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1.
Circulation. 2018 Jul 17;138(3):305-315. doi: 10.1161/CIRCULATIONAHA.118.033704.

Deciphering the Role of Lipid Droplets in Cardiovascular Disease: A Report From the 2017 National Heart, Lung, and Blood Institute Workshop.

Author information

1
New York University, New York City (I.J.G., E.A.F.).
2
University of California, Los Angeles (K.R.).
3
Washington University in St. Louis, MO (N.A.A., J.E.S.).
4
University of Texas Southwestern Medical Center, Dallas (P.E.B.).
5
University of North Carolina at Chapel Hill (S.C.).
6
National Institutes of Health/National, Heart, Lung, and Blood Institute, Bethesda, MD (Z.S.G., M.O., L.S.-L., J.C.).
7
Wayne State University, Detroit, MI (J.G.G.).
8
The Ohio State University Wexner Medical Center, Columbus (E.D.L.).
9
University of Colorado Denver (R.M.).
10
Yale University, Howard Hughes Medical Institute, New Haven, CT (G.I.S.).
11
Harvard University, Howard Hughes Medical Institute, Boston, MA (T.C.W.).
12
National Institutes of Health/National, Heart, Lung, and Blood Institute, Bethesda, MD (Z.S.G., M.O., L.S.-L., J.C.). jue.chen@nih.gov.

Abstract

Lipid droplets (LDs) are distinct and dynamic organelles that affect the health of cells and organs. Much progress has been made in understanding how these structures are formed, how they interact with other cellular organelles, how they are used for storage of triacylglycerol in adipose tissue, and how they regulate lipolysis. Our understanding of the biology of LDs in the heart and vascular tissue is relatively primitive in comparison with LDs in adipose tissue and liver. The National Heart, Lung, and Blood Institute convened a working group to discuss how LDs affect cardiovascular diseases. The goal of the working group was to examine the current state of knowledge on the cell biology of LDs, including current methods to study them in cells and organs and reflect on how LDs influence the development and progression of cardiovascular diseases. This review summarizes the working group discussion and recommendations on research areas ripe for future investigation that will likely improve our understanding of atherosclerosis and heart function.

KEYWORDS:

atherosclerosis; heart failure; metabolic syndrome; obesity; triglycerides

PMID:
30012703
PMCID:
PMC6056021
[Available on 2019-07-17]
DOI:
10.1161/CIRCULATIONAHA.118.033704
Icon for Atypon
2.
Cell Metab. 2018 Aug 7;28(2):300-309.e4. doi: 10.1016/j.cmet.2018.05.025. Epub 2018 Jun 21.

Deconstructing Adipogenesis Induced by β3-Adrenergic Receptor Activation with Single-Cell Expression Profiling.

Author information

1
Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA; Center for Integrative Metabolic and Endocrine Research, Wayne State University, Detroit, MI, USA.
2
Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA.
3
College of Pharmacy, Yonsei University, Incheon, South Korea.
4
Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA; Center for Integrative Metabolic and Endocrine Research, Wayne State University, Detroit, MI, USA. Electronic address: jgranne@med.wayne.edu.

Abstract

Recruitment of brown/beige adipocytes (BAs) in white adipose tissue (WAT) involves proliferation and differentiation of adipocyte stem cells (ASCs) in concert with close interactions with resident immune cells. To deconvolve stromal cell heterogeneity in a comprehensive and unbiased fashion, we performed single-cell RNA sequencing (scRNA-seq) of >33,000 stromal/vascular cells from epididymal WAT (eWAT) and inguinal WAT (iWAT) under control conditions and during β3-adrenergic receptor (ADRB3) activation. scRNA-seq identified distinct ASC subpopulations in eWAT and iWAT that appeared to be differentially poised to enter the adipogenic pathway. ADRB3 activation triggered the dramatic appearance of proliferating ASCs in eWAT, whose differentiation into BAs could be inferred from a single time point. scRNA-seq identified various immune cell types in eWAT, including a proliferating macrophage subpopulation that occupies adipogenic niches. These results demonstrate the power of scRNA-seq to deconstruct adipogenic niches and suggest novel functional interactions among resident stromal cell subpopulations.

KEYWORDS:

RNA-seq; adipocyte stem cell; adipogenesis; brown adipocyte; browning; differentiation trajectory; macrophage; recuitment; stromal cells

PMID:
29937373
PMCID:
PMC6082711
[Available on 2019-08-07]
DOI:
10.1016/j.cmet.2018.05.025
Icon for Elsevier Science
3.
Sci Signal. 2018 Apr 24;11(527). pii: eaai7838. doi: 10.1126/scisignal.aai7838.

Jak-TGFβ cross-talk links transient adipose tissue inflammation to beige adipogenesis.

Author information

1
DKFZ Junior Group Metabolism and Stem Cell Plasticity (A171), German Cancer Research Center, Heidelberg 69120, Germany.
2
Université Côte d'Azur, CNRS, Inserm, Institute of Biology Valrose, Nice 06100, France.
3
Department of Toxicology, School of Public Health, Peking University, Beijing 100191, China.
4
Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
5
Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Heidelberg 69120, Germany.
6
Light Microscopy Facility, German Cancer Research Center, Heidelberg 69120, Germany.
7
Max Planck Institute for Metabolism Research Cologne, Cologne 50931, Germany.
8
College of Pharmacy, Yonsei University, Incheon 406-840, South Korea.
9
Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, MI 48201, USA.
10
Division of Chronic Inflammation and Cancer (F180), German Cancer Research Center, Heidelberg 69120, Germany.
11
Helmholtz Center Munich, Institute for Diabetes and Cancer (IDC), Neuherberg 85764, Germany. a.vegiopoulos@dkfz.de stephan.herzig@helmholtz-muenchen.de.
12
Joint Heidelberg-Institute for Diabetes and Cancer Translational Diabetes Program, Heidelberg University Hospital, Heidelberg 69120, Germany.
13
DKFZ Junior Group Metabolism and Stem Cell Plasticity (A171), German Cancer Research Center, Heidelberg 69120, Germany. a.vegiopoulos@dkfz.de stephan.herzig@helmholtz-muenchen.de.

