Publications by authors named "Jerrold Olefsky"

172 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gad.346312.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919414PMC
March 2021

MiR-690, an exosomal-derived miRNA from M2-polarized macrophages, improves insulin sensitivity in obese mice.

Cell Metab 2021 Apr 14;33(4):781-790.e5. Epub 2021 Jan 14.

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

Insulin resistance is a major pathophysiologic defect in type 2 diabetes and obesity, while anti-inflammatory M2-like macrophages are important in maintaining normal metabolic homeostasis. Here, we show that M2 polarized bone marrow-derived macrophages (BMDMs) secrete miRNA-containing exosomes (Exos), which improve glucose tolerance and insulin sensitivity when given to obese mice. Depletion of their miRNA cargo blocks the ability of M2 BMDM Exos to enhance insulin sensitivity. We found that miR-690 is highly expressed in M2 BMDM Exos and functions as an insulin sensitizer both in vivo and in vitro. Expressing an miR-690 mimic in miRNA-depleted BMDMs generates Exos that recapitulate the effects of M2 BMDM Exos on metabolic phenotypes. Nadk is a bona fide target mRNA of miR-690, and Nadk plays a role in modulating macrophage inflammation and insulin signaling. Taken together, these data suggest miR-690 could be a new therapeutic insulin-sensitizing agent for metabolic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2020.12.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035248PMC
April 2021

Positive Reinforcing Mechanisms between GPR120 and PPARγ Modulate Insulin Sensitivity.

Cell Metab 2020 Jun 14;31(6):1173-1188.e5. Epub 2020 May 14.

Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

G protein-coupled receptor 120 (GPR120) and PPARγ agonists each have insulin sensitizing effects. But whether these two pathways functionally interact and can be leveraged together to markedly improve insulin resistance has not been explored. Here, we show that treatment with the PPARγ agonist rosiglitazone (Rosi) plus the GPR120 agonist Compound A leads to additive effects to improve glucose tolerance and insulin sensitivity, but at lower doses of Rosi, thus avoiding its known side effects. Mechanistically, we show that GPR120 is a PPARγ target gene in adipocytes, while GPR120 augments PPARγ activity by inducing the endogenous ligand 15d-PGJ2 and by blocking ERK-mediated inhibition of PPARγ. Further, we used macrophage- (MKO) or adipocyte-specific GPR120 KO (AKO) mice to show that GRP120 has anti-inflammatory effects via macrophages while working with PPARγ in adipocytes to increase insulin sensitivity. These results raise the prospect of a safer way to increase insulin sensitization in the clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2020.04.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337476PMC
June 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41574-019-0286-3DOI Listing
February 2020

Obesity Modulates Intestinal Intraepithelial T Cell Persistence, CD103 and CCR9 Expression, and Outcome in Dextran Sulfate Sodium-Induced Colitis.

J Immunol 2019 12 11;203(12):3427-3435. Epub 2019 Nov 11.

Department of Biology, California State University San Marcos, San Marcos, CA 92069;

Obesity impacts over 30% of the United States population, resulting in a wide array of complications. Included among these is the deterioration of the intestinal barrier, which has been implicated in type 2 diabetes and susceptibility to bacterial transepithelial migration. The intestinal epithelium is maintained by αβ and γδ intraepithelial T lymphocytes, which migrate along the epithelia, support epithelial homeostasis, and protect from infection. In this study, we investigate how obesity impacts intraepithelial lymphocyte (IEL) persistence and function in intestinal homeostasis and repair. Mice were fed a high-fat diet to induce obesity and to study immunomodulation in the intestine. There is a striking reduction in αβ and γδ IEL persistence as obesity progresses with a different mechanism in αβ versus γδ IEL populations. CD4 and CD4CD8 αβ intraepithelial T lymphocytes exhibit reduced homeostatic proliferation in obesity, whereas both αβ and γδ IELs downregulate CD103 and CCR9. The reduction in intraepithelial T lymphocytes occurs within 7 wk of high-fat diet administration and is not dependent on chronic inflammation via TNF-α. Young mice administered a high-fat diet upon weaning exhibit the most dramatic phenotype, showing that childhood obesity has consequences on intestinal IEL seeding. Together, this dysfunction in the intestinal epithelium renders obese mice more susceptible to dextran sulfate sodium-induced colitis. Diet-induced weight loss restores IEL number and CD103/CCR9 expression and improves outcome in colitis. Together, these data confirm that obesity has immunomodulatory consequences in intestinal tissues that can be improved with weight loss.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1900082DOI Listing
December 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2019.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784082PMC
January 2020

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42255-018-0003-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746433PMC
January 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db18-1307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609982PMC
July 2019

Neuronal SIRT1 Regulates Metabolic and Reproductive Function and the Response to Caloric Restriction.

