Triglyceride Synthesis by DGAT1 Protects Adipocytes from Lipid-Induced ER Stress during Lipolysis

Chitraju, Chandramohan; Mejhert, Niklas; Haas, Joel T.; Diaz‐Ramirez, L. Grisell; Grueter, Carrie A.; Imbriglio, Jason E.; Pinto, Shirly; Koliwad, Suneil K.; Walther, Tobias C.; Farese, Robert V.

doi:10.1016/j.cmet.2017.07.012

Cited by 253 publications

(218 citation statements)

References 66 publications

(108 reference statements)

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“…This finding is also consistent with our recent report of increased expression of ChREBP/MLX-target genes in cells lacking LDs through DGAT inhbition (Mejhert et al, 2020). Moreover, they agree with previous studies that suggest a feedback mechanism correlating reduced DGAT activity with inhibiton of the SREBP1mediated lipogenic pathway (Chitraju et al, 2017;Choi et al, 2007;Monetti et al, 2007).…”

Section: Discussionsupporting

confidence: 93%

“…Glycogen granules were visible in electron microscopy images of BAT from HFD-fed BA-DGAT KO mice ( Figures 4C and S4C). Since previous studies showed that DGAT-catalyzed TG synthesis is important to protect cells from high intracellular FA levels (Chitraju et al, 2017;Koliwad et al, 2010;Listenberger et al, 2003;Liu et al, 2014), we measured expression ER stress and inflammatory marker genes but found no increases ( Figure 4G).…”

Section: Ba-dgat Ko Mice Are Resistant To High-fat-diet-induced Glucomentioning

confidence: 81%

“…Upon cold exposure, activation of expression of BAT-specific and thermogenic genes, such as Ucp1, Pgc1α, CideA, and Dio2, was similar in BAT of BA-DGAT KO and control mice ( Figure 3B), as were the mRNA expression levels of genes involved in FA oxidation (Figures 3A,3B and S3A). Storing TG in LDs protects white adipocytes from lipid-ER stress (Chitraju et al, 2017).…”

Section: Bat Lacking Tg Stores Exhibits Adaptations To Maintain Thermmentioning

confidence: 99%

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Lipid Droplets in Brown Adipose Tissue Are Dispensable for Cold-Induced Thermogenesis

Chitraju

Fischer

Farese

et al. 2020

Preprint

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Brown adipocytes store metabolic energy as triglycerides (TG) in multilocular lipid droplets (LDs). Fatty acids released from brown adipocyte LDs by lipolysis are thought to activate and fuel UCP1-mediated thermogenesis. Here we test this hypothesis by preventing fatty acid storage in murine brown adipocytes through brown adipose tissue (BAT)-specific deletions of the TG synthesis enzymes, DGAT1 and DGAT2 (BA-DGAT KO). Despite the absence of LDs, BA-DGAT KO mice had functional BAT and maintained euthermia during acute or chronic cold exposure. As apparent adaptations to the lack of TG, brown adipocytes of BA-DGAT KO mice appear to utilize circulating glucose and fatty acids, as well as stored glycogen to fuel thermogenesis. Moreover, BA-DGAT KO mice were resistant to diet-induced glucose intolerance, likely due to increased glucose disposal by BAT. Thus, surprisingly, TGs in BAT are dispensable for its function, in part through adaptations to utilize other fuel sources.

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Section: Discussionsupporting

confidence: 93%

Section: Ba-dgat Ko Mice Are Resistant To High-fat-diet-induced Glucomentioning

confidence: 81%

Section: Bat Lacking Tg Stores Exhibits Adaptations To Maintain Thermmentioning

confidence: 99%

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Lipid Droplets in Brown Adipose Tissue Are Dispensable for Cold-Induced Thermogenesis

Chitraju

Fischer

Farese

et al. 2020

Preprint

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“…However, LDs are recognized to mediate additional functions including the sequestration of toxic lipids and the prevention of excessive endoplasmic reticulum (ER) stress, and as lipid donors for autophagosome formation 2,12,13 .…”

