Publications by authors named "Yun Sok Lee"

38 Publications

Chronic tissue inflammation and metabolic disease.

Genes Dev 2021 Mar;35(5-6):307-328

Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, California 92093, USA.

Obesity is the most common cause of insulin resistance, and the current obesity epidemic is driving a parallel rise in the incidence of T2DM. It is now widely recognized that chronic, subacute tissue inflammation is a major etiologic component of the pathogenesis of insulin resistance and metabolic dysfunction in obesity. Here, we summarize recent advances in our understanding of immunometabolism. We discuss the characteristics of chronic inflammation in the major metabolic tissues and how obesity triggers these events, including a focus on the role of adipose tissue hypoxia and macrophage-derived exosomes. Last, we also review current and potential new therapeutic strategies based on immunomodulation.
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http://dx.doi.org/10.1101/gad.346312.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919414PMC
March 2021

Inhibition of prolyl hydroxylases increases hepatic insulin and decreases glucagon sensitivity by an HIF-2α-dependent mechanism.

Mol Metab 2020 11 11;41:101039. Epub 2020 Jun 11.

Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address:

Objective: Recent evidence indicates that inhibition of prolyl hydroxylase domain (PHD) proteins can exert beneficial effects to improve metabolic abnormalities in mice and humans. However, the underlying mechanisms are not clearly understood. This study was designed to address this question.

Methods: A pan-PHD inhibitor compound was injected into WT and liver-specific hypoxia-inducible factor (HIF)-2α KO mice, after onset of obesity and glucose intolerance, and changes in glucose and glucagon tolerance were measured. Tissue-specific changes in basal glucose flux and insulin sensitivity were also measured by hyperinsulinemic euglycemic clamp studies. Molecular and cellular mechanisms were assessed in normal and type 2 diabetic human hepatocytes, as well as in mouse hepatocytes.

Results: Administration of a PHD inhibitor compound (PHDi) after the onset of obesity and insulin resistance improved glycemic control by increasing insulin and decreasing glucagon sensitivity in mice, independent of body weight change. Hyperinsulinemic euglycemic clamp studies revealed that these effects of PHDi treatment were mainly due to decreased basal hepatic glucose output and increased liver insulin sensitivity. Hepatocyte-specific deletion of HIF-2α markedly attenuated these effects of PHDi treatment, showing PHDi effects are HIF-2α dependent. At the molecular level, HIF-2α induced increased Irs2 and cyclic AMP-specific phosphodiesterase gene expression, leading to increased and decreased insulin and glucagon signaling, respectively. These effects of PHDi treatment were conserved in human and mouse hepatocytes.

Conclusions: Our results elucidate unknown mechanisms for how PHD inhibition improves glycemic control through HIF-2α-dependent regulation of hepatic insulin and glucagon sensitivity.
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http://dx.doi.org/10.1016/j.molmet.2020.101039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393408PMC
November 2020

The role of macrophages in obesity-associated islet inflammation and β-cell abnormalities.

Nat Rev Endocrinol 2020 02 13;16(2):81-90. Epub 2019 Dec 13.

Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA, USA.

Chronic, unresolved tissue inflammation is a well-described feature of obesity, type 2 diabetes mellitus (T2DM) and other insulin-resistant states. In this context, adipose tissue and liver inflammation have been particularly well studied; however, abundant evidence demonstrates that inflammatory processes are also activated in pancreatic islets from obese animals and humans with obesity and/or T2DM. In this Review, we focus on the characteristics of immune cell-mediated inflammation in islets and the consequences of this with respect to β-cell function. In contrast to type 1 diabetes mellitus, the dominant immune cell type causing inflammation in obese and T2DM islets is the macrophage. The increased macrophage accumulation in T2DM islets primarily arises through local proliferation of resident macrophages, which then provide signals (such as platelet-derived growth factor) that drive β-cell hyperplasia (a classic feature of obesity). In addition, islet macrophages also impair the insulin secretory capacity of β-cells. Through these mechanisms, islet-resident macrophages underlie the inflammatory response in obesity and mechanistically participate in the β-cell hyperplasia and dysfunction that characterizes this insulin-resistant state. These findings point to the possibility of therapeutics that target islet inflammation to elicit beneficial effects on β-cell function and glycaemia.
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http://dx.doi.org/10.1038/s41574-019-0286-3DOI Listing
February 2020

TAZ Is a Negative Regulator of PPARγ Activity in Adipocytes and TAZ Deletion Improves Insulin Sensitivity and Glucose Tolerance.

Cell Metab 2020 01 7;31(1):162-173.e5. Epub 2019 Nov 7.

Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address:

Insulin resistance is a major factor in obesity-linked type 2 diabetes. PPARγ is a master regulator of adipogenesis, and small molecule agonists, termed thiazolidinediones, are potent therapeutic insulin sensitizers. Here, we studied the role of transcriptional co-activator with PDZ-binding motif (TAZ) as a transcriptional co-repressor of PPARγ. We found that adipocyte-specific TAZ knockout (TAZ AKO) mice demonstrate a constitutively active PPARγ state. Obese TAZ AKO mice show improved glucose tolerance and insulin sensitivity compared to littermate controls. PPARγ response genes are upregulated in adipose tissue from TAZ AKO mice and adipose tissue inflammation was also decreased. In vitro and in vivo mechanistic studies revealed that the TAZ-PPARγ interaction is partially dependent on ERK-mediated Ser112 PPARγ phosphorylation. As adipocyte PPARγ Ser112 phosphorylation is increased in obesity, repression of PPARγ activity by TAZ could contribute to insulin resistance. These results identify TAZ as a new factor in the development of obesity-induced insulin resistance.
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http://dx.doi.org/10.1016/j.cmet.2019.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784082PMC
January 2020

Adipocyte PU.1 knockout promotes insulin sensitivity in HFD-fed obese mice.

