Nod1-mediated lipolysis promotes diacylglycerol accumulation and successive inflammation via PKCδ-IRAK axis in adipocytes

Sharma, Aditya; Maurya, Chandan Kumar; Arha, Deepti; Amit, K.; Singh, Sushmita; Varshney, Salil; Schertzer, Jonathan D.; Tamrakar, Akhilesh K.

doi:10.1016/j.bbadis.2018.10.036

Cited by 22 publications

(14 citation statements)

References 43 publications

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“…The HFD used promoted a modest increase in body weight of the WT animals (9.8% increase after 6 weeks); however, in the absence of NOD1 the body weight gain was 33.3% during this period, reflecting this obesity in adipose tissue and in the liver. In addition to this, these tissues became more infiltrated by immune cells, such as macrophages and neutrophils, as it has been previously described 4 , 22 , 24 . The idea that lipids and bacterial-derived molecules cooperate in the induction of ‘metabolic inflammation’ and obesity comes from the fact that particularly NOD1 is overexpressed and activated in adipose tissue in response to these challenges 10 , 18 , 20 , 23 .…”

Section: Discussionsupporting

confidence: 57%

NOD1 deficiency promotes an imbalance of thyroid hormones and microbiota homeostasis in mice fed high fat diet

González-Ramos

Paz-García

Fernández-García

et al. 2020

Sci Rep

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The contribution of the nucleotide-binding oligomerization domain protein NOD1 to obesity has been investigated in mice fed a high fat diet (HFD). Absence of NOD1 accelerates obesity as early as 2 weeks after feeding a HFD. The obesity was due to increases in abdominal and inguinal adipose tissues. Analysis of the resting energy expenditure showed an impaired function in NOD1-deficient animals, compatible with an alteration in thyroid hormone homeostasis. Interestingly, free thyroidal T4 increased in NOD1-deficient mice fed a HFD and the expression levels of UCP1 in brown adipose tissue were significantly lower in NOD1-deficient mice than in the wild type animals eating a HFD, thus contributing to the observed adiposity in NOD1-deficient mice. Feeding a HFD resulted in an alteration of the proinflammatory profile of these animals, with an increase in the infiltration of inflammatory cells in the liver and in the white adipose tissue, and an elevation of the circulating levels of TNF-α. In addition, alterations in the gut microbiota in NOD1-deficient mice correlate with increased vulnerability of their ecosystem to the HFD challenge and affect the immune-metabolic phenotype of obese mice. Together, the data are compatible with a protective function of NOD1 against low-grade inflammation and obesity under nutritional conditions enriched in saturated lipids. Moreover, one of the key players of this early obesity onset is a dysregulation in the metabolism and release of thyroid hormones leading to reduced energy expenditure, which represents a new role for these hormones in the metabolic actions controlled by NOD1.

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Section: Discussionsupporting

confidence: 57%

NOD1 deficiency promotes an imbalance of thyroid hormones and microbiota homeostasis in mice fed high fat diet

González-Ramos

Paz-García

Fernández-García

et al. 2020

Sci Rep

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“…The mTOR complex, mTORC1, coordinates a negative feedback loop on insulin signalling, for example, through activation of GRB10 or via S6K1 ( Um et al, 2004 ). mTORC1 signalling is also regulated by protein kinase C (PKC) ( Zhan et al, 2019 ), and specific PKC isoforms are dysregulated in ageing, metabolic, neurodegenerative and inflammatory diseases ( Li et al, 2015 ; Sajan et al, 2018 ; Sharma et al, 2019 ). We observed that the broad-spectrum PKC inhibitor, bisindolylmaleimide I, induced a strong positive IR signature score (+87) and the related compound, ruboxistaurin, reverses IR in vivo ( Guo et al, 2020 ; Naruse et al, 2006 ).…”

Section: Resultsmentioning

confidence: 99%

A human-based multi-gene signature enables quantitative drug repurposing for metabolic disease