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confidence: 99%

Triacylglycerol synthesis enhances macrophage inflammatory function

Castoldi

Monteiro

Bakker

et al. 2020

Preprint

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Macrophages are integral to most tissues. Foam cells, macrophages with lipid droplets (LDs) which are stores of triacylglycerols (TGs) and cholesterol esters (CEs), are found in various disease states 1 . LDs can act as energy stores since TG lipolysis releases fatty acids (FAs) for mitochondrial oxidation (FAO), a process that relies on long-chain FA conversion into acylcarnitines by the enzyme Cpt1a 2 . However, in macrophages, proinflammatory signals result in diminished FAO and increased TG synthesis with LD development 3,4 . We explored the significance of LDs in cells that do not utilize FAO. We show that macrophages stimulated with lipopolysaccharide (LPS) plus interferon-g (IFNg) accumulate TGs in LDs, and long-chain acylcarnitines. In these cells, inhibition of TG synthesis results in diminished LD development, and increased long chain acylcarnitine levels, suggesting that FA fate is balanced between TG and acylcarnitine synthesis. Nevertheless, TG-synthesis is required for inflammatory macrophage function, since its inhibition negatively affects production of proinflammatory IL-1b, IL-6 and PGE2, and phagocytic capacity, and protects against LPS-induced shock in vivo. Failure to make PGE2 is critical for this phenotype, since exogenous PGE2 reverses the anti-inflammatory effects of TG-synthesis inhibition. These findings place LDs in a position of central functional importance in inflammatory macrophages. EJP and ELP are Founders of Rheos Medicines MethodsMice and in vivo experiments C57BL/6 mice (RRID: IMSR_JAX:000664) were from The Jackson Laboratory, and were maintained in specific pathogen-free conditions under protocols approved by the animal care committee of the Regierungspräsidium Freiburg, Germany, in compliance with all relevant ethical regulations. Animals were 6-8 weeks old when used. They were euthanized by carbon dioxide asphyxiation followed by cervical

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“…The re-esterification seems to be a central part of this control system. Recently published data show that reesterification during lipolysis in adipocytes protects against ER-stress and that DGAT1 is responsible for the protection of ER lipotoxic stress [193]. DGAT is one of the three acyltransferases involved in TAG synthesis.…”

Section: Lipolysis In T2dmentioning

confidence: 99%

Insulin Signalling in Human Adipocytes and its Interplay with beta-Adrenergic Control of Lipolysis

Karlsson¹

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Cover: Fluorescence microscopic image demonstrating the association of caveolin-1 and IQGAP1 (paper II). In a proximity ligation assay each red dot represents a single IQGAP1 -caveolin-1 complex stained with Hoechst, nucleus is stained with DAPI. © Cecilia Jönsson 2018Published articles in this thesis have been reprinted with the permission of respective copyright holders. Printed by LiU-Tryck, Linköping 2018 During the course of the research underlying this thesis, Cecilia Jönsson was enrolled in Forum Scientium, a multidisciplinary doctoral program at Linköping University, Sweden AbstractThe prevalence of obesity has over the last 40 years nearly tripled and obesity is one of the major risk factors of developing type 2 diabetes. Type 2 diabetes was formerly called adultonset diabetes but today, probably due to the rise in childhood obesity, it is also seen in children and adolescents. Type 2 diabetes is diagnosed when the body no longer can control the glucose levels in the blood. This is due to an insulin resistant state in the insulin responding tissues, liver, adipose and muscle and insufficient production of insulin in the pancreas. However, in spite of extensive research the mechanisms behind insulin resistance is still not known.The adipose tissue is believed to play a major role in the development of whole body insulin resistance. Adipocytes are the most important sites for storage of the high energy containing triacylglycerols. Insulin stimulation causes the adipocyte to increase the uptake of glucose and to reduce lipolysis: the hydrolysis of triacylglycerol and release of glycerol and fatty acids. The insulin signalling network is complex with numerous proteins involved. These signalling proteins not only transmit the insulin signal but also create negative and positive feedbackloops and induce cross talk between different parts of the network and with the signalling of other hormones. One important positive feedback in insulin signalling is the mTORC1 mediated feedback to phosphorylation of IRS1 at serine 307. In paper I we found that in human adipocytes this feedback is not likely catalysed by the assumed kinase S6K1. However we find an immunoprecipitate of mTOR to contain a ser307 phosphorylating kinase.Scaffolding proteins serve as docking sites for several proteins to promote protein-protein interactions that facilitate signal transduction. In paper II we demonstrate the existence of the scaffolding protein IQGAP1 in human adipocytes and that the expression of IQGAP1 is downregulated in type 2 diabetes. We reveal that IQGAP1 co-localises with caveolae, invaginations of the plasma membrane where the insulin receptor is situated, and that this interaction is increased upon insulin stimulation.In paper III we focus on the control of lipolysis, and sought to understand the interplay between insulin and beta-adrenergic stimulation. We demonstrated that the re-esterification of fatty acids is downregulated in type 2 diabetes causing an increased release of fatty acids from the cells. We showed th...

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Triglyceride Synthesis by DGAT1 Protects Adipocytes from Lipid-Induced ER Stress during Lipolysis

Cited by 253 publications

References 66 publications

Lipid Droplets in Brown Adipose Tissue Are Dispensable for Cold-Induced Thermogenesis

Lipid Droplets in Brown Adipose Tissue Are Dispensable for Cold-Induced Thermogenesis

Triacylglycerol synthesis enhances macrophage inflammatory function

Insulin Signalling in Human Adipocytes and its Interplay with beta-Adrenergic Control of Lipolysis

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