Abstract

The transient activation of inflammatory networks is required for adipose tissue remodeling including the "browning" of white fat in response to stimuli such as β3-adrenergic receptor activation. In this process, white adipose tissue acquires thermogenic characteristics through the recruitment of so-called beige adipocytes. We investigated the downstream signaling pathways impinging on adipocyte progenitors that promote de novo formation of adipocytes. We showed that the Jak family of kinases controlled TGFβ signaling in the adipose tissue microenvironment through Stat3 and thereby adipogenic commitment, a function that was required for beige adipocyte differentiation of murine and human progenitors. Jak/Stat3 inhibited TGFβ signaling to the transcription factors Srf and Smad3 by repressing local Tgfb3 and Tgfb1 expression before the core transcriptional adipogenic cascade was activated. This pathway cross-talk was triggered in stromal cells by ATGL-dependent adipocyte lipolysis and a transient wave of IL-6 family cytokines at the onset of adipose tissue remodeling induced by β3-adrenergic receptor stimulation. Our results provide insight into the activation of adipocyte progenitors and are relevant for the therapeutic targeting of adipose tissue inflammatory pathways.

4.
Cell Metab. 2018 Jan 9;27(1):7-9. doi: 10.1016/j.cmet.2017.12.015.

SERCA2b Cycles Its Way to UCP1-Independent Thermogenesis in Beige Fat.

Author information

1
Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, MI 48202, USA.
2
Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, MI 48202, USA. Electronic address: jgranne@med.wayne.edu.

Abstract

A new study in Nature Medicine, by Ikeda et al. (2017), reports that calcium cycling in beige adipocytes elevates energy expenditure and glucose oxidation in the absence of uncoupling protein 1. Thermogenic calcium cycling in beige fat is mediated by SERCA2b and improves cold tolerance and metabolic status.

5.
Mol Metab. 2018 Jan;7:57-70. doi: 10.1016/j.molmet.2017.10.014. Epub 2017 Nov 12.

Vacuolar protein sorting 13C is a novel lipid droplet protein that inhibits lipolysis in brown adipocytes.

Author information

1
Center for Metabolic Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI, USA.
2
Eye Research Institute, Oakland University, Rochester, MI, USA.
3
Center for Metabolic Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI, USA. Electronic address: jgranne@med.wayne.edu.

Abstract

OBJECTIVE:

Brown adipose tissue (BAT) thermogenesis depends on the mobilization and oxidation of fatty acids from intracellular lipid droplets (LD) within brown adipocytes (BAs); however, the identity and function of LD proteins that control BAT lipolysis remain incomplete. Proteomic analysis of mouse BAT subcellular fractions identified vacuolar protein sorting 13C (VPS13C) as a novel LD protein. The aim of this work was to investigate the role of VPS13C on BA LDs.

METHODS:

Biochemical fractionation and high resolution confocal and immuno-transmission electron microscopy (TEM) were used to determine the subcellular distribution of VPS13C in mouse BAT, white adipose tissue, and BA cell culture. Lentivirus-delivered shRNA was used to determine the role of VPS13C in regulating lipolysis and gene expression in cultured BA cells.

RESULTS:

We found that VPS13C is highly expressed in mouse BAT where it is targeted to multilocular LDs in a subspherical subdomain. In inguinal white adipocytes, VPS13C was mainly observed on small LDs and β3-adrenergic stimulation increased VPS13C in this depot. Silencing of VPS13C in cultured BAs decreased LD size and triglyceride content, increased basal free fatty acid release, augmented the expression of thermogenic genes, and enhanced the lipolytic potency and efficacy of isoproterenol. Mechanistically, we found that BA lipolysis required activation of adipose tissue triglyceride lipase (ATGL) and that loss of VPS13C greatly increased the association of ATGL to LDs.

CONCLUSIONS:

VPS13C is present on BA LDs where is targeted to a distinct subdomain. VPS13C limits the access of ATGL to LD and loss of VPS13C elevates lipolysis and promotes oxidative gene expression.

KEYWORDS:

ATGL; Brown adipose tissue; Free fatty acids; Oxidative genes; Perilipin 1; Thermogenesis

6.
Sci Rep. 2017 Oct 12;7(1):13021. doi: 10.1038/s41598-017-13398-w.

Loss of ABHD5 promotes the aggressiveness of prostate cancer cells.

Author information

1
Department of Pathology, Wayne State University, Detroit, MI, 48201, USA.
2
Biomedical Research Informatics Core, Clinical and Translational Sciences Institute, Michigan State University, East Lansing, MI, 48824, USA.
3
Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA.
4
Department of Laboratory Medicine, Foshan University Medical College, Foshan, Guangdong, 528000, China.
5
Department of Pharmacology, Wayne State University, Detroit, MI, 48201, USA.
6
Department of Pathology, Wayne State University, Detroit, MI, 48201, USA. jianwang@med.wayne.edu.
7
Cardiovascular Research Institute, Wayne State University, Detroit, MI, 48201, USA. jianwang@med.wayne.edu.