Sci Rep 2019 10 14;9(1):14779. Epub 2019 Oct 14.

Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.

Insulin resistance is a key feature of obesity and type 2 diabetes. PU.1 is a master transcription factor predominantly expressed in macrophages but after HFD feeding PU.1 expression is also significantly increased in adipocytes. We generated adipocyte specific PU.1 knockout mice using adiponectin cre to investigate the role of PU.1 in adipocyte biology, insulin and glucose homeostasis. In HFD-fed obese mice systemic glucose tolerance and insulin sensitivity were improved in PU.1 AKO mice and clamp studies indicated improvements in both adipose and liver insulin sensitivity. At the level of adipose tissue, macrophage infiltration and inflammation was decreased and glucose uptake was increased in PU.1 AKO mice compared with controls. While PU.1 deletion in adipocytes did not affect the gene expression of PPARg itself, we observed increased expression of PPARg target genes in eWAT from HFD fed PU.1 AKO mice compared with controls. Furthermore, we observed decreased phosphorylation at serine 273 in PU.1 AKO mice compared with fl/fl controls, indicating that PPARg is more active when PU.1 expression is reduced in adipocytes. Therefore, in obesity the increased expression of PU.1 in adipocytes modifies the adipocyte PPARg cistrome resulting in impaired glucose tolerance and insulin sensitivity.
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http://dx.doi.org/10.1038/s41598-019-51196-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791934PMC
October 2019

Knockdown of Reduces Adipocyte Hypoxia And Improves Insulin Resistance in Obesity.

Nat Metab 2019 01 19;1(1):86-97. Epub 2018 Nov 19.

Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA 92093, USA.

Decreased adipose tissue oxygen tension and increased HIF-1α expression can trigger adipose tissue inflammation and dysfunction in obesity. Our current understanding of obesity-associated decreased adipose tissue oxygen tension is mainly focused on changes in oxygen supply and angiogenesis. Here, we demonstrate that increased adipocyte O demand, mediated by ANT2 activity, is the dominant cause of adipocyte hypoxia. Deletion of adipocyte improves obesity-induced intracellular adipocyte hypoxia by decreasing obesity-induced adipocyte oxygen demand, without effects on mitochondrial number or mass, or oligomycin-sensitive respiration. This led to decreased adipose tissue HIF-1α expression and inflammation with improved glucose tolerance and insulin resistance in both a preventative or therapeutic setting. Our results suggest that ANT2 may be a target for the development of insulin sensitizing drugs and that ANT2 inhibition might have clinical utility.
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http://dx.doi.org/10.1038/s42255-018-0003-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746433PMC
January 2019

Hepatocyte-specific HIF-1α ablation improves obesity-induced glucose intolerance by reducing first-pass GLP-1 degradation.

Sci Adv 2019 07 3;5(7):eaaw4176. Epub 2019 Jul 3.

Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.

The decrease in incretin effects is an important etiologic component of type 2 diabetes with unknown mechanisms. In an attempt to understand obesity-induced changes in liver oxygen homeostasis, we found that liver HIF-1α expression was increased mainly by soluble factors released from obese adipocytes, leading to decreased incretin effects. Deletion of hepatocyte HIF-1α protected obesity-induced glucose intolerance without changes in body weight, liver steatosis, or insulin resistance. In-depth mouse metabolic phenotyping revealed that obesity increased first-pass degradation of an incretin hormone GLP-1 with increased liver DPP4 expression and decreased sinusoidal blood flow rate, reducing active GLP-1 levels in peripheral circulation. Hepatocyte HIF-1α KO blocked these changes induced by obesity. Deletion of hepatocyte HIF-2α did not change liver DPP4 expression but improved hepatic steatosis. Our results identify a previously unknown pathway for obesity-induced impaired beta cell glucose response (incretin effects) and the development of glucose intolerance through inter-organ communications.
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http://dx.doi.org/10.1126/sciadv.aaw4176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609217PMC
July 2019

Microbiota-Produced -Formyl Peptide fMLF Promotes Obesity-Induced Glucose Intolerance.

Diabetes 2019 07 22;68(7):1415-1426. Epub 2019 Apr 22.

Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA

The composition of the gastrointestinal microbiota and associated metabolites changes dramatically with diet and the development of obesity. Although many correlations have been described, specific mechanistic links between these changes and glucose homeostasis remain to be defined. Here we show that blood and intestinal levels of the microbiota-produced formyl peptide, formyl-methionyl-leucyl-phenylalanine, are elevated in high-fat diet-induced obese mice. Genetic or pharmacological inhibition of the formyl peptide receptor Fpr1 leads to increased insulin levels and improved glucose tolerance, dependent upon glucagon-like peptide 1. Obese Fpr1 knockout mice also display an altered microbiome, exemplifying the dynamic relationship between host metabolism and microbiota. Overall, we describe a new mechanism by which the gut microbiota can modulate glucose metabolism, providing a potential approach for the treatment of metabolic disease.
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http://dx.doi.org/10.2337/db18-1307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609982PMC
July 2019

Expansion of Islet-Resident Macrophages Leads to Inflammation Affecting β Cell Proliferation and Function in Obesity.

