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Adipose tissue B2 cells promote insulin resistance through leukotriene LTB4/LTB4R1 signaling
Open accessAbstract
Tissue inflammation is a key component of obesity-induced insulin resistance, with a variety of immune cell types accumulating in adipose tissue. Here, we have demonstrated increased numbers of B2 lymphocytes in obese adipose tissue and have shown that high-fat diet-induced (HFD-induced) insulin resistance is mitigated in B cell-deficient (Bnull) mice. Adoptive transfer of adipose tissue B2 cells (ATB2) from wild-type HFD donor mice into HFD Bnull recipients completely restored the effect of HFD to induce insulin resistance. Recruitment and activation of ATB2 cells was mediated by signaling through the chemokine leukotriene B4 (LTB4) and its receptor LTB4R1. Furthermore, the adverse effects of ATB2 cells on glucose homeostasis were partially dependent upon T cells and macrophages. These results demonstrate the importance of ATB2 cells in obesity-induced insulin resistance and suggest that inhibition of the LTB4/LTB4R1 axis might be a useful approach for developing insulin-sensitizing therapeutics.
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“Although the mechanisms underlying the expansion or infiltration of B cells into obese adipose tissue are poorly defined, signaling through the chemokine, leukotriene B4, and its receptor is required.( 46 )”
From The Emerging Role of B Cells in the Pathogenesis of NAFLD (2021) · cites this paper as [46]
In the citing paper
“B2 cells accumulate in the obese adipose tissue where they contribute to local and systemic IR through pathogenic IgG antibodies( 45 ) and activation of T cells and macrophages.( 46 )”
From The Emerging Role of B Cells in the Pathogenesis of NAFLD (2021) · cites this paper as [46]
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BackgroundAdipose tissue lymphocytes and obesity
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“Reports on changes in AT B1 cells in obesity were not consistent, with some studies [29,90] showing reductions but another study [24] showing slight increases in AT B1 cells in mice with obesity.”
BackgroundResultInfluentialDissecting the mechanisms of MASLD fibrosis in the era of single-cell and spatial omics
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“However, a detailed study defining the molecular changes in human LSEC during different stages of MASLD is still lacking.”
Virk, R., Buddenbaum, N., Al‐Shaer, A. E., Armstrong, M., Manke, J., Reisdorph, N. A., Sergin, S., Fenton, J. I., Wallace, E. D., Ehrmann, B. M., et al. (2022) · Journal of Lipid Research · doi:10.1016/j.jlr.2022.100267 · Cited by 20
“One, select B cell subsets are drivers of inflammation and B2 cells infiltrate white adipose tissue and promote inflammation through a leukotriene B4-mediated mechanism (16, 45).”
BackgroundImmunometabolism in type 2 diabetes mellitus: tissue-specific interactions
Pinheiro-Machado, E., Gurgul-Convey, E., & Marzec, M. (2020) · Archives of Medical Science · doi:10.5114/aoms.2020.92674 · Cited by 19
“B lymphocytes have been shown to accumulate before T cells in the AT in HFD models [95] and are recruited by the pro-inflammatory chemokines produced by the AT (CXCL10/CCL2/CCL5) [96], and through leukotriene LTB4 signaling [97].”
BackgroundRamalho, T. R. D. O., Pahlavani, M., Kalupahana, N. S., Wijayatunga, N. N., Ramalingam, L., Jancar, S., & Moustaïd‐Moussa, N. (2020) · Biomolecules · doi:10.3390/biom10091292 · Cited by 17
“Regarding the PI3K signaling in B lymphocytes, there is evidence for the role of active B cells in the milieu of inflamed fat [26].”
BackgroundNeuroimmune regulation of white adipose tissues
Qian, X., Meng, X., Zhang, S., & Zeng, W. (2021) · FEBS Journal · doi:10.1111/febs.16213 · Cited by 17
Blood glucose regulation in context of infection
Wensveen, F. M., Šestan, M., Wensveen, T. T., & Polić, B. (2021) · Vitamins and hormones · doi:10.1016/bs.vh.2021.06.009 · Cited by 20
Adaptive Immunity and Metabolic Health: Harmony Becomes Dissonant in Obesity and Aging
Bharath, L. P., Ip, B. C., & Nikolajczyk, B. S. (2017) · Comprehensive physiology · doi:10.1002/cphy.c160042 · Cited by 21
“tions of the importance of immune cell cross-talk for “diabetogenic” inflammation (51, 108, 262, 279).”