Abstract

The accumulation of neutral lipids in intracellular lipid droplets has been associated with the formation and progression of many cancers, including prostate cancer (PCa). Alpha-beta Hydrolase Domain Containing 5 (ABHD5) is a key regulator of intracellular neutral lipids that has been recently identified as a tumor suppressor in colorectal cancer, yet its potential role in PCa has not been investigated. Through mining publicly accessible PCa gene expression datasets, we found that ABHD5 gene expression is markedly decreased in metastatic castration-resistant PCa (mCRPC) samples. We further demonstrated that RNAi-mediated ABHD5 silencing promotes, whereas ectopic ABHD5 overexpression inhibits, the invasion and proliferation of PCa cells. Mechanistically, we found that ABHD5 knockdown induces epithelial to mesenchymal transition, increasing aerobic glycolysis by upregulating the glycolytic enzymes hexokinase 2 and phosphofrucokinase, while decreasing mitochondrial respiration by downregulating respiratory chain complexes I and III. Interestingly, knockdown of ATGL, the best-known molecular target of ABHD5, impeded the proliferation and invasion, suggesting an ATGL-independent role of ABHD5 in modulating PCa aggressiveness. Collectively, these results provide evidence that ABHD5 acts as a metabolic tumor suppressor in PCa that prevents EMT and the Warburg effect, and indicates that ABHD5 is a potential therapeutic target against mCRPC, the deadly aggressive PCa.

7.
J Pharmacol Exp Ther. 2017 Dec;363(3):367-376. doi: 10.1124/jpet.117.243253. Epub 2017 Sep 19.

Novel Pharmacological Probes Reveal ABHD5 as a Locus of Lipolysis Control in White and Brown Adipocytes.

Author information

1
Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan (E.A.R., L.M.-L., J.G.G.); Department of Chemistry, Scripps Research Institute, Jupiter, Florida (W.R.R., G.T.H.); and Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada (A.E.G.).
2
Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan (E.A.R., L.M.-L., J.G.G.); Department of Chemistry, Scripps Research Institute, Jupiter, Florida (W.R.R., G.T.H.); and Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada (A.E.G.) jgranne@med.wayne.edu.

Abstract

Current knowledge regarding acute regulation of adipocyte lipolysis is largely based on receptor-mediated activation or inhibition of pathways that influence intracellular levels of cAMP, thereby affecting protein kinase A (PKA) activity. We recently identified synthetic ligands of α-β-hydrolase domain containing 5 (ABHD5) that directly activate adipose triglyceride lipase (ATGL) by dissociating ABHD5 from its inhibitory regulator, perilipin-1 (PLIN1). In the current study, we used these novel ligands to determine the direct contribution of ABHD5 to various aspects of lipolysis control in white (3T3-L1) and brown adipocytes. ABHD5 ligands stimulated adipocyte lipolysis without affecting PKA-dependent phosphorylation on consensus sites of PLIN1 or hormone-sensitive lipase (HSL). Cotreatment of adipocytes with synthetic ABHD5 ligands did not alter the potency or maximal lipolysis efficacy of the β-adrenergic receptor (ADRB) agonist isoproterenol (ISO), indicating that both target a common pool of ABHD5. Reducing ADRB/PKA signaling with insulin or desensitizing ADRB suppressed lipolysis responses to a subsequent challenge with ISO, but not to ABHD5 ligands. Lastly, despite strong treatment differences in PKA-dependent phosphorylation of HSL, we found that ligand-mediated activation of ABHD5 led to complete triglyceride hydrolysis, which predominantly involved ATGL, but also HSL. These results indicate that the overall pattern of lipolysis controlled by ABHD5 ligands is similar to that of isoproterenol, and that ABHD5 plays a central role in the regulation of adipocyte lipolysis. As lipolysis is critical for adaptive thermogenesis and in catabolic tissue remodeling, ABHD5 ligands may provide a means of activating these processes under conditions where receptor signaling is compromised.

PMID:
28928121
PMCID:
PMC5698943
[Available on 2018-12-01]
DOI:
10.1124/jpet.117.243253
[Indexed for MEDLINE]
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8.
Sci Rep. 2017 Aug 2;7(1):7159. doi: 10.1038/s41598-017-07658-y.

Connexin 43 is required for the maintenance of mitochondrial integrity in brown adipose tissue.

Author information

1
College of Pharmacy, Yonsei University, Incheon, 21983, South Korea.
2
College of Pharmacy, Pusan National University, Busan, 46241, South Korea.
3
Department of Anatomy, Korea University College of Medicine, Seoul, 02841, South Korea.
4
Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University, Korea Mouse Phenotyping Center (KMPC), Seoul, 08826, South Korea.
5
Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, MI, USA, 48201.
6
College of Pharmacy, Yonsei University, Incheon, 21983, South Korea. yunhee.lee@yonsei.ac.kr.

Abstract

We investigated the role of connexin 43 (Cx43) in maintaining the integrity of mitochondria in brown adipose tissue (BAT). The functional effects of Cx43 were evaluated using inducible, adipocyte-specific Cx43 knockout in mice (Gja1 adipoq KO) and by overexpression and knockdown of Cx43 in cultured adipocytes. Mitochondrial morphology was evaluated by electron microscopy and mitochondrial function and autophagy were assessed by immunoblotting, immunohistochemistry, and qPCR. The metabolic effects of adipocyte-specific knockout of Cx43 were assessed during cold stress and following high fat diet feeding. Cx43 expression was higher in BAT compared to white adipose tissue. Treatment with the β3-adrenergic receptor agonist CL316,243 increased Cx43 expression and mitochondrial localization. Gja1 adipoq KO mice reduced mitochondrial density and increased the presence of damaged mitochondria in BAT. Moreover, metabolic activation with CL316,243 further reduced mitochondrial integrity and upregulated autophagy in the BAT of Gja1 adipoq KO mice. Inhibition of Cx43 in cultured adipocytes increased the generation of reactive oxygen species and induction of autophagy during β-adrenergic stimulation. Gja1 adipoq KO mice were cold intolerant, expended less energy in response to β3-adrenergic receptor activation, and were more insulin resistant after a high-fat diet challenge. Collectively, our data demonstrate that Cx43 is required for maintaining the mitochondrial integrity and metabolic activity of BAT.