Cell Metab 2019 02 27;29(2):457-474.e5. Epub 2018 Dec 27.

Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address:

The nature of obesity-associated islet inflammation and its impact on β cell abnormalities remains poorly defined. Here, we explore immune cell components of islet inflammation and define their roles in regulating β cell function and proliferation. Islet inflammation in obese mice is dominated by macrophages. We identify two islet-resident macrophage populations, characterized by their anatomical distributions, distinct phenotypes, and functional properties. Obesity induces the local expansion of resident intra-islet macrophages, independent of recruitment from circulating monocytes. Functionally, intra-islet macrophages impair β cell function in a cell-cell contact-dependent manner. Increased engulfment of β cell insulin secretory granules by intra-islet macrophages in obese mice may contribute to restricting insulin secretion. In contrast, both intra- and peri-islet macrophage populations from obese mice promote β cell proliferation in a PDGFR signaling-dependent manner. Together, these data define distinct roles and mechanisms for islet macrophages in the regulation of islet β cells.
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http://dx.doi.org/10.1016/j.cmet.2018.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701710PMC
February 2019

CX3CL1-Fc treatment prevents atherosclerosis in Ldlr KO mice.

Mol Metab 2019 02 2;20:89-101. Epub 2018 Dec 2.

Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address:

Objective: Atherosclerosis is a major cause of cardiovascular disease. Monocyte-endothelial cell interactions are partly mediated by expression of monocyte CX3CR1 and endothelial cell fractalkine (CX3CL1). Interrupting the interaction between this ligand-receptor pair should reduce monocyte binding to the endothelial wall and reduce atherosclerosis. We sought to reduce atherosclerosis by preventing monocyte-endothelial cell interactions through use of a long-acting CX3CR1 agonist.

Methods: In this study, the chemokine domain of CX3CL1 was fused to the mouse Fc region to generate a long-acting soluble form of CX3CL1 suitable for chronic studies. CX3CL1-Fc or saline was injected twice a week (30 mg/kg) for 4 months into Ldlr knockout (KO) mice on an atherogenic western diet.

Results: CX3CL1-Fc-treated Ldlr KO mice showed decreased en face aortic lesion surface area and reduced aortic root lesion size with decreased necrotic core area. Flow cytometry analyses of CX3CL1-Fc-treated aortic wall cell digests revealed a decrease in M1-like polarized macrophages and T cells. Moreover, CX3CL1-Fc administration reduced diet-induced atherosclerosis after switching from an atherogenic to a normal chow diet. In vitro monocyte adhesion studies revealed that CX3CL1-Fc treatment caused fewer monocytes to adhere to a human umbilical vein endothelial cell monolayer. Furthermore, a dorsal window chamber model demonstrated that CX3CL1-Fc treatment decreased in vivo leukocyte adhesion and rolling in live capillaries after short-term ischemia-reperfusion.

Conclusion: These results indicate that CX3CL1-Fc can inhibit monocyte/endothelial cell adhesion as well as reduce atherosclerosis.
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http://dx.doi.org/10.1016/j.molmet.2018.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358552PMC
February 2019

Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function.

J Clin Invest 2018 04 5;128(4):1458-1470. Epub 2018 Mar 5.

Department of Medicine, Division of Endocrinology and Metabolism, UCSD, La Jolla, California, USA.

We have previously reported that the fractalkine (FKN)/CX3CR1 system represents a novel regulatory mechanism for insulin secretion and β cell function. Here, we demonstrate that chronic administration of a long-acting form of FKN, FKN-Fc, can exert durable effects to improve glucose tolerance with increased glucose-stimulated insulin secretion and decreased β cell apoptosis in obese rodent models. Unexpectedly, chronic FKN-Fc administration also led to decreased α cell glucagon secretion. In islet cells, FKN inhibited ATP-sensitive potassium channel conductance by an ERK-dependent mechanism, which triggered β cell action potential (AP) firing and decreased α cell AP amplitude. This results in increased glucose-stimulated insulin secretion and decreased glucagon secretion. Beyond its islet effects, FKN-Fc also exerted peripheral effects to enhance hepatic insulin sensitivity due to inhibition of glucagon action. In hepatocytes, FKN treatment reduced glucagon-stimulated cAMP production and CREB phosphorylation in a pertussis toxin-sensitive manner. Together, these results raise the possibility of use of FKN-based therapy to improve type 2 diabetes by increasing both insulin secretion and insulin sensitivity.
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http://dx.doi.org/10.1172/JCI94330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873865PMC
April 2018

An Integrated View of Immunometabolism.

Cell 2018 01;172(1-2):22-40

Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

The worldwide obesity epidemic has emerged as a major cause of insulin resistance and Type 2 diabetes. Chronic tissue inflammation is a well-recognized feature of obesity, and the field of immunometabolism has witnessed many advances in recent years. Here, we review the major features of our current understanding with respect to chronic obesity-related inflammation in metabolic tissues and focus on how these inflammatory changes affect insulin sensitivity, insulin secretion, food intake, and glucose homeostasis. There is a growing appreciation of the varied and sometimes integrated crosstalk between cells within a tissue (intraorgan) and tissues within an organism (interorgan) that supports inflammation in the context of metabolic dysregulation. Understanding these pathways and modes of communication has implications for translational studies. We also briefly summarize the state of this field with respect to potential current and developing therapeutics.
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http://dx.doi.org/10.1016/j.cell.2017.12.025DOI Listing
January 2018

Adipose tissue B2 cells promote insulin resistance through leukotriene LTB4/LTB4R1 signaling.