J Endocr Soc 2019 Feb 24;3(2):427-445. Epub 2018 Dec 24.

VA San Diego Healthcare System, San Diego, California.

Sirt1 is an NAD-dependent, class III deacetylase that functions as a cellular energy sensor. In addition to its well-characterized effects in peripheral tissues, emerging evidence suggests that neuronal Sirt1 activity plays a role in the central regulation of energy balance and glucose metabolism. In this study, we generated mice expressing an enzymatically inactive form (-MUT) or wild-type (WT) SIRT1 (-OX) in mature neurons. -OX male and female mice had impaired glucose tolerance, and -MUT female, but not male, mice had improved glucose tolerance compared with that of WT littermates. Furthermore, glucose tolerance was improved in all mice with caloric restriction (CR) but was greater in the -OX mice, who had better glucose tolerance than their littermates. At the reproductive level, -OX females had impaired estrous cycles, with increased cycle length and more time in estrus. LH and progesterone surges were absent on the evening of proestrus in the -OX mice, suggesting a defect in spontaneous ovulation, which was confirmed by the ovarian histology revealing fewer corpora lutea. Despite this defect, the mice were still fertile when mated to WT mice on the day of proestrus, indicating that the mice could respond to normal pheromonal or environmental cues. When subjected to CR, the -OX mice went into diestrus arrest earlier than their littermates. Together, these results suggested that the overexpression of SIRT1 rendered the mice more sensitive to the metabolic improvements and suppression of reproductive cycles by CR, which was independent of circadian rhythms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/js.2018-00318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364627PMC
February 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmet.2018.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358552PMC
February 2019

N-Thiazolylamide-based free fatty-acid 2 receptor agonists: Discovery, lead optimization and demonstration of off-target effect in a diabetes model.

Bioorg Med Chem 2018 10 18;26(18):5169-5180. Epub 2018 Sep 18.

University of California, Department of Medicine, San Diego, CA 92161, USA.

Free fatty acid-2 (FFA2) receptor is a G-protein coupled receptor of interest in the development of therapeutics in metabolic and inflammatory disease areas. The discovery and optimization of an N-thiazolylamide carboxylic acid FFA2 agonist scaffold is described. Dual key objectives were to i) evaluate the potential of this scaffold for lead optimization in particular with respect to safety de-risking physicochemical properties, i.e. lipophilicity and aromatic content, and ii) to demonstrate the utility of selected lead analogues from this scaffold in a pertinent in vivo model such as oral glucose tolerance test (OGTT). As such, a concomitant improvement in bioactivity together with lipophilic ligand efficiency (LLE) and fraction sp content (Fsp) parameters guided these efforts. Compound 10 was advanced into studies in mice on the basis of its optimized profile vs initial lead 1 (ΔLLE = 0.3, ΔFsp = 0.24). Although active in OGTT, 10 also displayed similar activity in the FFA2-knockout mice. Given this off-target OGTT effect, we discontinued development of this FFA2 agonist scaffold.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2018.09.015DOI Listing
October 2018

Role of Host GPR120 in Mediating Dietary Omega-3 Fatty Acid Inhibition of Prostate Cancer.

J Natl Cancer Inst 2019 01;111(1):52-59

Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.

Background: GPR120, a G protein-coupled receptor for long-chain polyunsaturated fatty acids (FAs), mediates the anti-inflammatory effects of omega-3 (ω-3) FAs. We investigated whether host or tumor GPR120 plays a role in the anti-prostate cancer effects of ω-3 FAs.

Methods: MycCap prostate cancer allografts were grown in immunocompetent wild-type (WT) and GPR120 knockout (KO) mice fed ω-3 (fish oil) or ω-6 (corn oil) diets. Immune cell infiltration was quantified by flow cytometry, and gene expression of immune cell markers in isolated tumor-associated macrophages (TAMs) was quantified by quantitative real-time polymerase chain reaction. Archived tissue from a fish oil intervention trial was used to correlate gene expression of GPR120 with cell cycle progression (CCP) genes and Ki67 index (n = 11-15 per group). All statistical tests were two-sided.