9.
Mol Metab. 2017 Apr 5;6(6):471-481. doi: 10.1016/j.molmet.2017.04.001. eCollection 2017 Jun.

FGF21 does not require adipocyte AMP-activated protein kinase (AMPK) or the phosphorylation of acetyl-CoA carboxylase (ACC) to mediate improvements in whole-body glucose homeostasis.

Author information

1
Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario, L8N 3Z5, Canada.
2
Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
3
Liver Disease Research, Takeda Pharmaceuticals, 35 Landsdowne Street, Cambridge, MA, 02139, USA.
4
Cardiovascular & Metabolic Diseases, Novartis Institute of Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA.
5
Wayne State University School of Medicine, Detroit, MI, 48201, USA.
6
Cardiometabolic Diseases, Merck Research Laboratories South San Francisco LLC, 630 Gateway Boulevard, South San Francisco, CA, 94080, USA.
7
Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St. W., Hamilton, Ontario, L8N 3Z5, Canada.

Abstract

OBJECTIVE:

Fibroblast growth factor 21 (FGF21) shows great potential for the treatment of obesity and type 2 diabetes, as its long-acting analogue reduces body weight and improves lipid profiles of participants in clinical studies; however, the intracellular mechanisms mediating these effects are poorly understood. AMP-activated protein kinase (AMPK) is an important energy sensor of the cell and a molecular target for anti-diabetic medications. This work examined the role of AMPK in mediating the glucose and lipid-lowering effects of FGF21.

METHODS:

Inducible adipocyte AMPK β1β2 knockout mice (iβ1β2AKO) and littermate controls were fed a high fat diet (HFD) and treated with native FGF21 or saline for two weeks. Additionally, HFD-fed mice with knock-in mutations on the AMPK phosphorylation sites of acetyl-CoA carboxylase (ACC)1 and ACC2 (DKI mice) along with wild-type (WT) controls received long-acting FGF21 for two weeks.

RESULTS:

Consistent with previous studies, FGF21 treatment significantly reduced body weight, adiposity, and liver lipids in HFD fed mice. To add, FGF21 improved circulating lipids, glycemic control, and insulin sensitivity. These effects were independent of adipocyte AMPK and were not associated with changes in browning of white (WAT) and brown adipose tissue (BAT). Lastly, we assessed whether FGF21 exerted its effects through the AMPK/ACC axis, which is critical in the therapeutic benefits of the anti-diabetic medication metformin. ACC DKI mice had improved glucose and insulin tolerance and a reduction in body weight, body fat and hepatic steatosis similar to WT mice in response to FGF21 administration.

CONCLUSIONS:

These data illustrate that the metabolic improvements upon FGF21 administration are independent of adipocyte AMPK, and do not require the inhibitory action of AMPK on ACC. This is in contrast to the anti-diabetic medication metformin and suggests that the treatment of obesity and diabetes with the combination of FGF21 and AMPK activators merits consideration.

KEYWORDS:

ACC; ACC DKI, ACC1-S79A and ACC2-S212A double knock-in; ACC, acetyl-CoA carboxylase; AKT, protein kinase B; AMPK; AMPK, AMP-activated protein kinase; Adipocyte; BAT, brown adipose tissue; Brown fat; CNS, central nervous system; COX, cytochrome c oxidase; CreERT2, Cre recombinase – estrogen receptor T2; DAG, diacylglycerol; Diabetes; FFA, free fatty acid; FGF21; FGF21, fibroblast growth factor 21; FGFR1c, fibroblast growth factor receptor 1c; GTT, glucose tolerance test; H&E, hematoxylin and eosin; HFD, high fat diet; ITT, insulin tolerance test; KLB, beta klotho; NAFLD, non-alcoholic fatty liver disease; Obesity; RER, respiratory exchange ratio; TAG, triacylglycerol; UCP1, uncoupling protein 1; WAT, white adipose tissue; WT, wildtype; gWAT, gonadal white adipose tissue; iWAT, inguinal white adipose tissue; iβ1β2AKO, inducible AMPK β1β2 adipocyte knockout; mTORC1, mammalian target of rapamycin

10.
Elife. 2017 Feb 28;6. pii: e21771. doi: 10.7554/eLife.21771.

Lipid droplet biology and evolution illuminated by the characterization of a novel perilipin in teleost fish.

Author information

1
Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, United States.
2
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, United States.
3
Department of Ophthalmology, Wayne State University School of Medicine, Detroit, United States.
4
Institute of Neuroscience, University of Oregon, Eugene, United States.
5
Department of Biology, University of Oregon, Eugene, United States.

Abstract

Perilipin (PLIN) proteins constitute an ancient family important in lipid droplet (LD) formation and triglyceride metabolism. We identified an additional PLIN clade (plin6) that is unique to teleosts and can be traced to the two whole genome duplications that occurred early in vertebrate evolution. Plin6 is highly expressed in skin xanthophores, which mediate red/yellow pigmentation and trafficking, but not in tissues associated with lipid metabolism. Biochemical and immunochemical analyses demonstrate that zebrafish Plin6 protein targets the surface of pigment-containing carotenoid droplets (CD). Protein kinase A (PKA) activation, which mediates CD dispersion in xanthophores, phosphorylates Plin6 on conserved residues. Knockout of plin6 in zebrafish severely impairs the ability of CD to concentrate carotenoids and prevents tight clustering of CD within carotenoid bodies. Ultrastructural and functional analyses indicate that LD and CD are homologous structures, and that Plin6 was functionalized early in vertebrate evolution for concentrating and trafficking pigment.