J Clin Invest 2017 Mar 13;127(3):1019-1030. Epub 2017 Feb 13.

Tissue inflammation is a key component of obesity-induced insulin resistance, with a variety of immune cell types accumulating in adipose tissue. Here, we have demonstrated increased numbers of B2 lymphocytes in obese adipose tissue and have shown that high-fat diet-induced (HFD-induced) insulin resistance is mitigated in B cell-deficient (Bnull) mice. Adoptive transfer of adipose tissue B2 cells (ATB2) from wild-type HFD donor mice into HFD Bnull recipients completely restored the effect of HFD to induce insulin resistance. Recruitment and activation of ATB2 cells was mediated by signaling through the chemokine leukotriene B4 (LTB4) and its receptor LTB4R1. Furthermore, the adverse effects of ATB2 cells on glucose homeostasis were partially dependent upon T cells and macrophages. These results demonstrate the importance of ATB2 cells in obesity-induced insulin resistance and suggest that inhibition of the LTB4/LTB4R1 axis might be a useful approach for developing insulin-sensitizing therapeutics.
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http://dx.doi.org/10.1172/JCI90350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330737PMC
March 2017

Lipoxin A4 Attenuates Obesity-Induced Adipose Inflammation and Associated Liver and Kidney Disease.

Cell Metab 2015 Jul 4;22(1):125-37. Epub 2015 Jun 4.

Diabetes Complications Research Centre, UCD Conway Institute, School of Medicine, University College Dublin, Dublin 4, Ireland.

The role of inflammation in obesity-related pathologies is well established. We investigated the therapeutic potential of LipoxinA4 (LXA4:5(S),6(R),15(S)-trihydroxy-7E,9E,11Z,13E,-eicosatetraenoic acid) and a synthetic 15(R)-Benzo-LXA4-analog as interventions in a 3-month high-fat diet (HFD; 60% fat)-induced obesity model. Obesity caused distinct pathologies, including impaired glucose tolerance, adipose inflammation, fatty liver, and chronic kidney disease (CKD). Lipoxins (LXs) attenuated obesity-induced CKD, reducing glomerular expansion, mesangial matrix, and urinary H2O2. Furthermore, LXA4 reduced liver weight, serum alanine-aminotransferase, and hepatic triglycerides. LXA4 decreased obesity-induced adipose inflammation, attenuating TNF-α and CD11c(+) M1-macrophages (MΦs), while restoring CD206(+) M2-MΦs and increasing Annexin-A1. LXs did not affect renal or hepatic MΦs, suggesting protection occurred via attenuation of adipose inflammation. LXs restored adipose expression of autophagy markers LC3-II and p62. LX-mediated protection was demonstrable in adiponectin(-/-) mice, suggesting that the mechanism was adiponectin independent. In conclusion, LXs protect against obesity-induced systemic disease, and these data support a novel therapeutic paradigm for treating obesity and associated pathologies.
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http://dx.doi.org/10.1016/j.cmet.2015.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4584026PMC
July 2015

GPR43 Potentiates β-Cell Function in Obesity.

Diabetes 2015 Sep 28;64(9):3203-17. Epub 2015 May 28.

Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA

The intestinal microbiome can regulate host energy homeostasis and the development of metabolic disease. Here we identify GPR43, a receptor for bacterially produced short-chain fatty acids (SCFAs), as a modulator of microbiota-host interaction. β-Cell expression of GPR43 and serum levels of acetate, an endogenous SCFA, are increased with a high-fat diet (HFD). HFD-fed GPR43 knockout (KO) mice develop glucose intolerance due to a defect in insulin secretion. In vitro treatment of isolated murine islets, human islets, and Min6 cells with (S)-2-(4-chlorophenyl)-3,3-dimethyl-N-(5-phenylthiazol-2-yl)butanamide (PA), a specific agonist of GPR43, increased intracellular inositol triphosphate and Ca(2+) levels, and potentiated insulin secretion in a GPR43-, Gαq-, and phospholipase C-dependent manner. In addition, KO mice fed an HFD displayed reduced β-cell mass and expression of differentiation genes, and the treatment of Min6 cells with PA increased β-cell proliferation and gene expression. Together these findings identify GPR43 as a potential target for therapeutic intervention.
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http://dx.doi.org/10.2337/db14-1938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4542437PMC
September 2015

Lipid-overloaded enlarged adipocytes provoke insulin resistance independent of inflammation.

Mol Cell Biol 2015 May 2;35(10):1686-99. Epub 2015 Mar 2.

National Creative Research Initiatives Center for Adipose Tissue Remodeling, Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, South Korea

In obesity, adipocyte hypertrophy and proinflammatory responses are closely associated with the development of insulin resistance in adipose tissue. However, it is largely unknown whether adipocyte hypertrophy per se might be sufficient to provoke insulin resistance in obese adipose tissue. Here, we demonstrate that lipid-overloaded hypertrophic adipocytes are insulin resistant independent of adipocyte inflammation. Treatment with saturated or monounsaturated fatty acids resulted in adipocyte hypertrophy, but proinflammatory responses were observed only in adipocytes treated with saturated fatty acids. Regardless of adipocyte inflammation, hypertrophic adipocytes with large and unilocular lipid droplets exhibited impaired insulin-dependent glucose uptake, associated with defects in GLUT4 trafficking to the plasma membrane. Moreover, Toll-like receptor 4 mutant mice (C3H/HeJ) with high-fat-diet-induced obesity were not protected against insulin resistance, although they were resistant to adipose tissue inflammation. Together, our in vitro and in vivo data suggest that adipocyte hypertrophy alone may be crucial in causing insulin resistance in obesity.
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http://dx.doi.org/10.1128/MCB.01321-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405637PMC
May 2015

Increased adipocyte O2 consumption triggers HIF-1α, causing inflammation and insulin resistance in obesity.