Results: In WT mice (n = 7 per group), dietary ω-3 FAs decreased MycCap allograft tumor growth (mean [SD] final tumor volume ω-6 = 491 [437] mm3 vs ω-3 = 127 [77] mm3, P = .04), whereas in global GPR120KO mice (n = 7 per group) ω-3 FAs had no anticancer effects. Dietary ω-3 FAs inhibited GPR120KO-MycCaP allografts grown in WT mice (n = 8 per group; mean [SD] final tumor volume ω-6 = 776 [767] mm3 vs ω-3 = 36 [34] mm3, P = .02). Omega-3 FA treatment decreased the number of M2-like TAMs in tumor tissue and gene expression of M2 markers in isolated TAMs compared with ω-6 controls in WT (n = 7 per group) but not in GPR120KO mice (n = 7 per group). In human tissue, higher expression of stromal GPR120 correlated with greater reduction in expression of CCP genes in men with prostate cancer on a high-ω-3 diet (r = -.57, P = .04).

Conclusions: Host GPR120 plays a central role in the anti-prostate cancer effects of dietary ω-3 FAs. Future studies are required to determine if the anticancer effects of ω-3 FAs are mediated through inhibition of M2-like macrophages and if host GPR120 status predicts anticancer effects of dietary ω-3 FAs in men with prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djy125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335116PMC
January 2019

Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis.

Arthritis Res Ther 2018 07 11;20(1):145. Epub 2018 Jul 11.

Northwestern Scleroderma Program, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: A pivotal role for adipose tissue homeostasis in systemic sclerosis (SSc) skin fibrosis is increasingly recognized. The nuclear receptor PPAR-γ is the master regulator of adipogenesis. Peroxisome proliferator activated receptor-γ (PPAR-γ) has antifibrotic effects by blocking transforming growth factor-β (TGF-β) and is dysregulated in SSc. To unravel the impact of dysregulated PPAR-γ in SSc, we focused on nuclear corepressor (NCoR), which negatively regulates PPAR-γ activity and suppresses adipogenesis.

Methods: An NCoR-regulated gene signature was measured in the SSc skin transcriptome. Experimental skin fibrosis was examined in mice with adipocyte-specific NCoR ablation.

Results: SSc skin biopsies demonstrated deregulated NCoR signaling. A 43-gene NCoR gene signature showed strong positive correlation with PPAR-γ signaling (R = 0.919, p < 0.0001), whereas negative correlations with TGF-β signaling (R = - 0.796, p < 0.0001) and the modified Rodnan skin score (R = - 0.49, p = 0.004) were found. Mice with adipocyte-specific NCoR ablation demonstrated significant protection from experimental skin fibrosis and inflammation. The protective effects were mediated primarily through endogenous PPAR-γ.

Conclusions: Our results implicate, for the first time, to our knowledge, deregulated NCoR/PPAR-γ pathways in SSc, and they support a role of adipocyte modulation of skin fibrosis. Pharmacologic restoration of NCoR/PPAR-γ signaling may represent a novel strategy to control skin fibrosis in SSc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13075-018-1630-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042240PMC
July 2018

RalA controls glucose homeostasis by regulating glucose uptake in brown fat.

Proc Natl Acad Sci U S A 2018 07 18;115(30):7819-7824. Epub 2018 Jun 18.

Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093;

Insulin increases glucose uptake into adipose tissue and muscle by increasing trafficking of the glucose transporter Glut4. In cultured adipocytes, the exocytosis of Glut4 relies on activation of the small G protein RalA by insulin, via inhibition of its GTPase activating complex RalGAP. Here, we evaluate the role of RalA in glucose uptake in vivo with specific chemical inhibitors and by generation of mice with adipocyte-specific knockout of RalGAPB. RalA was profoundly activated in brown adipose tissue after feeding, and its inhibition prevented Glut4 exocytosis. RalGAPB knockout mice with diet-induced obesity were protected from the development of metabolic disease due to increased glucose uptake into brown fat. Thus, RalA plays a crucial role in glucose transport in adipose tissue in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1801050115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065037PMC
July 2018

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2017.12.025DOI Listing
January 2018

Adipose Tissue Macrophage-Derived Exosomal miRNAs Can Modulate In Vivo and In Vitro Insulin Sensitivity.

Cell 2017 Oct 21;171(2):372-384.e12. Epub 2017 Sep 21.