KEYWORDS:

carotenoid; cell biology; evolutionary biology; genomics; lipid; perilipin; spotted gar; teleost; xanthophore; zebrafish

PMID:
28244868
PMCID:
PMC5342826
DOI:
10.7554/eLife.21771
[Indexed for MEDLINE]
Free PMC Article
Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
11.
Sci Rep. 2017 Feb 17;7:42589. doi: 10.1038/srep42589.

Molecular Basis of ABHD5 Lipolysis Activation.

Author information

1
Center for Integrative Metabolic and Endocrine Research Wayne State University School of Medicine, Detroit, MI 48201, USA.
2
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.

Abstract

Alpha-beta hydrolase domain-containing 5 (ABHD5), the defective gene in human Chanarin-Dorfman syndrome, is a highly conserved regulator of adipose triglyceride lipase (ATGL)-mediated lipolysis that plays important roles in metabolism, tumor progression, viral replication, and skin barrier formation. The structural determinants of ABHD5 lipolysis activation, however, are unknown. We performed comparative evolutionary analysis and structural modeling of ABHD5 and ABHD4, a functionally distinct paralog that diverged from ABHD5 ~500 million years ago, to identify determinants of ABHD5 lipolysis activation. Two highly conserved ABHD5 amino acids (R299 and G328) enabled ABHD4 (ABHD4 N303R/S332G) to activate ATGL in Cos7 cells, brown adipocytes, and artificial lipid droplets. The corresponding ABHD5 mutations (ABHD5 R299N and ABHD5 G328S) selectively disrupted lipolysis without affecting ATGL lipid droplet translocation or ABHD5 interactions with perilipin proteins and ABHD5 ligands, demonstrating that ABHD5 lipase activation could be dissociated from its other functions. Structural modeling placed ABHD5 R299/G328 and R303/G332 from gain-of-function ABHD4 in close proximity on the ABHD protein surface, indicating they form part of a novel functional surface required for lipase activation. These data demonstrate distinct ABHD5 functional properties and provide new insights into the functional evolution of ABHD family members and the structural basis of lipase regulation.

12.
Sci Rep. 2017 Jan 3;7:39794. doi: 10.1038/srep39794.

Metabolic heterogeneity of activated beige/brite adipocytes in inguinal adipose tissue.

Author information

1
College of Pharmacy, Yonsei University, Incheon, 21983, South Korea.
2
Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, MI, 48201, USA.

Abstract

Sustained β3 adrenergic receptor (ADRB3) activation simultaneously upregulates fatty acid synthesis and oxidation in mouse brown, beige, and white adipose tissues; however, the cellular basis of this dual regulation is not known. Treatment of mice with the ADRB3 agonist CL316,243 (CL) increased expression of fatty acid synthase (FASN) and medium chain acyl-CoA dehydrogenase (MCAD) protein within the same cells in classic brown and white adipose tissues. Surprisingly, in inguinal adipose tissue, CL-upregulated FASN and MCAD in distinct cell populations: high MCAD expression occurred in multilocular adipocytes that co-expressed UCP1+, whereas high FASN expression occurred in paucilocular adipocytes lacking detectable UCP1. Genetic tracing with UCP1-cre, however, indicated nearly half of adipocytes with a history of UCP1 expression expressed high levels of FASN without current expression of UCP1. Global transcriptomic analysis of FACS-isolated adipocytes confirmed the presence of distinct anabolic and catabolic phenotypes, and identified differential expression of transcriptional pathways known to regulate lipid synthesis and oxidation. Surprisingly, paternally-expressed genes of the non-classical gene imprinted network were strikingly enriched in anabolic phenotypes, suggesting possible involvement in maintaining the balance of metabolic phenotypes. The results indicate that metabolic heterogeneity is a distinct property of activated beige/brite adipocytes that might be under epigenetic control.

13.
Oncotarget. 2017 Jan 31;8(5):8043-8056. doi: 10.18632/oncotarget.13302.

The secretion and biological function of tumor suppressor maspin as an exosome cargo protein.

Dean I1,2,3,4, Dzinic SH1,3, Bernardo MM1,3, Zou Y5, Kimler V6,7, Li X1,3,8, Kaplun A1,3,9, Granneman J3,5, Mao G3,6, Sheng S1,2,3.

Author information

1
Department of Pathology, Wayne State University School of Medicine, MI, USA.
2
Department of Oncology, Wayne State University School of Medicine, MI, USA.
3
The Tumor Biology and Microenvironment Program, Karmanos Cancer Institute, MI, USA.
4
Current address: Center for Bioengineering and Tissue Regeneration, The University of California San Francisco, San Francisco, CA, USA.
5
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, MI, USA.
6
Department of Chemical Engineering and Materials Science, Wayne State University, MI, USA.
7
Current address: Ocular Structure and Imaging Facility, Eye Research Institute, Oakland University, Rochester Hills, MI, USA.
8
Current address: Zhangjiagang Aoyang Hospital, Nanjing Medical University, Jiangsu, China.
9
Current address: Variantyx, Framingham, MA, USA.