Cell 2014 Jun;157(6):1339-1352

Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

Adipose tissue hypoxia and inflammation have been causally implicated in obesity-induced insulin resistance. Here, we report that, early in the course of high-fat diet (HFD) feeding and obesity, adipocyte respiration becomes uncoupled, leading to increased oxygen consumption and a state of relative adipocyte hypoxia. These events are sufficient to trigger HIF-1α induction, setting off the chronic adipose tissue inflammatory response characteristic of obesity. At the molecular level, these events involve saturated fatty acid stimulation of the adenine nucleotide translocase 2 (ANT2), an inner mitochondrial membrane protein, which leads to the uncoupled respiratory state. Genetic or pharmacologic inhibition of either ANT2 or HIF-1α can prevent or reverse these pathophysiologic events, restoring a state of insulin sensitivity and glucose tolerance. These results reveal the sequential series of events in obesity-induced inflammation and insulin resistance.
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http://dx.doi.org/10.1016/j.cell.2014.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4114226PMC
June 2014

Quantitative proteomic and functional analysis of liver mitochondria from high fat diet (HFD) diabetic mice.

Mol Cell Proteomics 2013 Dec 12;12(12):3744-58. Epub 2013 Sep 12.

Department of Pharmacology, and.

Insulin resistance plays a major role in the development of type 2 diabetes and obesity and affects a number of biological processes such as mitochondrial biogenesis. Though mitochondrial dysfunction has been linked to the development of insulin resistance and pathogenesis of type 2 diabetes, the precise mechanism linking the two is not well understood. We used high fat diet (HFD)-induced obesity dependent diabetes mouse models to gain insight into the potential pathways altered with metabolic disease, and carried out quantitative proteomic analysis of liver mitochondria. As previously reported, proteins involved in fatty acid oxidation, branched chain amino acid degradation, tricarboxylic acid cycle, and oxidative phosphorylation were uniformly up-regulated in the liver of HFD fed mice compared with that of normal diet. Further, our studies revealed that retinol metabolism is distinctly down-regulated and the mitochondrial structural proteins-components of mitochondrial inter-membrane space bridging (MIB) complex (Mitofilin, Sam50, and ChChd3), and Tim proteins-essential for protein import, are significantly up-regulated in HFD fed mice. Structural and functional studies on HFD and normal diet liver mitochondria revealed remodeling of HFD mitochondria to a more condensed form with increased respiratory capacity and higher ATP levels compared with normal diet mitochondria. Thus, it is likely that the structural remodeling is essential to accommodate the increased protein content in presence of HFD: the mechanism could be through the MIB complex promoting contact site and crista junction formation and in turn facilitating the lipid and protein uptake.
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http://dx.doi.org/10.1074/mcp.M113.027441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3861721PMC
December 2013

The fractalkine/CX3CR1 system regulates β cell function and insulin secretion.

Cell 2013 Apr;153(2):413-25

Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA.

Here, we demonstrate that the fractalkine (FKN)/CX3CR1 system represents a regulatory mechanism for pancreatic islet β cell function and insulin secretion. CX3CR1 knockout (KO) mice exhibited a marked defect in glucose and GLP1-stimulated insulin secretion, and this defect was also observed in vitro in isolated islets from CX3CR1 KO mice. In vivo administration of FKN improved glucose tolerance with an increase in insulin secretion. In vitro treatment of islets with FKN increased intracellular Ca(2+) and potentiated insulin secretion in both mouse and human islets. The KO islets exhibited reduced expression of a set of genes necessary for the fully functional, differentiated β cell state, whereas treatment of wild-type (WT) islets with FKN led to increased expression of these genes. Lastly, expression of FKN in islets was decreased by aging and high-fat diet/obesity, suggesting that decreased FKN/CX3CR1 signaling could be a mechanism underlying β cell dysfunction in type 2 diabetes.
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http://dx.doi.org/10.1016/j.cell.2013.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3717389PMC
April 2013

A novel function of adipocytes in lipid antigen presentation to iNKT cells.

Mol Cell Biol 2013 Jan 12;33(2):328-39. Epub 2012 Nov 12.

School of Biological Science, Institute of Molecular Biology & Genetics, Seoul National University, Seoul, South Korea.