Division of Endocrinology and Metabolism, Department of Medicine, UC San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address:

MiRNAs are regulatory molecules that can be packaged into exosomes and secreted from cells. Here, we show that adipose tissue macrophages (ATMs) in obese mice secrete miRNA-containing exosomes (Exos), which cause glucose intolerance and insulin resistance when administered to lean mice. Conversely, ATM Exos obtained from lean mice improve glucose tolerance and insulin sensitivity when administered to obese recipients. miR-155 is one of the miRNAs overexpressed in obese ATM Exos, and earlier studies have shown that PPARγ is a miR-155 target. Our results show that miR-155KO animals are insulin sensitive and glucose tolerant compared to controls. Furthermore, transplantation of WT bone marrow into miR-155KO mice mitigated this phenotype. Taken together, these studies show that ATMs secrete exosomes containing miRNA cargo. These miRNAs can be transferred to insulin target cell types through mechanisms of paracrine or endocrine regulation with robust effects on cellular insulin action, in vivo insulin sensitivity, and overall glucose homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2017.08.035DOI Listing
October 2017

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI90350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330737PMC
March 2017

Inflammatory mechanisms linking obesity and metabolic disease.

J Clin Invest 2017 01 3;127(1):1-4. Epub 2017 Jan 3.

There are currently over 1.9 billion people who are obese or overweight, leading to a rise in related health complications, including insulin resistance, type 2 diabetes, cardiovascular disease, liver disease, cancer, and neurodegeneration. The finding that obesity and metabolic disorder are accompanied by chronic low-grade inflammation has fundamentally changed our view of the underlying causes and progression of obesity and metabolic syndrome. We now know that an inflammatory program is activated early in adipose expansion and during chronic obesity, permanently skewing the immune system to a proinflammatory phenotype, and we are beginning to delineate the reciprocal influence of obesity and inflammation. Reviews in this series examine the activation of the innate and adaptive immune system in obesity; inflammation within diabetic islets, brain, liver, gut, and muscle; the role of inflammation in fibrosis and angiogenesis; the factors that contribute to the initiation of inflammation; and therapeutic approaches to modulate inflammation in the context of obesity and metabolic syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI92035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5199709PMC
January 2017

Obese Neuronal PPARγ Knockout Mice Are Leptin Sensitive but Show Impaired Glucose Tolerance and Fertility.

Endocrinology 2017 01;158(1):121-133

Department of Medicine, School of Medicine, and.

The peroxisome-proliferator activated receptor γ (PPARγ) is expressed in the hypothalamus in areas involved in energy homeostasis and glucose metabolism. In this study, we created a deletion of PPARγ brain-knockout (BKO) in mature neurons in female mice to investigate its involvement in metabolism and reproduction. We observed that there was no difference in age at puberty onset between female BKOs and littermate controls, but the BKOs gave smaller litters when mated and fewer oocytes when ovulated. The female BKO mice had regular cycles but showed an increase in the number of cycles with prolonged estrus. The mice also had increased luteinizing hormone (LH) levels during the LH surge and histological examination showed hemorrhagic corpora lutea. The mice were challenged with a 60% high-fat diet (HFD). Metabolically, the female BKO mice showed normal body weight, glucose and insulin tolerance, and leptin levels but were protected from obesity-induced leptin resistance. The neuronal knockout also prevented the reduction in estrous cycles due to the HFD. Examination of ovarian histology showed a decrease in the number of primary and secondary follicles in both genotypes due to the HFD, but the BKO ovaries showed an increase in the number of hemorrhagic follicles. In summary, our results show that neuronal PPARγ is required for optimal female fertility but is also involved in the adverse effects of diet-induced obesity by creating leptin resistance potentially through induction of the repressor Socs3.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/en.2016-1818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412981PMC
January 2017

Hematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance.

Cell 2016 11;167(4):973-984.e12

Division of Endocrinology and Metabolism, UC, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address:

In obesity, macrophages and other immune cells accumulate in insulin target tissues, promoting a chronic inflammatory state and insulin resistance. Galectin-3 (Gal3), a lectin mainly secreted by macrophages, is elevated in both obese subjects and mice. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese mice. In vitro treatment with Gal3 directly enhanced macrophage chemotaxis, reduced insulin-stimulated glucose uptake in myocytes and 3T3-L1 adipocytes and impaired insulin-mediated suppression of glucose output in primary mouse hepatocytes. Importantly, we found that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These observations elucidate a novel role for Gal3 in hepatocyte, adipocyte, and myocyte insulin resistance, suggesting that Gal3 can link inflammation to decreased insulin sensitivity. Inhibition of Gal3 could be a new approach to treat insulin resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2016.10.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179329PMC
November 2016

G protein-coupled receptors as targets for anti-diabetic therapeutics.

