during lobulo-alveologenesis in the murine mammary gland.

Nat Commun 2019 04 15;10(1):1760. Epub 2019 Apr 15.

Princess Margaret Cancer Centre, Toronto, ON, M5G 1L7, Canada.

The mammary gland experiences substantial remodeling and regeneration during development and reproductive life, facilitated by stem cells and progenitors that act in concert with physiological stimuli. While studies have focused on deciphering regenerative cells within the parenchymal epithelium, cell lineages in the stroma that may directly contribute to epithelial biology is unknown. Here we identify, in mouse, the transition of a PDGFRα mesenchymal cell population into mammary epithelial progenitors. In addition to being adipocyte progenitors, PDGFRα cells make a de novo contribution to luminal and basal epithelia during mammary morphogenesis. In the adult, this mesenchymal lineage primarily generates luminal progenitors within lobuloalveoli during sex hormone exposure or pregnancy. We identify cell migration as a key molecular event that is activated in mesenchymal progenitors in response to epithelium-derived chemoattractant. These findings demonstrate a stromal reservoir of epithelial progenitors and provide insight into cell origins and plasticity during mammary tissue growth.
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http://dx.doi.org/10.1038/s41467-019-09748-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465250PMC
April 2019

Sox9-Meis1 Inactivation Is Required for Adipogenesis, Advancing Pref-1 to PDGFRα Cells.

Cell Rep 2018 10;25(4):1002-1017.e4

Endocrinology Program, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address:

Adipocytes arise from the commitment and differentiation of adipose precursors in white adipose tissue (WAT). In studying adipogenesis, precursor markers, including Pref-1 and PDGFRα, are used to isolate precursors from stromal vascular fractions of WAT, but the relation among the markers is not known. Here, we used the Pref-1 promoter-rtTA system in mice for labeling Pref-1 cells and for inducible inactivation of the Pref-1 target Sox9. We show the requirement of Sox9 for the maintenance of Pref-1 proliferative, early precursors. Upon Sox9 inactivation, these Pref-1 cells become PDGFRα cells that express early adipogenic markers. Thus, we show that Pref-1 cells precede PDGFRα cells in the adipogenic pathway and that Sox9 inactivation is required for WAT growth and expansion. Furthermore, we show that in maintaining early adipose precursors, Sox9 activates Meis1, which prevents adipogenic differentiation. Our study also demonstrates the Pref-1 promoter-rtTA system for inducible gene inactivation in early adipose precursor populations.
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http://dx.doi.org/10.1016/j.celrep.2018.09.086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903418PMC
October 2018

Genetic and epigenetic control of adipose development.

Biochim Biophys Acta Mol Cell Biol Lipids 2019 01 25;1864(1):3-12. Epub 2018 Apr 25.

Endocrinology Program, University of California, Berkeley, CA 94720, USA; Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94720, USA. Electronic address:

White adipose tissue (WAT) is the primary energy storage organ and its excess contributes to obesity, while brown adipose tissue (BAT) and inducible thermogenic (beige/brite) adipocytes in WAT dissipate energy via Ucp1 to maintain body temperature. BAT and subcutaneous WAT develop perinatally while visceral WAT forms after birth from precursors expressing distinct markers, such as Myf5, Pref-1, Wt1, and Prx1, depending on the anatomical location. In addition to the embryonic adipose precursors, a pool of endothelial cells or mural cells expressing Pparγ, Pdgfrβ, Sma and Zfp423 may become adipocytes during WAT expansion in adults. Several markers, such as Cd29, Cd34, Sca1, Cd24, Pdgfrα and Pref-1 are detected in adult WAT SVF cells that can be differentiated into adipocytes. However, potential heterogeneity and differences in developmental stage of these cells are not clear. Beige cells form in a depot- and condition-specific manner by de novo differentiation of precursors or by transdifferentiation. Thermogenic gene activation in brown and beige adipocytes relies on common transcriptional machinery that includes Prdm16, Zfp516, Pgc1α and Ebf2. Moreover, through changing the chromatin landscape, histone methyltransferases, such as Mll3/4 and Ehmt1, as well as demethylases, such as Lsd1, play an important role in regulating the thermogenic gene program. With the presence of BAT and beige/brite cells in human adults, increasing thermogenic activity of BAT and BAT-like tissues may help promote energy expenditure to combat obesity.
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http://dx.doi.org/10.1016/j.bbalip.2018.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203673PMC
January 2019

Actomyosin-Mediated Tension Orchestrates Uncoupled Respiration in Adipose Tissues.