Systemic low-grade chronic inflammation has been intensively investigated in obese subjects. Recently, various immune cell types, such as macrophages, granulocytes, helper T cells, cytotoxic T cells, and B cells, have been implicated in the pathogenesis of adipose tissue inflammation. However, the roles of invariant natural killer T cells (iNKT cells) and the regulation of iNKT cell activity in adipose tissue are not thoroughly understood. Here, we demonstrated that iNKT cells were decreased in number in the adipose tissue of obese subjects. Interestingly, CD1d, a molecule involved in lipid antigen presentation to iNKT cells, was highly expressed in adipocytes, and CD1d-expressing adipocytes stimulated iNKT cell activity through physical interaction. iNKT cell population and CD1d expression were reduced in the adipose tissue of obese mice and humans compared to those of lean subjects. Moreover, iNKT cell-deficient Jα18 knockout mice became more obese and exhibited increased adipose tissue inflammation at the early stage of obesity. These data suggest that adipocytes regulate iNKT cell activity via CD1d and that the interaction between adipocytes and iNKT cells may modulate adipose tissue inflammation in obesity.
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http://dx.doi.org/10.1128/MCB.00552-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3554106PMC
January 2013

Loss of fibroblast HIF-1α accelerates tumorigenesis.

Cancer Res 2012 Jul 3;72(13):3187-95. Epub 2012 May 3.

Molecular Biology Section, Division of Biological Sciences, Department of Medicine, University of California, San Diego, La Jolla, California, USA.

Solid tumors consist of malignant cells and associated stromal components, including fibroblastic cells that contribute to tumor growth and progression. Although tumor fibrosis and aberrant vascularization contribute to the hypoxia often found in advanced tumors, the contribution of hypoxic signaling within tumor-associated fibroblasts to tumorigenesis remains unknown. In this study, we used a fibroblast-specific promoter to create mice in which key hypoxia regulatory genes, including VHL, HIF-1α, HIF-2α, and VEGF-A, were knocked out specifically in tumor stromal fibroblasts. We found that loss of HIF-1α and its target gene VEGF-A accelerated tumor growth in murine model of mammary cancer. HIF-1α and VEGF-A loss also led to a reduction in vascular density and myeloid cell infiltration, which correlated with improved tumor perfusion. Together, our findings indicate that the fibroblast HIF-1α response is a critical component of tumor vascularization.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-0534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089958PMC
July 2012

Orosomucoid serum concentrations and fat depot-specific mRNA and protein expression in humans.

Mol Cells 2012 Jan 29;33(1):35-41. Epub 2011 Nov 29.

Obesity Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

Obesity is associated with chronic low-grade inflammation, which contributes to systemic metabolic irregularities and obesity-linked metabolic disorders. Orosomucoid (ORM), an acute phase reactant protein, was shown to be produced in response to metabolic and inflammatory signals in the adipose tissue of obese mice, which protects them from severe inflammation and subsequent metabolic dysfunction. In this study, we examined whether there are site-specific differences between visceral and subcutaneous adipose tissue (VAT and SAT, respectively) ORM gene and protein expression from individuals with a wide range of obesity and the relationship between expressed and circulating ORM levels and measures of adiposity, insulin resistance, and pro- and anti-inflammatory markers and adipokines. The level of circulating ORM correlated positively with BMI, body fat mass, and serum leptin. It also correlated with fasting insulin, HOMA-IR values and C-reactive protein in men. There were no site-specific differences in ORM mRNA and protein expression between VAT and SAT, nor did we find a relationship between circulating ORM levels and its mRNA expression in either fat depot. We found that ORM mRNA expression correlated with mRNA expression of TNF-α, IL-6, and adiponectin in VAT, and with TNF-α and adiponectin in SAT. These observations are the first description linking adipose tissue ORM and pro- and anti-inflammatory molecules in humans. The close links of ORM and measures of adiposity, insulin resistance, and adipose tissue inflammation in humans reinforce previous experimental data and warrant further studies to explore a possible role of ORM in the pathogenesis of obesity-associated metabolic derangements.
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http://dx.doi.org/10.1007/s10059-012-2181-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887744PMC
January 2012

Inflammation is necessary for long-term but not short-term high-fat diet-induced insulin resistance.

Diabetes 2011 Oct 12;60(10):2474-83. Epub 2011 Sep 12.

Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Korea.

Objective: Tissue inflammation is a key factor underlying insulin resistance in established obesity. Several models of immuno-compromised mice are protected from obesity-induced insulin resistance. However, it is unanswered whether inflammation triggers systemic insulin resistance or vice versa in obesity. The purpose of this study was to assess these questions.

Research Design And Methods: We fed a high-fat diet (HFD) to wild-type mice and three different immuno-compromised mouse models (lymphocyte-deficient Rag1 knockout, macrophage-depleted, and hematopoietic cell-specific Jun NH(2)-terminal kinase-deficient mice) and measured the time course of changes in macrophage content, inflammatory markers, and lipid accumulation in adipose tissue, liver, and skeletal muscle along with systemic insulin sensitivity.

Results: In wild-type mice, body weight and adipose tissue mass, as well as insulin resistance, were clearly increased by 3 days of HFD. Concurrently, in the short-term HFD period inflammation was selectively elevated in adipose tissue. Interestingly, however, all three immuno-compromised mouse models were not protected from insulin resistance induced by the short-term HFD. On the other hand, lipid content was markedly increased in liver and skeletal muscle at day 3 of HFD.

Conclusions: These data suggest that the initial stage of HFD-induced insulin resistance is independent of inflammation, whereas the more chronic state of insulin resistance in established obesity is largely mediated by macrophage-induced proinflammatory actions. The early-onset insulin resistance during HFD feeding is more likely related to acute tissue lipid overload.
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http://dx.doi.org/10.2337/db11-0194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178297PMC
October 2011

Adiponectin represses colon cancer cell proliferation via AdipoR1- and -R2-mediated AMPK activation.

