Dietary cholesterol is essential to mast cell activation and associated obesity and diabetes in mice

Zhang, Xian; Huang, Qin; Wang, Xin; Deng, Zhiyong; Li, Jie; Xiang, Yan; Jauhiainen, Matti; Metso, Jari; Libby, Peter; Liu, Jian; Shi, Guo Ping

doi:10.1016/j.bbadis.2019.04.006

Cited by 14 publications

(11 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In SAT from chow diet-fed mice, there is about 150 g of cholesterol per gram of SAT. LDL at 1 mg/mL showed a similar potency of MC activation as 50 µmg/mL of IgE antibody (Zhang et al, 2019). Although we did not quantitate the IgE content in SAT, plasma IgE levels from chow diet-fed mice reached about 100 ng/mL (Wang et al, 2011).…”

Section: Discussionmentioning

confidence: 94%

“…Live BMMCs or the BMMC lysate preparation also reduced expression of the same set of thermogenic genes from the SAT explants (Figure 4C). Adipose tissue is a major site for cholesterol storage (Krause and Hartman, 1984; Kovanen et al, 1975), which activates MCs much more potently than immunoglobulin E (IgE) (Zhang et al, 2019). Cell culture medium from low-density lipoprotein (LDL)-activated BMMCs, but not that from non-activated BMMCs, acted the same as live BMMCs or BMMC lysate in suppressing thermogenic gene expression in in vitro browning-differentiated SVF adipocytes (Figure 4B).…”

Section: Resultsmentioning

confidence: 99%

“…After 5 weeks, cell purity was confirmed by FACS to show the cell surface expression of FcεRI and CD117 (> 98%). To activate BMMCs, BMMCs were treated with 1 mg/mL LDL (Lee Biosolutions, Inc, Mary-land Heights, MO) for 48 hr as previously described (Zhang et al, 2019) with or without 1 µM, 10 mM or 50 µM of LX1031.…”

Section: Star*methodsmentioning

confidence: 99%

See 2 more Smart Citations

Functional Inactivation of Mast Cells Enhances Subcutaneous Adipose Tissue Browning in Mice

et al. 2019

Self Cite

View full text Add to dashboard Cite

SUMMARY Adipose tissue browning and systemic energy expenditure provide a defense mechanism against obesity and associated metabolic diseases. In high-cholesterol Western diet-fed mice, mast cell (MC) inactivation ameliorates obesity and insulin resistance and improves the metabolic rate, but a direct role of adipose tissue MCs in thermogenesis and browning remains unproven. Here, we report that adrenoceptor agonist norepinephrine-stimulated metabolic rate and subcutaneous adipose tissue (SAT) browning are enhanced in MC-deficient Kitw-sh/w-sh mice and MC-stabilized wild-type mice on a chow diet. MC reconstitution to SAT in Kitw-sh/w-sh mice blocks these changes. Mechanistic studies demonstrate that MC inactivation elevates SAT platelet-derived growth factor receptor A (PDGFRα+) adipocyte precursor proliferation and accelerates beige adipocyte differentiation. Using the tryptophan hydroxylase 1 (TPH1) inhibitor and TPH1-deficient MCs, we show that MC-derived serotonin inhibits SAT browning and systemic energy expenditure. Functional inactivation of MCs or inhibition of MC serotonin synthesis in SAT promotes adipocyte browning and systemic energy metabolism in mice.

show abstract

Section: Discussionmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Functional Inactivation of Mast Cells Enhances Subcutaneous Adipose Tissue Browning in Mice

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Of which Insulin resistance, a condition where cells become resistant to the effects of insulin and is often found in obesity, T2DM, non-alcoholic fatty liver disease, etc. [ 49 – 51 ]; for PPAR signaling pathway, which plays significantly in inflammation, insulin sensitivity, lipid metabolism, as well as the expression of hepatic enzymes regulating glucose homeostasis [ 52 , 53 ]; for FoxO signaling pathway, which controls important physiological events, including apoptosis, glucose metabolism, oxidative stress resistance, by converting the external stimuli of insulin, growth factors, cytokines, and oxidative stress into cell-specific biological responses by regulating the transcriptional activity of target genes [ 54 , 55 ]; for Fc epsilon RI signaling pathway, which contributes to inflammatory responses by regulating mediators and cytokines [ 56 , 57 ]; there are also pathways that influence diabetes primarily by regulating metabolism, such as cAMP signaling pathway [ 58 ], AMPK signaling pathway [ 59 ], Starch and sucrose metabolism [ 60 ], Carbohydrate digestion and absorption [ 61 ], Aldosterone-regulated sodium reabsorption [ 62 ], Adipocytokine signaling pathway [ 63 ]; and other T2DM directly related pathways like Insulin signaling pathway, and Type II diabetes mellitus, are involved. In addition, combined with literature search, the corresponding symptoms of these pathways were synthesized to construct the "herbs-targets-pathways- symptoms" network, which represents a global view of GQWTF in treating T2DM, with their pathways that functions and related possible symptomatic improvement.…”