Nat Rev Drug Discov 2016 03 29;15(3):161-72. Epub 2016 Jan 29.

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

The prevalence of obesity and type 2 diabetes (T2D) is increasing worldwide, and these two metabolic disorders are closely linked. Lifestyle modification, including weight loss and exercise, are effective treatments for T2D, but, unfortunately, most patients are unsuccessful at maintaining durable weight reduction and recidivism is all too common. Therefore, safe and efficacious drugs are required for the successful treatment of T2D in a large proportion of patients. Targeting G protein-coupled receptors (GPCRs) in metabolic tissues - such as adipose tissue, liver, muscle, pancreatic islets, immune cells and the central nervous system - has emerged as a key target for current and future anti-diabetic compounds. This Opinion focuses on the potential of GPCRs as targets for the discovery of new drugs to successfully treat T2D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nrd.2015.4DOI Listing
March 2016

p75 Neurotrophin Receptor Regulates Energy Balance in Obesity.

Cell Rep 2016 Jan 31;14(2):255-68. Epub 2015 Dec 31.

Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address:

Obesity and metabolic syndrome reflect the dysregulation of molecular pathways that control energy homeostasis. Here, we show that the p75 neurotrophin receptor (p75(NTR)) controls energy expenditure in obese mice on a high-fat diet (HFD). Despite no changes in food intake, p75(NTR)-null mice were protected from HFD-induced obesity and remained lean as a result of increased energy expenditure without developing insulin resistance or liver steatosis. p75(NTR) directly interacts with the catalytic subunit of protein kinase A (PKA) and regulates cAMP signaling in adipocytes, leading to decreased lipolysis and thermogenesis. Adipocyte-specific depletion of p75(NTR) or transplantation of p75(NTR)-null white adipose tissue (WAT) into wild-type mice fed a HFD protected against weight gain and insulin resistance. Our results reveal that signaling from p75(NTR) to cAMP/PKA regulates energy balance and suggest that non-CNS neurotrophin receptor signaling could be a target for treating obesity and the metabolic syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2015.12.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831919PMC
January 2016

Regulation of metabolism by the innate immune system.

Nat Rev Endocrinol 2016 Jan 10;12(1):15-28. Epub 2015 Nov 10.

Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0673, USA.

Low-grade tissue inflammation induced by obesity can result in insulin resistance, which in turn is a key cause of type 2 diabetes mellitus. Cells of the innate immune system produce cytokines and other factors that impair insulin signalling, which contributes to the connection between obesity and the onset of type 2 diabetes mellitus. Here, we review the innate immune cells involved in secreting inflammatory factors in the obese state. In the adipose tissue, these cells include proinflammatory adipose tissue macrophages and natural killer cells. We also discuss the role of innate immune cells, such as anti-inflammatory adipose tissue macrophages, eosinophils, group 2 innate lymphoid cells and invariant natural killer T cells, in maintaining an anti-inflammatory and insulin-sensitive environment in the lean state. In the liver, both Kupffer cells and recruited hepatic macrophages can contribute to decreased hepatic insulin sensitivity. Proinflammatory macrophages might also adversely affect insulin sensitivity in the skeletal muscle and pancreatic β-cell function. Finally, this Review provides an overview of the mechanisms for regulating proinflammatory immune responses that could lead to future therapeutic opportunities to improve insulin sensitivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nrendo.2015.189DOI Listing
January 2016

Spatial Cognition in Adult and Aged Mice Exposed to High-Fat Diet.

PLoS One 2015 8;10(10):e0140034. Epub 2015 Oct 8.

Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, California, United States of America.

