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  1. Article ; Online: Mice lacking triglyceride synthesis enzymes in adipose tissue are resistant to diet-induced obesity.

    Chitraju, Chandramohan / Fischer, Alexander W / Ambaw, Yohannes A / Wang, Kun / Yuan, Bo / Hui, Sheng / Walther, Tobias C / Farese, Robert V

    eLife

    2023  Volume 12

    Abstract: Triglycerides (TGs) in adipocytes provide the major stores of metabolic energy in the body. Optimal amounts of TG stores are desirable as insufficient capacity to store TG, as in lipodystrophy, or exceeding the capacity for storage, as in obesity, ... ...

    Abstract Triglycerides (TGs) in adipocytes provide the major stores of metabolic energy in the body. Optimal amounts of TG stores are desirable as insufficient capacity to store TG, as in lipodystrophy, or exceeding the capacity for storage, as in obesity, results in metabolic disease. We hypothesized that mice lacking TG storage in adipocytes would result in excess TG storage in cell types other than adipocytes and severe lipotoxicity accompanied by metabolic disease. To test this hypothesis, we selectively deleted both TG synthesis enzymes, DGAT1 and DGAT2, in adipocytes (ADGAT DKO mice). As expected with depleted energy stores, ADGAT DKO mice did not tolerate fasting well and, with prolonged fasting, entered torpor. However, ADGAT DKO mice were unexpectedly otherwise metabolically healthy and did not accumulate TGs ectopically or develop associated metabolic perturbations, even when fed a high-fat diet. The favorable metabolic phenotype resulted from activation of energy expenditure, in part via BAT (brown adipose tissue) activation and beiging of white adipose tissue. Thus, the ADGAT DKO mice provide a fascinating new model to study the coupling of metabolic energy storage to energy expenditure.
    MeSH term(s) Animals ; Mice ; Obesity ; Adipocytes ; Adipose Tissue, Brown ; Diet, High-Fat/adverse effects ; Triglycerides
    Chemical Substances Triglycerides
    Language English
    Publishing date 2023-10-02
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.88049
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Transcriptional determinants of lipid mobilization in human adipocytes.

    Ludzki, Alison C / Hansen, Mattias / Zareifi, Danae / Jalkanen, Jutta / Huang, Zhiqiang / Omar-Hmeadi, Muhmmad / Renzi, Gianluca / Klingelhuber, Felix / Boland, Sebastian / Ambaw, Yohannes A / Wang, Na / Damdimopoulos, Anastasios / Liu, Jianping / Jernberg, Tomas / Petrus, Paul / Arner, Peter / Krahmer, Natalie / Fan, Rongrong / Treuter, Eckardt /
    Gao, Hui / Rydén, Mikael / Mejhert, Niklas

    Science advances

    2024  Volume 10, Issue 1, Page(s) eadi2689

    Abstract: Defects in adipocyte lipolysis drive multiple aspects of cardiometabolic disease, but the transcriptional framework controlling this process has not been established. To address this, we performed a targeted perturbation screen in primary human ... ...

    Abstract Defects in adipocyte lipolysis drive multiple aspects of cardiometabolic disease, but the transcriptional framework controlling this process has not been established. To address this, we performed a targeted perturbation screen in primary human adipocytes. Our analyses identified 37 transcriptional regulators of lipid mobilization, which we classified as (i) transcription factors, (ii) histone chaperones, and (iii) mRNA processing proteins. On the basis of its strong relationship with multiple readouts of lipolysis in patient samples, we performed mechanistic studies on one hit,
    MeSH term(s) Humans ; Lipid Mobilization ; Adipocytes/metabolism ; Lipolysis/genetics ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Chromatin/genetics ; Chromatin/metabolism
    Chemical Substances Transcription Factors ; Chromatin
    Language English
    Publishing date 2024-01-03
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.adi2689
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis.

    Boland, Sebastian / Swarup, Sharan / Ambaw, Yohannes A / Malia, Pedro C / Richards, Ruth C / Fischer, Alexander W / Singh, Shubham / Aggarwal, Geetika / Spina, Salvatore / Nana, Alissa L / Grinberg, Lea T / Seeley, William W / Surma, Michal A / Klose, Christian / Paulo, Joao A / Nguyen, Andrew D / Harper, J Wade / Walther, Tobias C / Farese, Robert V

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 5924

    Abstract: Haploinsufficiency of GRN causes frontotemporal dementia (FTD). The GRN locus produces progranulin (PGRN), which is cleaved to lysosomal granulin polypeptides. The function of lysosomal granulins and why their absence causes neurodegeneration are unclear. ...

    Abstract Haploinsufficiency of GRN causes frontotemporal dementia (FTD). The GRN locus produces progranulin (PGRN), which is cleaved to lysosomal granulin polypeptides. The function of lysosomal granulins and why their absence causes neurodegeneration are unclear. Here we discover that PGRN-deficient human cells and murine brains, as well as human frontal lobes from GRN-mutation FTD patients have increased levels of gangliosides, glycosphingolipids that contain sialic acid. In these cells and tissues, levels of lysosomal enzymes that catabolize gangliosides were normal, but levels of bis(monoacylglycero)phosphates (BMP), lipids required for ganglioside catabolism, were reduced with PGRN deficiency. Our findings indicate that granulins are required to maintain BMP levels to support ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosidosis. Lysosomal ganglioside accumulation may contribute to neuroinflammation and neurodegeneration susceptibility observed in FTD due to PGRN deficiency and other neurodegenerative diseases.
    MeSH term(s) Animals ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/metabolism ; Gangliosides/metabolism ; Gangliosidoses/metabolism ; Granulins/metabolism ; Humans ; Lysosomes/metabolism ; Mice ; N-Acetylneuraminic Acid/metabolism ; Phosphates/metabolism ; Progranulins/genetics ; Progranulins/metabolism
    Chemical Substances GRN protein, human ; Gangliosides ; Granulins ; Grn protein, mouse ; Phosphates ; Progranulins ; N-Acetylneuraminic Acid (GZP2782OP0)
    Language English
    Publishing date 2022-10-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-33500-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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