Section: Discussionmentioning

confidence: 99%

Mechanism exploration of Gouqi-wentang formula against type 2 diabetes mellitus by phytochemistry and network pharmacology-based analysis and biological validation

et al. 2021

View full text Add to dashboard Cite

Background The Gouqi-wentang formula (GQWTF) is a herbal formula used by Academician Xiao-lin Tong for the clinical treatment of T2DM. GQWTF is beneficial to qi, nourishes Yin, clears heat, and promotes fluid production, but the effective components and their mechanism of action remain unclear. Methods The main components of GQWTF were detected by LC–MS, and the multi-target mechanisms of GQWTF in T2DM were elucidated using network pharmacology analysis, including target prediction, protein–protein interaction network construction and analysis, Gene Ontology (GO) terms, Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway annotation, and other network construction. Finally, the efficacy of the GQWTF was verified using biological experiments. Results First, the “herb-channel tropism” network suggested that GQWTF focuses more on treating diseases by recuperating the liver, which is considered as an important insulin-sensitive organ. Subsequently, a total of 16 active ingredients in GQWTF were detected and screened, and their biological targets were predicted. Then, “compound-target” network was constructed, where enrichment analysis of GQWTF targets reflected its potential pharmacological activities. After T2DM-related target identification, 39 cross targets of GQWTF and T2DM were obtained, and 30 key targets highly responsible for the beneficial effect of GQWTF on T2DM were identified by PPI analysis. GO analysis of these key targets showed that many biological processes of GQWTF in treating T2DM are key in the occurrence and development of T2DM, including components related to inflammatory/immune response, insulin, and metabolism. KEGG analysis revealed the regulation of multiple signalling pathways, such as insulin resistance, PPAR signalling pathway, FoxO signalling pathway, Fc epsilon RI signalling pathway, and pathways that influence diabetes primarily by regulating metabolism as well as other T2DM directly related pathways. Furthermore, a “formula-compound-pathway-symptom” network was constructed to represent a global view of GQWTF in the treatment of T2DM. Conclusions This study explored the mechanism of action of GQWTF in T2DM by multi-component and multi-target multi pathways, which could provide a theoretical basis for the development and clinical application of GQWTF.

show abstract

“…Mast cells increase in the visceral adipose tissue (VAT), particularly around CLSs and actively degranulate to release TNF-α, IL-6, and interferon-γ (IFN-γ) to promote obesity and diabetes ( Altintas et al., 2011 ; Liu et al., 2009 ). Recently, Zhang et al. (2019) have demonstrated that dietary cholesterol leads to activation of mast cells, suggesting mast cells might be directly sensing and responding to dysregulated metabolites.…”

Section: Effect Of Diet-induced Obesity On Adipose Leukocytesmentioning

confidence: 99%

Dietary Regulation of Immunity

Lee

Dixit

2020

Immunity

View full text Add to dashboard Cite

Integrated immunometabolic responses link dietary intake, energy utilization, and storage to immune regulation of tissue function and is therefore essential for the maintenance and restoration of homeostasis. Adipose-resident leukocytes have non-traditional immunological functions that regulate organismal metabolism by controlling insulin action, lipolysis, and mitochondrial respiration to control the usage of substrates for production of heat versus ATP. Energetically expensive vital functions such as immunological responses might have thus evolved to respond accordingly to dietary surplus and deficit of macronutrient intake. Here, we review the interaction of dietary intake of macronutrients and their metabolism with the immune system. We discuss immunometabolic checkpoints that promote healthspan and highlight how dietary fate and regulation of glucose, fat, and protein metabolism might affect immunity.

show abstract

Dietary cholesterol is essential to mast cell activation and associated obesity and diabetes in mice

Cited by 14 publications

References 46 publications

Functional Inactivation of Mast Cells Enhances Subcutaneous Adipose Tissue Browning in Mice

Functional Inactivation of Mast Cells Enhances Subcutaneous Adipose Tissue Browning in Mice

Mechanism exploration of Gouqi-wentang formula against type 2 diabetes mellitus by phytochemistry and network pharmacology-based analysis and biological validation

Dietary Regulation of Immunity

Contact Info

Product

Resources

About