Abstract

Maspin is an epithelial-specific tumor suppressor shown to exert its biological effects as an intracellular, cell membrane-associated, and secreted free molecule. A recent study suggests that upon DNA-damaging g-irradiation, tumor cells can secrete maspin as an exosome-associated protein. To date, the biological significance of exosomal secretion of maspin is unknown. The current study aims at addressing whether maspin is spontaneously secreted as an exosomal protein to regulate tumor/stromal interactions. We prepared exosomes along with cell extracts and vesicle-depleted conditioned media (VDCM) from normal epithelial (CRL2221, MCF-10A and BEAS-2B) and cancer (LNCaP, PC3 and SUM149) cell lines. Atomic force microscopy and dynamic light scattering analysis revealed similar size distribution patterns and surface zeta potentials between the normal cells-derived and tumor cells-derived exosomes. Electron microscopy revealed that maspin was encapsulated by the exosomal membrane as a cargo protein. While western blotting revealed that the level of exosomal maspin from tumor cell lines was disproportionally lower relative to the levels of corresponding intracellular and VDCM maspin, as compared to that from normal cell lines, maspin knockdown in MCF-10A cells led to maspin-devoid exosomes, which exhibited significantly reduced suppressive effects on the chemotaxis activity of recipient NIH3T3 fibroblast cells. These data are the first to demonstrate the potential of maspin delivered by exosomes to block tumor-induced stromal response, and support the clinical application of exosomal maspin in cancer diagnosis and treatment.

KEYWORDS:

electron microscopy; exosome; exosome cargo; tumor microenvironment; tumor progression

PMID:
28009978
PMCID:
PMC5352381
DOI:
10.18632/oncotarget.13302
[Indexed for MEDLINE]
Free PMC Article
Icon for Impact Journals, LLC Icon for PubMed Central
14.
Biol Sex Differ. 2016 Dec 9;7:67. doi: 10.1186/s13293-016-0121-7. eCollection 2016.

Sex differences in sympathetic innervation and browning of white adipose tissue of mice.

Author information

1
College of Pharmacy, Yonsei University, 310 Veritas Hall D, 85 Songdogwahak-ro, Yeonsu-gu Incheon, 21983 South Korea.
2
College of Pharmacy, Pusan National University, Busan, 46241 South Korea.
3
BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science, and Korea Mouse Phenotyping Center, Seoul National University, Seoul, 08826 South Korea.
4
School of Medicine, Wayne State University, Detroit, MI 48201 USA.
#
Contributed equally

Abstract

BACKGROUND:

The higher prevalence of obesity-related metabolic disease in males suggests that female sex hormones provide protective mechanisms against the pathogenesis of metabolic syndrome. Because browning of white adipose tissue (WAT) is protective against obesity-related metabolic disease, we examined sex differences in β3-adrenergic remodeling of WAT in mice.

METHODS:

Effects of the β3-adrenergic receptor agonist CL316,243 (CL) on browning of white adipose tissue were investigated in male and female C57BL mice. The role of ovarian hormones in female-specific browning was studied in control female C57BL mice and mice with ovarian failure induced by 4-vinylcyclohexene diepoxide treatment for 15 days.

RESULTS:

We found that treatment with CL-induced upregulation of brown adipocyte markers and mitochondrial respiratory chain proteins in gonadal WAT (gWAT) of female mice, but was without effect in males. In contrast, CL treatment was equally effective in males and females in inducing brown adipocyte phenotypes in inguinal WAT. The tissue- and sex-specific differences in brown adipocyte recruitment were correlated with differences in sympathetic innervation, as determined by tyrosine hydroxylase immunostaining and western blotting. Levels of the neurotrophins NGF and BDNF were significantly higher in gWAT of female mice. CL treatment significantly increased NGF levels in gWAT of female mice but did not affect BDNF expression. In contrast, estradiol treatment doubled BDNF expression in female adipocytes differentiated in vitro. Ovarian failure induced by 4-vinylcyclohexene diepoxide treatment dramatically reduced BDNF and TH expression in gWAT, eliminated induction of UCP1 by CL, and reduced tissue metabolic rate.

CONCLUSIONS:

Collectively, these data demonstrate that female mice are more responsive than males to the recruitment of brown adipocytes in gonadal WAT and this difference corresponds to greater levels of estrogen-dependent sympathetic innervation.

KEYWORDS:

Brown adipocytes; Sex differences; Sympathetic innervation; UCP1; White adipose tissue

15.
J Nucl Med. 2017 May;58(5):799-806. doi: 10.2967/jnumed.116.180992. Epub 2016 Oct 27.

Sympathetic Innervation of Cold-Activated Brown and White Fat in Lean Young Adults.

Author information

1
Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan otto@pet.wayne.edu.
2
Department of Radiology, Wayne State University School of Medicine, Detroit, Michigan.
3
Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan.
4
Department of Anthropology, Northwestern University, Evanston, Illinois.
5
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan; and.
6
Center for Integrative Metabolic and Endocrine Research and Family Medicine.