Timmons

Anighoro²,

Brogan

et al. 2022

eLife

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Insulin resistance (IR) contributes to the pathophysiology of diabetes, dementia, viral infection, and cardiovascular disease. Drug repurposing (DR) may identify treatments for IR; however, barriers include uncertainty whether in vitro transcriptomic assays yield quantitative pharmacological data, or how to optimise assay design to best reflect in vivo human disease. We developed a clinical-based human tissue IR signature by combining lifestyle-mediated treatment responses (>500 human adipose and muscle biopsies) with biomarkers of disease status (fasting IR from >1200 biopsies). The assay identified a chemically diverse set of >130 positively acting compounds, highly enriched in true positives, that targeted 73 proteins regulating IR pathways. Our multi-gene RNA assay score reflected the quantitative pharmacological properties of a set of epidermal growth factor receptor-related tyrosine kinase inhibitors, providing insight into drug target specificity; an observation supported by deep learning-based genome-wide predicted pharmacology. Several drugs identified are suitable for evaluation in patients, particularly those with either acute or severe chronic IR.

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“…Oil red O staining was done to measure the lipid accumulation in 3T3-L1 adipocytes [20]. After the treatment (on day 10), cells were gently washed with ice-cold PBS and fixed in 3% paraformaldehyde for 30 min, followed by washing with PBS and staining with filtered oil red O solution (3 mg/mL in isopropanol, 60% oil red O dye, and 40% distilled water) for 30 min.…”

Section: Methodsmentioning

confidence: 99%

A Novel Partial PPARγ Agonist Has Weaker Lipogenic Effect in Adipocytes and Stimulates GLUT4 Translocation in Skeletal Muscle Cells via AMPK-Dependent Signaling

et al. 2021

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Introduction: Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are highly effective in treating insulin resistance. However, associated side effects such as weight gain due to increase in adipogenesis and lipogenesis hinder their clinical use. The aim of the study was to design and synthesize novel partial PPARγ agonists with weaker lipogenic effect in adipocytes and enhanced glucose transporter 4 (GLUT4) translocation stimulatory effect in skeletal muscle cells. Methods: Novel partial PPARγ agonists (GS1, GS2, and GS3) were designed and screened to predict their binding interactions with PPARγ by molecular docking. The stability of the docked ligand-PPARγ complex was studied by molecular dynamics (MD) simulation. The cytotoxicity of synthesized compounds was tested in 3T3-L1 adipocytes and L6 myoblasts by MTT assay. The lipogenic effect was investigated in 3T3-L1 adipocytes using oil red O staining and GLUT4 translocation stimulatory effect in L6-GLUT4myc myotubes by an antibody-coupled colorimetric assay. Results: The molecular docking showed the binding interactions between designed agonists and PPARγ. MD simulation demonstrated good stability between the GS2-PPARγ complex. GS2 and GS3 did not show any significant effect on cell viability up to 80 or 100 μM concentration. Pioglitazone treatment significantly increased intracellular lipid accumulation in adipocytes compared to control. However, this effect was significantly less in GS2- and GS3-treated conditions compared to pioglitazone at 10 μM concentration, indicating weaker lipogenic effect. Furthermore, GS2 significantly stimulated GLUT4 translocation to the plasma membrane in a dose-dependent manner via the AMPK-dependent signaling pathway in skeletal muscle cells. Conclusion: GS2 may be a promising therapeutic agent for the treatment of insulin resistance and type 2 diabetes mellitus without adiposity.

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Nod1-mediated lipolysis promotes diacylglycerol accumulation and successive inflammation via PKCδ-IRAK axis in adipocytes

Cited by 22 publications

References 43 publications

NOD1 deficiency promotes an imbalance of thyroid hormones and microbiota homeostasis in mice fed high fat diet

NOD1 deficiency promotes an imbalance of thyroid hormones and microbiota homeostasis in mice fed high fat diet

A human-based multi-gene signature enables quantitative drug repurposing for metabolic disease

A Novel Partial PPARγ Agonist Has Weaker Lipogenic Effect in Adipocytes and Stimulates GLUT4 Translocation in Skeletal Muscle Cells via AMPK-Dependent Signaling

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