Cell Metab 2018 03;27(3):602-615.e4

Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address:

The activation of brown/beige adipose tissue (BAT) metabolism and the induction of uncoupling protein 1 (UCP1) expression are essential for BAT-based strategies to improve metabolic homeostasis. Here, we demonstrate that BAT utilizes actomyosin machinery to generate tensional responses following adrenergic stimulation, similar to muscle tissues. The activation of actomyosin mechanics is critical for the acute induction of oxidative metabolism and uncoupled respiration in UCP1 adipocytes. Moreover, we show that actomyosin-mediated elasticity regulates the thermogenic capacity of adipocytes via the mechanosensitive transcriptional co-activators YAP and TAZ, which are indispensable for normal BAT function. These biomechanical signaling mechanisms may inform future strategies to promote the expansion and activation of brown/beige adipocytes.
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http://dx.doi.org/10.1016/j.cmet.2018.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897043PMC
March 2018

Targeting lipogenesis in the treatment of metabolic diseases and cancer.

Oncotarget 2018 Jan 6;9(3):2969-2970. Epub 2017 Dec 6.

Hei Sook Sul: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA.

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http://dx.doi.org/10.18632/oncotarget.23004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790437PMC
January 2018

Transcriptional activation of lipogenesis by insulin requires phosphorylation of MED17 by CK2.

Sci Signal 2017 02 21;10(467). Epub 2017 Feb 21.

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

De novo lipogenesis is precisely regulated by nutritional and hormonal conditions. The genes encoding various enzymes involved in this process, such as fatty acid synthase (FASN), are transcriptionally activated in response to insulin. We showed that USF1, a key transcription factor for activation, directly interacted with the Mediator subunit MED17 at the promoter. This interaction recruited Mediator, which can bring POL II and other general transcription machinery to the complex. Moreover, we showed that MED17 was phosphorylated at Ser by casein kinase 2 (CK2) in the livers of fed mice or insulin-stimulated hepatocytes, but not in the livers of fasted mice or untreated hepatocytes. Furthermore, activation of the promoter in response to insulin required this CK2-mediated phosphorylation event, which occurred only in the absence of p38 MAPK-mediated phosphorylation at Thr Overexpression of a nonphosphorylatable S53A MED17 mutant or knockdown of MED17, as well as CK2 knockdown or inhibition, impaired hepatic de novo fatty acid synthesis and decreased triglyceride content in mice. These results demonstrate that CK2-mediated phosphorylation of Ser in MED17 is required for the transcriptional activation of lipogenic genes in response to insulin.
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http://dx.doi.org/10.1126/scisignal.aai8596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376069PMC
February 2017

Epigenetic Regulation of the Thermogenic Adipose Program.

Trends Endocrinol Metab 2017 01 28;28(1):19-31. Epub 2016 Sep 28.

Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Program, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address:

In contrast to white adipose tissue (WAT), which stores energy in the form of triglycerides, brown adipose tissue (BAT) dissipates energy by producing heat to maintain body temperature by burning glucose and fatty acids in a process called adaptive thermogenesis. The presence of an inducible thermogenic adipose tissue, and its beneficial effects for maintaining body weight and glucose and lipid homeostasis, has raised intense interest in understanding the regulation of thermogenesis. Elucidating the regulatory mechanisms underlying the thermogenic adipose program may provide excellent targets for therapeutics against obesity and diabetes. Here we review recent research on the role of epigenetics in the thermogenic gene program, focusing on DNA methylation and histone modifications.
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http://dx.doi.org/10.1016/j.tem.2016.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5183481PMC
January 2017

LSD1 Interacts with Zfp516 to Promote UCP1 Transcription and Brown Fat Program.

Cell Rep 2016 06 2;15(11):2536-49. Epub 2016 Jun 2.

Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Program, University of California, Berkeley, Berkeley, CA 94720, USA; Comparative Biochemistry Program, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address:

Zfp516, a brown fat (BAT)-enriched and cold-inducible transcription factor, promotes transcription of UCP1 and other BAT-enriched genes for non-shivering thermogenesis. Here, we identify lysine-specific demethylase 1 (LSD1) as a direct binding partner of Zfp516. We show that, through interaction with Zfp516, LSD1 is recruited to UCP1 and other BAT-enriched genes, such as PGC1α, to function as a coactivator by demethylating H3K9. We also show that LSD1 is induced during brown adipogenesis and that LSD1 and its demethylase activity is required for the BAT program. Furthermore, we show that LSD1 ablation in mice using Myf5-Cre alters embryonic BAT development. Moreover, BAT-specific deletion of LSD1 via the use of UCP1-Cre impairs the BAT program and BAT development, making BAT resemble WAT, reducing thermogenic activity and promoting obesity. Finally, we demonstrate an in vivo requirement of the Zfp516-LSD1 interaction for LSD1 function in BAT gene activation.
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http://dx.doi.org/10.1016/j.celrep.2016.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916264PMC
June 2016

AMPK Phosphorylates Desnutrin/ATGL and Hormone-Sensitive Lipase To Regulate Lipolysis and Fatty Acid Oxidation within Adipose Tissue.

Mol Cell Biol 2016 07 29;36(14):1961-76. Epub 2016 Jun 29.

Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA Endocrinology Program, University of California, Berkeley, California, USA

The role of AMP-activated protein kinase (AMPK) in promoting fatty acid (FA) oxidation in various tissues, such as liver and muscle, has been well understood. However, the role of AMPK in lipolysis and FA metabolism in adipose tissue has been controversial. To investigate the role of AMPK in the regulation of adipose lipolysis in vivo, we generated mice with adipose-tissue-specific knockout of both the α1 and α2 catalytic subunits of AMPK (AMPK-ASKO mice) by using aP2-Cre and adiponectin-Cre. Both models of AMPK-ASKO ablation show no changes in desnutrin/ATGL levels but have defective phosphorylation of desnutrin/ATGL at S406 to decrease its triacylglycerol (TAG) hydrolase activity, lowering basal lipolysis in adipose tissue. These mice also show defective phosphorylation of hormone-sensitive lipase (HSL) at S565, with higher phosphorylation at protein kinase A sites S563 and S660, increasing its hydrolase activity and isoproterenol-stimulated lipolysis. With higher overall adipose lipolysis, both models of AMPK-ASKO mice are lean, having smaller adipocytes with lower TAG and higher intracellular free-FA levels. Moreover, FAs from higher lipolysis activate peroxisome proliferator-activated receptor delta to induce FA oxidative genes and increase FA oxidation and energy expenditure. Overall, for the first time, we provide in vivo evidence of the role of AMPK in the phosphorylation and regulation of desnutrin/ATGL and HSL and thus adipose lipolysis.
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http://dx.doi.org/10.1128/MCB.00244-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936063PMC
July 2016

Preadipocyte factor 1 induces pancreatic ductal cell differentiation into insulin-producing cells.

Sci Rep 2016 Apr 5;6:23960. Epub 2016 Apr 5.

Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.

The preadipocyte factor 1 (Pref-1) is involved in the proliferation and differentiation of various precursor cells. However, the intracellular signaling pathways that control these processes and the role of Pref-1 in the pancreas remain poorly understood. Here, we showed that Pref-1 induces insulin synthesis and secretion via two independent pathways. The overexpression of Pref-1 activated MAPK signaling, which induced nucleocytoplasmic translocation of FOXO1 and PDX1 and led to the differentiation of human pancreatic ductal cells into β-like cells and an increase in insulin synthesis. Concurrently, Pref-1 activated Akt signaling and facilitated insulin secretion. A proteomics analysis identified the Rab43 GTPase-activating protein as a downstream target of Akt. A serial activation of both proteins induced various granular protein syntheses which led to enhanced glucose-stimulated insulin secretion. In a pancreatectomised diabetic animal model, exogenous Pref-1 improved glucose homeostasis by accelerating pancreatic ductal and β-cell regeneration after injury. These data establish a novel role for Pref-1, opening the possibility of applying this molecule to the treatment of diabetes.
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http://dx.doi.org/10.1038/srep23960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820710PMC
April 2016

Transcriptional regulation of hepatic lipogenesis.