Abstract

Recent work in rodents has demonstrated that basal activity of the local sympathetic nervous system is critical for maintaining brown adipocyte phenotypes in classic brown adipose tissue (BAT) and white adipose tissue (WAT). Accordingly, we sought to assess the relationship between sympathetic innervation and cold-induced activation of BAT and WAT in lean young adults. Methods: Twenty adult lean normal subjects (10 women and 10 men; mean age ± SD, 23.3 ± 3.8 y; body mass index, 23.7 ± 2.5 kg/m2) underwent 11C-meta-hydroxyephedrin (11C-HED) and 15O-water PET imaging at rest and after exposure to mild cold (16°C) temperature. In addition, 18F-FDG images were obtained during the cold stress condition to assess cold-activated BAT mass. Subjects were divided into 2 groups (high BAT and low BAT) based on the presence of 18F-FDG tracer uptake. Blood flow and 11C-HED retention index (RI, an indirect measure of sympathetic innervation) were calculated from dynamic PET scans at the location of BAT and WAT. Whole-body daily energy expenditure (DEE) during rest and cold stress was measured by indirect calorimetry. Tissue level oxygen consumption (MRO2) was determined and used to calculate the contribution of cold-activated BAT and WAT to daily DEE. Results:18F-FDG uptake identified subjects with high and low levels of cold-activated BAT mass (high BAT, 96 ± 37 g; low-BAT, 16 ± 4 g). 11C-HED RI under thermoneutral conditions significantly predicted 18F-FDG uptake during cold stress (R2 = 0.68, P < 0.01). In contrast to the significant increase of 11C-HED RI during cold in BAT (2.42 ± 0.85 vs. 3.43 ± 0.93, P = 0.02), cold exposure decreased the 11C-HED RI in WAT (0.44 ± 0.22 vs. 0.41 ± 0.18) as a consequence of decreased perfusion (1.22 ± 0.20 vs. 1.12 ± 0.16 mL/100 g/min). The contribution of WAT to whole-body DEE was approximately 150 kcal/d at rest (149 ± 52 kcal/d), which decreased to approximately 100 kcal/d during cold (102 ± 47 kcal/d). Conclusion: The level of sympathetic innervation, as determined by 11C-HED RI, can predict levels of functional BAT. Overall, blood flow is the best independent predictor of 11C-HED RI and 18F-FDG uptake across thermoneutral and cold conditions. In contrast to BAT, cold stress reduces blood flow and 18F-FDG uptake in subcutaneous WAT, indicating that the physiologic response is to reduce heat loss rather than to generate heat.

KEYWORDS:

HED PET imaging; brown fat; subcutaneous fat; sympathetic innervation

PMID:
27789721
PMCID:
PMC5414500
DOI:
10.2967/jnumed.116.180992
[Indexed for MEDLINE]
Free PMC Article
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16.
Cell Metab. 2016 Jul 12;24(1):118-29. doi: 10.1016/j.cmet.2016.06.006.

Lack of Adipocyte AMPK Exacerbates Insulin Resistance and Hepatic Steatosis through Brown and Beige Adipose Tissue Function.

Author information

1
Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
2
Nestlé Institute of Health Sciences SA, EPFL Innovation Park, Lausanne, Switzerland.
3
The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
4
Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
5
Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
6
The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen N, Denmark.
7
St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Victoria 3065, Australia; Mary MacKillop Institute for Health Research Australian Catholic University, Victoria Parade, Fitzroy, Victoria 3065, Australia.
8
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit 48201, MI, USA.
9
Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada. Electronic address: gsteinberg@mcmaster.ca.

Abstract

Brown (BAT) and white (WAT) adipose tissues play distinct roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. The AMP-activated protein kinase (AMPK) is a cellular energy sensor, but its role in regulating BAT and WAT metabolism is unclear. We generated an inducible model for deletion of the two AMPK β subunits in adipocytes (iβ1β2AKO) and found that iβ1β2AKO mice were cold intolerant and resistant to β-adrenergic activation of BAT and beiging of WAT. BAT from iβ1β2AKO mice had impairments in mitochondrial structure, function, and markers of mitophagy. In response to a high-fat diet, iβ1β2AKO mice more rapidly developed liver steatosis as well as glucose and insulin intolerance. Thus, AMPK in adipocytes is vital for maintaining mitochondrial integrity, responding to pharmacological agents and thermal stress, and protecting against nutrient-overload-induced NAFLD and insulin resistance.

PMID:
27411013
PMCID:
PMC5239668
DOI:
10.1016/j.cmet.2016.06.006
[Indexed for MEDLINE]
Free PMC Article
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17.
Adipocyte. 2016 Feb 18;5(2):119-29. doi: 10.1080/21623945.2016.1145846. eCollection 2016 Apr-Jun.

Adrenergic regulation of cellular plasticity in brown, beige/brite and white adipose tissues.

Author information

1
Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University , Detroit, MI, USA.
2
Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI, USA; John Dingell Vet Administration Medical Center, Detroit, MI, USA.

Abstract

The discovery of brown adipose tissue in adult humans along with the recognition of adipocyte heterogeneity and plasticity of white fat depots has renewed the interest in targeting adipose tissue for therapeutic benefit. Adrenergic activation is a well-established means of recruiting catabolic adipocyte phenotypes in brown and white adipose tissues. In this article, we review mechanisms of brown adipocyte recruitment by the sympathetic nervous system and by direct β-adrenergic receptor activation. We highlight the distinct modes of brown adipocyte recruitment in brown, beige/brite, and white adipose tissues, UCP1-independent thermogenesis, and potential non-thermogenic, metabolically beneficial effects of brown adipocytes.

KEYWORDS:

PDGFR α; PGC1 α; UCP1; energy metabolism; gonadal adipose tissue; inguinal adipose tissue; innervation; multilocular; sympathetic nervous system; thermogenesis

18.
J Biol Chem. 2016 Jul 29;291(31):16001-10. doi: 10.1074/jbc.M116.725937. Epub 2016 May 31.

Characterization of Eicosanoids Produced by Adipocyte Lipolysis: IMPLICATION OF CYCLOOXYGENASE-2 IN ADIPOSE INFLAMMATION.

Author information

1
From the Bioactive Lipid Research Program, Department of Pathology.
2
Department of Pathology.
3
Department of Chemistry.
4
Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
5
Center for Integrative Metabolic and Endocrine Research, Center for Molecular Medicine and Genetics.
6
From the Bioactive Lipid Research Program, Department of Pathology, Cardiovascular Research Institute, and Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48202 and menqjer.lee@wayne.edu.