Mol Endocrinol 2010 Jul 5;24(7):1441-52. Epub 2010 May 5.

Department of Biophysics and Chemical Biology, School of Biological Sciences, Institute of Molecular Biology & Genetics, Seoul National University, Seoul 151-742, Korea.

In obesity, dysregulation of adipocytokines is involved in several pathological conditions including diabetes and certain cancers. As a member of the adipocytokines, adiponectin plays crucial roles in whole-body energy homeostasis. Recently, it has been reported that the level of plasma adiponectin is reduced in several types of cancer patients. However, it is largely unknown whether and how adiponectin affects colon cancer cell growth. Here, we show that adiponectin suppresses the proliferation of colon cancer cells including HCT116, HT29, and LoVo. In colon cancer cells, adiponectin attenuated cell cycle progression at the G(1)/S boundary and concurrently increased expression of cyclin-dependent kinase inhibitors such as p21 and p27. Adiponectin stimulated AMP-activated protein kinase (AMPK) phosphorylation whereas inhibition of AMPK activity blunted the effect of adiponectin on the proliferation of colon cancer cells. Furthermore, knockdown of adiponectin receptors such as AdipoR1 and AdipoR2 relieved the suppressive effect of adiponectin on the growth of colon cancer cells. In addition, adiponectin repressed the expression of sterol regulatory element binding protein-1c, which is a key lipogenic transcription factor associated with colon cancers. These results suggest that adiponectin could inhibit the growth of colon cancer cells through stimulating AMPK activity.
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http://dx.doi.org/10.1210/me.2009-0498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417469PMC
July 2010

Adipocytokine orosomucoid integrates inflammatory and metabolic signals to preserve energy homeostasis by resolving immoderate inflammation.

J Biol Chem 2010 Jul 4;285(29):22174-85. Epub 2010 May 4.

Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Korea.

Orosomucoid (ORM), also called alpha-1 acid glycoprotein, is an abundant plasma protein that is an immunomodulator induced by stressful conditions such as infections. In this study, we reveal that Orm is induced selectively in the adipose tissue of obese mice to suppress excess inflammation that otherwise disturbs energy homeostasis. Adipose Orm levels were elevated by metabolic signals, including insulin, high glucose, and free fatty acid, as well as by the proinflammatory cytokine tumor necrosis factor-alpha, which is found in increased levels in the adipose tissue of morbid obese subjects. In both adipocytes and macrophages, ORM suppressed proinflammatory gene expression and pathways such as NF-kappaB and mitogen-activated protein kinase signalings and reactive oxygen species generation. Concomitantly, ORM relieved hyperglycemia-induced insulin resistance as well as tumor necrosis factor-alpha-mediated lipolysis in adipocytes. Accordingly, ORM improved glucose and insulin tolerance in obese and diabetic db/db mice. Taken together, our results suggest that ORM integrates inflammatory and metabolic signals to modulate immune responses to protect adipose tissue from excessive inflammation and thereby from metabolic dysfunction.
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http://dx.doi.org/10.1074/jbc.M109.085464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903347PMC
July 2010

miR-27a is a negative regulator of adipocyte differentiation via suppressing PPARgamma expression.

Biochem Biophys Res Commun 2010 Feb 7;392(3):323-8. Epub 2010 Jan 7.

Institute of Molecular Biology & Genetics, Seoul National University, Kwanak-Gu, Seoul, Republic of Korea.

microRNAs (miRNAs) are non-coding small RNAs regulating gene expression, cell growth, and differentiation. Although several miRNAs have been implicated in cell growth and differentiation, it is barely understood their roles in adipocyte differentiation. In the present study, we reveal that miR-27a is involved in adipocyte differentiation by binding to the PPARgamma 3'-UTR whose sequence motifs are highly conserved in mammals. During adipogenesis, the expression level of miR-27a was inversely correlated with that of adipogenic marker genes such as PPARgamma and adiponectin. In white adipose tissue, miR-27a was more abundantly expressed in stromal vascular cell fraction than in mature adipocyte fraction. Ectopic expression of miR-27a in 3T3-L1 pre-adipocytes repressed adipocyte differentiation by reducing PPARgamma expression. Interestingly, the level of miR-27a in mature adipocyte fraction of obese mice was down-regulated than that of lean mice. Together, these results suggest that miR-27a would suppress adipocyte differentiation through targeting PPARgamma and thereby down-regulation of miR-27a might be associated with adipose tissue dysregulation in obesity.
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http://dx.doi.org/10.1016/j.bbrc.2010.01.012DOI Listing
February 2010

Adipose tissue-specific dysregulation of angiotensinogen by oxidative stress in obesity.

Metabolism 2010 Sep 4;59(9):1241-51. Epub 2010 Jan 4.

Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.