Nat Rev Mol Cell Biol 2015 Nov;16(11):678-89

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

Fatty acid and fat synthesis in the liver is a highly regulated metabolic pathway that is important for very low-density lipoprotein (VLDL) production and thus energy distribution to other tissues. Having common features at their promoter regions, lipogenic genes are coordinately regulated at the transcriptional level. Transcription factors, such as upstream stimulatory factors (USFs), sterol regulatory element-binding protein 1C (SREBP1C), liver X receptors (LXRs) and carbohydrate-responsive element-binding protein (ChREBP) have crucial roles in this process. Recently, insights have been gained into the signalling pathways that regulate these transcription factors. After feeding, high blood glucose and insulin levels activate lipogenic genes through several pathways, including the DNA-dependent protein kinase (DNA-PK), atypical protein kinase C (aPKC) and AKT-mTOR pathways. These pathways control the post-translational modifications of transcription factors and co-regulators, such as phosphorylation, acetylation or ubiquitylation, that affect their function, stability and/or localization. Dysregulation of lipogenesis can contribute to hepatosteatosis, which is associated with obesity and insulin resistance.
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http://dx.doi.org/10.1038/nrm4074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884795PMC
November 2015

Shades of brown: a model for thermogenic fat.

Front Endocrinol (Lausanne) 2015 8;6:71. Epub 2015 May 8.

Comparative Biochemistry Program, Department of Nutritional Science and Toxicology, University of California Berkeley , Berkeley, CA , USA.

Brown adipose tissue (BAT) is specialized to burn fuels to perform thermogenesis in defense of body temperature against cold. Recent discovery of metabolically active and relevant amounts of BAT in adult humans have made it a potentially attractive target for development of anti-obesity therapeutics. There are two types of brown adipocytes: classical brown adipocytes and brown adipocyte-like cells, so-called beige/brite cells, which arise in white adipose tissue in response to cold and hormonal stimuli. These cells may derive from distinct origins, and while functionally similar, have different gene signatures. Here, we highlight recent advances in the understanding of brown and beige/brite adipocytes as well as transcriptional regulation for development and function of murine brown and beige/brite adipocytes focusing on EBF2, IRF4, and ZFP516, in addition to PRDM16 as a coregulator. We also discuss hormonal regulation of brown and beige/brite adipocytes including several factors secreted from various tissues, including BMP7, FGF21, and irisin, as well as those from BAT itself, such as Nrg4 and adenosine.
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http://dx.doi.org/10.3389/fendo.2015.00071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424901PMC
May 2015

Overexpression of Pref-1 in pancreatic islet β-cells in mice causes hyperinsulinemia with increased islet mass and insulin secretion.

Biochem Biophys Res Commun 2015 Jun 24;461(4):630-5. Epub 2015 Apr 24.

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

Preadipocyte factor-1 (Pref-1) is made as a transmembrane protein containing EGF-repeats at the extracellular domain that can be cleaved to generate a biologically active soluble form. Pref-1 is found in islet β-cells and its level has been reported to increase in neonatal rat islets upon growth hormone treatment. We found here that Pref-1 can promote growth of pancreatic tumor derived AR42J cells. To examine Pref-1 function in pancreatic islets in vivo, we generated transgenic mouse lines overexpressing the Pref-1/hFc in islet β-cells using rat insulin II promoter (RIP). These transgenic mice exhibit an increase in islet mass with higher proportion of larger islets in pancreas compared to wild-type littermates. This is in contrast to pancreas from Pref-1 null mice that show higher proportion of smaller islets. Insulin expression and insulin secretion from pancreatic islets from RIP-Pref-1/hFc transgenic mice are increased also. Thus, RIP-Pref-1/hFc transgenic mice show normal glucose levels but with higher plasma insulin levels in both fasting and fed conditions. These mice show improved glucose tolerance. Taken together, we conclude Pref-1 as a positive regulator of islet β-cells and insulin production.
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http://dx.doi.org/10.1016/j.bbrc.2015.04.078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439292PMC
June 2015

Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes.

Cell 2015 Feb 5;160(4):745-758. Epub 2015 Feb 5.