Abstract

Excessive adipocyte lipolysis generates lipid mediators and triggers inflammation in adipose tissue. However, the specific roles of lipolysis-generated mediators in adipose inflammation remain to be elucidated. In the present study, cultured 3T3-L1 adipocytes were treated with isoproterenol to activate lipolysis and the fatty acyl lipidome of released lipids was determined by using LC-MS/MS. We observed that β-adrenergic activation elevated levels of approximately fifty lipid species, including metabolites of cyclooxygenases, lipoxygenases, epoxygenases, and other sources. Moreover, we found that β-adrenergic activation induced cyclooxygenase 2 (COX-2), not COX-1, expression in a manner that depended on activation of hormone-sensitive lipase (HSL) in cultured adipocytes and in the epididymal white adipose tissue (EWAT) of C57BL/6 mice. We found that lipolysis activates the JNK/NFκB signaling pathway and inhibition of the JNK/NFκB axis abrogated the lipolysis-stimulated COX-2 expression. In addition, pharmacological inhibition of COX-2 activity diminished levels of COX-2 metabolites during lipolytic activation. Inhibition of COX-2 abrogated the induction of CCL2/MCP-1 expression by β-adrenergic activation and prevented recruitment of macrophage/monocyte to adipose tissue. Collectively, our data indicate that excessive adipocyte lipolysis activates the JNK/NFκB pathway leading to the up-regulation of COX-2 expression and recruitment of inflammatory macrophages.

KEYWORDS:

NF-kappa B (NF-κB); adipocyte; adrenergic receptor; cyclooxygenase (COX); eicosanoid; inflammation; lipolysis; prostaglandin

PMID:
27246851
PMCID:
PMC4965551
DOI:
10.1074/jbc.M116.725937
[Indexed for MEDLINE]
Free PMC Article
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19.
Int J Obes Suppl. 2015 Aug;5(Suppl 1):S7-S10. doi: 10.1038/ijosup.2015.3. Epub 2015 Aug 4.

Renaissance of brown adipose tissue research: integrating the old and new.

Author information

1
Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine , Detroit, MI, USA.

Abstract

The recent demonstration of active brown adipose tissue (BAT) in adult humans, along with the discovery of vast cellular and metabolic plasticity of adipocyte phenotypes, has given new hope of targeting adipose tissue for therapeutic benefit. Application of principles learned from the first wave of obesity-related BAT research, conducted 30 years earlier, suggests that the activity and/or mass of brown fat will need to be greatly expanded for it to significantly contribute to total energy expenditure. Although the thermogenic capacity of human brown fat is very modest, its presence often correlates with improved metabolic status, suggesting possible beneficial endocrine functions. Recent advances in our understanding of the nature of progenitors and the transcriptional programs that guide phenotypic diversity have demonstrated the possibility of expanding the population of brown adipocytes in rodent models. Expanded populations of brown and beige adipocytes will require tight control of their metabolic activity, which might be achieved by selective neural activation, tissue-selective signaling or direct activation of lipolysis, which supplies the central fuel of thermogenesis.

20.
Am J Physiol Regul Integr Comp Physiol. 2016 Jan 1;310(1):R55-65. doi: 10.1152/ajpregu.00355.2015. Epub 2015 Nov 4.

Adipogenic role of alternatively activated macrophages in β-adrenergic remodeling of white adipose tissue.

Author information

1
College of Pharmacy, Yonsei University, Incheon, South Korea;
2
Lipidomics Core Facility and Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan; and.
3
Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, Michigan jgranne@med.wayne.edu.

Abstract

De novo brown adipogenesis involves the proliferation and differentiation of progenitors, yet the mechanisms that guide these events in vivo are poorly understood. We previously demonstrated that treatment with a β3-adrenergic receptor (ADRB3) agonist triggers brown/beige adipogenesis in gonadal white adipose tissue following adipocyte death and clearance by tissue macrophages. The close physical relationship between adipocyte progenitors and tissue macrophages suggested that the macrophages that clear dying adipocytes might generate proadipogenic factors. Flow cytometric analysis of macrophages from mice treated with CL 316,243 identified a subpopulation that contained elevated lipid and expressed CD44. Lipidomic analysis of fluorescence-activated cell sorting-isolated macrophages demonstrated that CD44+ macrophages contained four- to five-fold higher levels of the endogenous peroxisome-proliferator activated receptor gamma (PPARγ) ligands 9-hydroxyoctadecadienoic acid (HODE), and 13-HODE compared with CD44- macrophages. Gene expression profiling and immunohistochemistry demonstrated that ADRB3 agonist treatment upregulated expression of ALOX15, the lipoxygenase responsible for generating 9-HODE and 13-HODE. Using an in vitro model of adipocyte efferocytosis, we found that IL-4-primed tissue macrophages accumulated lipid from dying fat cells and upregulated expression of Alox15. Furthermore, treatment of differentiating adipocytes with 9-HODE and 13-HODE potentiated brown/beige adipogenesis. Collectively, these data indicate that noninflammatory removal of adipocyte remnants and coordinated generation of PPARγ ligands by M2 macrophages provides localized adipogenic signals to support de novo brown/beige adipogenesis.

KEYWORDS:

adipogenesis; adipose tissue macrophages; beige adipocytes; brown adipocytes; phagocytosis

PMID:
26538237
PMCID:
PMC4796635
DOI:
10.1152/ajpregu.00355.2015
[Indexed for MEDLINE]
Free PMC Article
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