Aging is associated with a decline in multiple aspects of cognitive function, with spatial cognition being particularly sensitive to age-related decline. Environmental stressors, such as high-fat diet (HFD) exposure, that produce a diabetic phenotype and metabolic dysfunction may indirectly lead to exacerbated brain aging and promote the development of cognitive deficits. The present work investigated whether exposure to HFD exacerbates age-related cognitive deficits in adult versus aged mice. Adult (5 months old) and aged (15 months old) mice were exposed to control diet or HFD for three months prior to, and throughout, behavioral testing. Anxiety-like behavior in the light-dark box test, discrimination learning and memory in the novel object/place recognition tests, and spatial learning and memory in the Barnes maze test were assessed. HFD resulted in significant gains in body weight and fat mass content with adult mice gaining significantly more weight and adipose tissue due to HFD than aged mice. Weight gain was attributed to food calories sourced from fat, but not total calorie intake. HFD increased fasting insulin levels in all mice, but adult mice showed a greater increase relative to aged mice. Behaviorally, HFD increased anxiety-like behavior in adult but not aged mice without significantly affecting spatial cognition. In contrast, aged mice fed either control or HFD diet displayed deficits in novel place discrimination and spatial learning. Our results suggest that adult mice are more susceptible to the physiological and anxiety-like effects of HFD consumption than aged mice, while aged mice displayed deficits in spatial cognition regardless of dietary influence. We conclude that although HFD induces systemic metabolic dysfunction in both adult and aged mice, overall cognitive function was not adversely affected under the current experimental conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140034PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4598128PMC
May 2016

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db14-1938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4542437PMC
September 2015

Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity.

Mol Metab 2015 May 5;4(5):378-91. Epub 2015 Mar 5.

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

Objective: Adipose tissue is the primary site for lipid deposition that protects the organisms in cases of nutrient excess during obesogenic diets. The histone deacetylase Sirtuin 1 (SIRT1) inhibits adipocyte differentiation by targeting the transcription factor peroxisome proliferator activated-receptor gamma (PPARγ).

Methods: To assess the specific role of SIRT1 in adipocytes, we generated Sirt1 adipocyte-specific knockout mice (ATKO) driven by aP2 promoter onto C57BL/6 background. Sirt1 (flx/flx) aP2Cre (+) (ATKO) and Sirt1 (flx/flx) aP2Cre (-) (WT) mice were fed high-fat diet for 5 weeks (short-term) or 15 weeks (chronic-term). Metabolic studies were combined with gene expression analysis and phosphorylation/acetylation patterns in adipose tissue.

Results: On standard chow, ATKO mice exhibit low-grade chronic inflammation in adipose tissue, along with glucose intolerance and insulin resistance compared with control fed mice. On short-term HFD, ATKO mice become more glucose intolerant, hyperinsulinemic, insulin resistant and display increased inflammation. During chronic HFD, WT mice developed a metabolic dysfunction, higher than ATKO mice, and thereby, knockout mice are more glucose tolerant, insulin sensitive and less inflamed relative to control mice. SIRT1 attenuates adipogenesis through PPARγ repressive acetylation and, in the ATKO mice adipocyte PPARγ was hyperacetylated. This high acetylation was associated with a decrease in Ser273-PPARγ phosphorylation. Dephosphorylated PPARγ is constitutively active and results in higher expression of genes associated with increased insulin sensitivity.

Conclusion: Together, these data establish that SIRT1 downregulation in adipose tissue plays a previously unknown role in long-term inflammation resolution mediated by PPARγ activation. Therefore, in the context of obesity, the development of new therapeutics that activate PPARγ by targeting SIRT1 may provide novel approaches to the treatment of T2DM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmet.2015.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4421024PMC
May 2015

High fat diet causes depletion of intestinal eosinophils associated with intestinal permeability.

PLoS One 2015 2;10(4):e0122195. Epub 2015 Apr 2.

Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, San Diego, California, United States of America.

The development of intestinal permeability and the penetration of microbial products are key factors associated with the onset of metabolic disease. However, the mechanisms underlying this remain unclear. Here we show that, unlike liver or adipose tissue, high fat diet (HFD)/obesity in mice does not cause monocyte/macrophage infiltration into the intestine or pro-inflammatory changes in gene expression. Rather HFD causes depletion of intestinal eosinophils associated with the onset of intestinal permeability. Intestinal eosinophil numbers were restored by returning HFD fed mice to normal chow and were unchanged in leptin-deficient (Ob/Ob) mice, indicating that eosinophil depletion is caused specifically by a high fat diet and not obesity per se. Analysis of different aspects of intestinal permeability in HFD fed and Ob/Ob mice shows an association between eosinophil depletion and ileal paracelullar permeability, as well as leakage of albumin into the feces, but not overall permeability to FITC dextran. These findings provide the first evidence that a high fat diet causes intestinal eosinophil depletion, rather than inflammation, which may contribute to defective barrier integrity and the onset of metabolic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122195PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383570PMC
April 2016