Howard Hughes Medical Institute, Yale University, New Haven, CT 06519, USA; Department of Internal Medicine, Yale University, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA. Electronic address:

Impaired insulin-mediated suppression of hepatic glucose production (HGP) plays a major role in the pathogenesis of type 2 diabetes (T2D), yet the molecular mechanism by which this occurs remains unknown. Using a novel in vivo metabolomics approach, we show that the major mechanism by which insulin suppresses HGP is through reductions in hepatic acetyl CoA by suppression of lipolysis in white adipose tissue (WAT) leading to reductions in pyruvate carboxylase flux. This mechanism was confirmed in mice and rats with genetic ablation of insulin signaling and mice lacking adipose triglyceride lipase. Insulin's ability to suppress hepatic acetyl CoA, PC activity, and lipolysis was lost in high-fat-fed rats, a phenomenon reversible by IL-6 neutralization and inducible by IL-6 infusion. Taken together, these data identify WAT-derived hepatic acetyl CoA as the main regulator of HGP by insulin and link it to inflammation-induced hepatic insulin resistance associated with obesity and T2D.
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http://dx.doi.org/10.1016/j.cell.2015.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498261PMC
February 2015

Cold-inducible Zfp516 activates UCP1 transcription to promote browning of white fat and development of brown fat.

Mol Cell 2015 Jan 8;57(2):235-46. Epub 2015 Jan 8.

Department of Nutritional Science & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Comparative Biochemistry Program, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Program, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address:

Uncoupling protein 1 (UCP1) mediates nonshivering thermogenesis and, upon cold exposure, is induced in brown adipose tissue (BAT) and subcutaneous white adipose tissue (iWAT). Here, by high-throughput screening using the UCP1 promoter, we identify Zfp516 as a transcriptional activator of UCP1 as well as PGC1α, thereby promoting a BAT program. Zfp516 itself is induced by cold and sympathetic stimulation through the cAMP-CREB/ATF2 pathway. Zfp516 directly binds to the proximal region of the UCP1 promoter, not to the enhancer region where other transcription factors bind, and interacts with PRDM16 to activate the UCP1 promoter. Although ablation of Zfp516 causes embryonic lethality, knockout embryos still show drastically reduced BAT mass. Overexpression of Zfp516 in adipose tissue promotes browning of iWAT even at room temperature, increasing body temperature and energy expenditure and preventing diet-induced obesity. Zfp516 may represent a future target for obesity therapeutics.
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http://dx.doi.org/10.1016/j.molcel.2014.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304950PMC
January 2015

Pref-1 marks very early mesenchymal precursors required for adipose tissue development and expansion.

Cell Rep 2014 Aug 31;8(3):678-87. Epub 2014 Jul 31.

Department of Nutritional Sciences & Toxicology, 119 Morgan Hall, University of California, Berkeley, CA 94720, USA; Endocrinology Program, 299 LSA, University of California, Berkeley, CA 94720, USA. Electronic address:

Pref-1 is an EGF-repeat-containing protein that inhibits adipocyte differentiation. To better understand the origin and development of white adipose tissue (WAT), we generated transgenic mouse models for transient or permanent fluorescent labeling of cells using the Pref-1 promoter, facilitating inducible ablation. We show that Pref-1-marked cells retain proliferative capacity and are very early adipose precursors, prior to expression of Zfp423 or PPARγ. In addition, the Pref-1-marked cells establish that adipose precursors are mesenchymal, but not endothelial or pericytal, in origin. During embryogenesis, Pref-1-marked cells first appear in the dorsal mesenteric region as early as embryonic day 10.5 (E10.5). These cells become lipid-laden adipocytes at E17.5 in the subcutaneous region, whereas visceral WAT develops after birth. Finally, ablation of Pref-1-marked cells prevents not only embryonic WAT development but also later adult adipose expansion upon high-fat feeding, demonstrating the requirement of Pref-1 cells for adipogenesis.
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http://dx.doi.org/10.1016/j.celrep.2014.06.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138044PMC
August 2014

Desnutrin/ATGL activates PPARδ to promote mitochondrial function for insulin secretion in islet β cells.

Cell Metab 2013 Dec 21;18(6):883-95. Epub 2013 Nov 21.