Adipose tissue expresses all components of the renin-angiotensin system including angiotensinogen (AGT). Recent studies have highlighted a potential role of AGT in adipose tissue function and homeostasis. However, some controversies surround the regulatory mechanisms of AGT in obese adipose tissue. In this context, we here demonstrated that the AGT messenger RNA (mRNA) level in human subcutaneous adipose tissue was significantly reduced in obese subjects as compared with nonobese subjects. Adipose tissue AGT mRNA level in obese mice was also lower as compared with their lean littermates; however, the hepatic AGT mRNA level remained unchanged. When 3T3-L1 adipocytes were cultured for a long period, the adipocytes became hypertrophic with a marked increase in the production of reactive oxygen species. Expression and secretion of AGT continued to decrease during the course of adipocyte hypertrophy. Treatment of the 3T3-L1 and primary adipocytes with reactive oxygen species (hydrogen peroxide) or tumor necrosis factor alpha caused a significant decrease in the expression and secretion of AGT. On the other hand, treatment with the antioxidant N-acetyl cysteine suppressed the decrease in the expression and secretion of AGT in the hypertrophied 3T3-L1 adipocytes. Finally, treatment of obese db/db mice with N-acetyl cysteine augmented the expression of AGT in the adipose tissue, but not in the liver. The present study demonstrates for the first time that oxidative stress dysregulates AGT in obese adipose tissue, providing a novel insight into the adipose tissue-specific interaction between the regulation of AGT and oxidative stress in the pathophysiology of obesity.
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http://dx.doi.org/10.1016/j.metabol.2009.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891233PMC
September 2010

Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity.

Am J Physiol Endocrinol Metab 2009 Apr 27;296(4):E812-9. Epub 2009 Jan 27.

Institute of Molecular Biology and Genetics, Department of Biological Sciences, Seoul National University, San 56-1, Sillim-Dong, Kwanak-Gu, Seoul 151-742, Korea.

AMP-activated protein kinase (AMPK) plays an important role in regulating whole body energy homeostasis. Recently, it has been demonstrated that berberine (BBR) exerts antiobesity and antidiabetic effects in obese and diabetic rodent models through the activation of AMPK in peripheral tissues. Here we show that BBR improves lipid dysregulation and fatty liver in obese mice through central and peripheral actions. In obese db/db and ob/ob mice, BBR treatment reduced liver weight, hepatic and plasma triglyceride, and cholesterol contents. In the liver and muscle of db/db mice, BBR promoted AMPK activity and fatty acid oxidation and changed expression of genes involved in lipid metabolism. Additionally, intracerebroventricular administration of BBR decreased the level of malonyl-CoA and stimulated the expression of fatty acid oxidation genes in skeletal muscle. Together, these data suggest that BBR would improve fatty liver in obese subjects, which is probably mediated not only by peripheral AMPK activation but also by neural signaling from the central nervous system.
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http://dx.doi.org/10.1152/ajpendo.90710.2008DOI Listing
April 2009

Glutathione peroxidase 3 mediates the antioxidant effect of peroxisome proliferator-activated receptor gamma in human skeletal muscle cells.

Mol Cell Biol 2009 Jan 20;29(1):20-30. Epub 2008 Oct 20.

Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, South Korea.

Oxidative stress plays an important role in the pathogenesis of insulin resistance and type 2 diabetes mellitus and in diabetic vascular complications. Thiazolidinediones (TZDs), a class of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, improve insulin sensitivity and are currently used for the treatment of type 2 diabetes mellitus. Here, we show that TZD prevents oxidative stress-induced insulin resistance in human skeletal muscle cells, as indicated by the increase in insulin-stimulated glucose uptake and insulin signaling. Importantly, TZD-mediated activation of PPARgamma induces gene expression of glutathione peroxidase 3 (GPx3), which reduces extracellular H(2)O(2) levels causing insulin resistance in skeletal muscle cells. Inhibition of GPx3 expression prevents the antioxidant effects of TZDs on insulin action in oxidative stress-induced insulin-resistant cells, suggesting that GPx3 is required for the regulation of PPARgamma-mediated antioxidant effects. Furthermore, reduced plasma GPx3 levels were found in patients with type 2 diabetes mellitus and in db/db/DIO mice. Collectively, these results suggest that the antioxidant effect of PPARgamma is exclusively mediated by GPx3 and further imply that GPx3 may be a therapeutic target for insulin resistance and diabetes mellitus.
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http://dx.doi.org/10.1128/MCB.00544-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612482PMC
January 2009

Dysregulation of adipose glutathione peroxidase 3 in obesity contributes to local and systemic oxidative stress.

Mol Endocrinol 2008 Sep 18;22(9):2176-89. Epub 2008 Jun 18.

Institute of Molecular Biology and Genetics, Seoul National University, San 56-1, Sillim-Dong, Kwanak-Gu, Seoul 151-742, Korea.

Glutathione peroxidase 3 (GPx3) accounts for the major antioxidant activity in the plasma. Here, we demonstrate that down-regulation of GPx3 in the plasma of obese subjects is associated with adipose GPx3 dysregulation, resulting from the increase of inflammatory signals and oxidative stress. Although GPx3 was abundantly expressed in kidney, lung, and adipose tissue, we observed that GPx3 expression was reduced selectively in the adipose tissue of several obese animal models as decreasing plasma GPx3 level. Adipose GPx3 expression was greatly suppressed by prooxidative conditions such as high levels of TNFalpha and hypoxia. In contrast, the antioxidant N-acetyl cysteine and the antidiabetic drug rosiglitazone increased adipose GPx3 expression in obese and diabetic db/db mice. Moreover, GPx3 overexpression in adipocytes improved high glucose-induced insulin resistance and attenuated inflammatory gene expression whereas GPx3 neutralization in adipocytes promoted expression of proinflammatory genes. Taken together, these data suggest that suppression of GPx3 expression in the adipose tissue of obese subjects might constitute a vicious cycle to expand local reactive oxygen species accumulation in adipose tissue potentially into systemic oxidative stress and obesity-related metabolic complications.
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http://dx.doi.org/10.1210/me.2008-0023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419460PMC
September 2008