Endocrinology Program, University of California, Berkeley, Berkeley, CA 94720, USA.

Excessive caloric intake leading to obesity is associated with insulin resistance and dysfunction of islet β cells. High-fat feeding decreases desnutrin (also called ATGL/PNPLA2) levels in islets. Here we show that desnutrin ablation via RIP-Cre (βKO) or RIP-CreER results in hyperglycemia with impaired glucose-stimulated insulin secretion (GSIS). Due to decreased lipolysis, islets have higher TAG content but lower free FA levels. βKO islets exhibit impaired mitochondrial respiration and lower production of ATP required for GSIS, along with decreased expression of PPARδ target genes involved in mitochondrial oxidation. Furthermore, synthetic PPARδ, but not PPARα, agonist restores GSIS and expression of mitochondrial oxidative genes in βKO mice, revealing that desnutrin-catalyzed lipolysis generates PPARδ ligands. Finally, adenoviral expression of desnutrin in βKO islets restores all defects of βKO islet phenotype and function, including GSIS and mitochondrial defects, demonstrating the critical role of the desnutrin-PPARδ-mitochondrial oxidation axis in regulating islet β cell GSIS.
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http://dx.doi.org/10.1016/j.cmet.2013.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871209PMC
December 2013

Pref-1, a gatekeeper of adipogenesis.

Front Endocrinol (Lausanne) 2013 3;4:79. Epub 2013 Jul 3.

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

Preadipocyte factor 1 (Pref-1, also called Dlk1/FA1) is a molecular gatekeeper of adipogenesis which acts by maintaining the preadipocyte state and preventing adipocyte differentiation. Pref-1 is made as an epidermal growth factor-like repeat containing transmembrane protein, and is cleaved by TNFα-converting enzyme (TACE) to generate a soluble form, which acts as an autocrine/paracrine factor. Pref-1 upregulates Sox9 expression by activating the ERK/MAPK pathway and the Pref-1 interaction with fibronectin is required for inhibition of adipogenesis. Pref-1 also prevents brown adipocyte differentiation and its thermogenic function. Here, we highlight the recent evidence for the role of Pref-1 in adipogenesis.
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http://dx.doi.org/10.3389/fendo.2013.00079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699714PMC
July 2013

Phosphorylation and recruitment of BAF60c in chromatin remodeling for lipogenesis in response to insulin.

Mol Cell 2013 Jan 6;49(2):283-97. Epub 2012 Dec 6.

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

Fatty acid and triglyceride synthesis is induced in response to feeding and insulin. This lipogenic induction involves coordinate transcriptional activation of lipogenic enzymes, including fatty acid synthase and glycerol-3-phosphate acyltransferase. We recently reported the importance of USF-1 phosphorylation and subsequent acetylation in insulin-induced lipogenic gene activation. Here, we show that Brg1/Brm-associated factor (BAF) 60c is a specific chromatin remodeling component for lipogenic gene transcription in liver. In response to insulin, BAF60c is phosphorylated at S247 by atypical PKCζ/λ, which causes translocation of BAF60c to the nucleus and allows a direct interaction of BAF60c with USF-1 that is phosphorylated by DNA-PK and acetylated by P/CAF. Thus, BAF60c is recruited to form the lipoBAF complex to remodel chromatin structure and to activate lipogenic genes. Consequently, BAF60c promotes lipogenesis in vivo and increases triglyceride levels, demonstrating its role in metabolic adaption to activate the lipogenic program in response to feeding and insulin.
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http://dx.doi.org/10.1016/j.molcel.2012.10.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3786575PMC
January 2013

Pref-1 in brown adipose tissue: specific involvement in brown adipocyte differentiation and regulatory role of C/EBPδ.

Biochem J 2012 May;443(3):799-810

Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB) and CIBER Fisiopatologia de la Obesidad y Nutrición (CIBEROBN), 08028 Barcelona, Spain.

Pref-1 (pre-adipocyte factor-1) is known to play a central role in regulating white adipocyte differentiation, but the role of Pref-1 in BAT (brown adipose tissue) has not been analysed. In the present study we found that Pref-1 expression is high in fetal BAT and declines progressively after birth. However, Pref-1-null mice showed unaltered fetal development of BAT, but exhibited signs of over-activation of BAT thermogenesis in the post-natal period. In C/EBP (CCAAT/enhancer-binding protein) α-null mice, a rodent model of impaired fetal BAT differentiation, Pref-1 was dramatically overexpressed, in association with reduced expression of the Ucp1 (uncoupling protein 1) gene, a BAT-specific marker of thermogenic differentiation. In brown adipocyte cell culture models, Pref-1 was mostly expressed in pre-adipocytes and declined with brown adipocyte differentiation. The transcription factor C/EBPδ activated the Pref-1 gene transcription in brown adipocytes, through binding to the proximal promoter region. Accordingly, siRNA (small interfering RNA)-induced C/EBPδ knockdown led to reduced Pref-1 gene expression. This effect is consistent with the observed overexpression of C/EBPδ in C/EBPα-null BAT and high expression of C/EBPδ in brown pre-adipocytes. Dexamethasone treatment of brown pre-adipocytes suppressed Pref-1 down-regulation occurring throughout the brown adipocyte differentiation process, increased the expression of C/EBPδ and strongly impaired expression of the thermogenic markers UCP1 and PGC-1α [PPARγ (peroxisome-proliferator-activated receptor γ) co-activator-α]. However, it did not alter normal fat accumulation or expression of non-BAT-specific genes. Collectively, these results specifically implicate Pref-1 in controlling the thermogenic gene expression program in BAT, and identify C/EBPδ as a novel transcriptional regulator of Pref-1 gene expression that may be related to the specific role of glucocorticoids in BAT differentiation.
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http://dx.doi.org/10.1042/BJ20111714DOI Listing
May 2012

Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype.

Cell Metab 2011 Jun;13(6):739-48

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

While fatty acids (FAs) released by white adipose tissue (WAT) provide energy for other organs, lipolysis is also critical in brown adipose tissue (BAT), generating FAs for oxidation and UCP-1 activation for thermogenesis. Here we show that adipose-specific ablation of desnutrin/ATGL in mice converts BAT to a WAT-like tissue. These mice exhibit severely impaired thermogenesis with increased expression of WAT-enriched genes but decreased BAT genes, including UCP-1 with lower PPARα binding to its promoter, revealing the requirement of desnutrin-catalyzed lipolysis for maintaining a BAT phenotype. We also show that desnutrin is phosphorylated by AMPK at S406, increasing TAG hydrolase activity, and provide evidence for increased lipolysis by AMPK phosphorylation of desnutrin in adipocytes and in vivo. Despite adiposity and impaired BAT function, desnutrin-ASKO mice have improved hepatic insulin sensitivity with lower DAG levels. Overall, desnutrin is phosphorylated/activated by AMPK to increase lipolysis and brings FA oxidation and UCP-1 induction for thermogenesis.
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http://dx.doi.org/10.1016/j.cmet.2011.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148136PMC
June 2011

Insulin signaling in fatty acid and fat synthesis: a transcriptional perspective.

Curr Opin Pharmacol 2010 Dec;10(6):684-91

Department of Nutritional Science and Toxicology, and Comparative Biochemistry Program, University of California, Berkeley, CA 94720, USA.

Transcription of enzymes involved in FA and TAG synthesis is coordinately induced in lipogenic tissues by feeding and insulin treatment. The three major transcription factors involved are USF, SREBP-1c, and LXRα. New insights into the insulin-signaling pathway(s) that control(s) lipogenic gene transcription via these factors have recently been revealed. Dephosphorylation/activation of DNA-PK by PP1 causes phosphorylation of USF that in turn recruits P/CAF to be acetylated for transcriptional activation. SREBP-1c can be induced by mTORC1, bifurcating lipogenesis from AKT-activated gluconeogenesis. LXRα may serve as a glucose sensor and, along with ChREBP, may activate lipogenic genes in the fed state. Dysregulation of FA and TAG metabolism often contributes to metabolic diseases such as obesity, diabetes, and cardiovascular diseases. Transcription factors and signaling molecules involved in transcriptional activation of FA and TAG synthesis represent attractive targets for the prevention and treatment of metabolic diseases.
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http://dx.doi.org/10.1016/j.coph.2010.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092640PMC
December 2010