Ağagündüz, D., Yeşildemir, Ö., Koçyiğit, E., Koçak, T., Ünaldı, B. Ö., Ayakdaş, G., & Budán, F. (2024) · Nutrients · doi:10.3390/nu16223812 · Cited by 18
Schweitzer, G. R. B., Rios, I. N. M. S., Gonçalves, V. S. S., Magalhães, K. G., & Pizato, N. (2021) · Journal of Nutritional Science · doi:10.1017/jns.2021.46 · Cited by 16
“The extracted information was categorised as follows: (1) Author, Year of publication, and Country; (2) Study design; (3) Study Period; (4) n-3 PUFA source; (5) Study Protocol; (6) Food or supplement adherence protocol; (7) Age; (8) Baseline BMI; (9) Baseline and Post-Intervention serum eicosanoids markers; and (10) M…”
BackgroundMethodFujimori, K., Uno, S., Kuroda, K., Matsumoto, C., & Maehara, T. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2021.119203 · Cited by 16
Garg, R., Agarwal, A. K., Katekar, R. A., Dadge, S. D., Yadav, S., & Gayen, J. R. (2023) · Amino Acids · doi:10.1007/s00726-023-03252-x · Cited by 18
Daley, A. D., & Bénézech, C. (2024) · Immunological Reviews · doi:10.1111/imr.13339 · Cited by 23
“105 Overall, this body of work demonstrates the pro-inflammatory effect of B2 cell accumulation in adipose tissue and suggests that the mechanisms underlying this could be related to autoreactive IgG secretion or activation and accumulation of other inflammatory immune cells by cytokine production…”
Vertical sleeve gastrectomy induces distinctive transcriptomic responses in liver, fat and muscle
Ahn, C. H., Choi, E. H., Lee, H.-J., Lee, W., Kim, J., & Cho, Y. M. (2021) · Scientific Reports · doi:10.1038/s41598-021-81866-5 · Cited by 16
The role of immunity in insulin resistance in patients with polycystic ovary syndrome
Zhang, Q., Yang, Z., Ou, X., Zhang, M., Qin, X., & Wu, G. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1464561 · Cited by 19
Huang, Q., Liu, J., Dong, H.-B., Wei, Z., Liu, J., Ren, Y., Jiang, X., & Jiang, B. (2023) · Hepatobiliary & pancreatic diseases international · doi:10.1016/j.hbpd.2023.11.006 · Cited by 11
Immune activation induced by dysregulated lipid metabolism in the pathogenesis of type 2 diabetes
Yang, H., Yu, W., Mao, Q., & Zhao, L. (2025) · World Journal of Diabetes · doi:10.4239/wjd.v16.i12.114395 · Cited by 11
Wu, X., Sun, A. R., Crawford, R., Xiao, Y., Wang, Y., Prasadam, I., & Mao, X. (2023) · Cartilage · doi:10.1177/19476035231169940 · Cited by 10
“46,47 In this study, we examined the role of the leukotriene pathway in the development of OA.”
BackgroundLipid nutrition: “In silico” studies and undeveloped experiments
Lands, B. (2021) · Progress in Lipid Research · doi:10.1016/j.plipres.2021.101142 · Cited by 10
Chang, Y., Xing, L., Zhou, W., & Zhang, W. (2021) · Cell Cycle · doi:10.1080/15384101.2021.1878330 · Cited by 10
The Role of LTB4 in Obesity-Induced Insulin Resistance Development: An Overview
Callegari, I. O. M., & Oliveira, A. G. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.848006 · Cited by 9
“However, as adipose tissue also presents eosinophiles, neutrophiles and other immune cells (3, 31), we cannot rule out their participation, besides adipocytes, in LTB4 synthesis during obesity development.”
BackgroundInfluentialRole for BLT1 in regulating inflammation within adipose tissue immune cells of aged mice
Shih, W.-C., Jang, I. H., Kruglov, V., Dickey, D. M., Cholensky, S. H., Bernlohr, D., & Camell, C. D. (2024) · Immunity & Ageing · doi:10.1186/s12979-024-00461-0 · Cited by 9
“BLT1 is also reported to be expressed on B2 B cells in the adipose tissue [47].”
BackgroundShades of white: new insights into tissue‐resident leukocyte heterogeneity
Psaila, A. M., Vohralik, E. J., & Quinlan, K. G. R. (2021) · FEBS Journal · doi:10.1111/febs.15737 · Cited by 9
Chen, W., Meng, F., Zeng, X., Cao, X., Bu, G., Du, X., Yu, G., Kong, F., Li, Y., Gan, T., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032308 · Cited by 10
“edu/, accessed on 28 October 2022) [47] was used to measure the relative proportions of the infiltrating immune cells in adipose tissue, based on the gene expression profile, the signature matrix file of the immune cells was built, based on the mouse tissue expression profiles [62].”
MethodLiu, Y., Luo, J., Cai, R., Zhang, J., Xu, Q., Tian, Y., & Zhou, M.-S. (2020) · BioMed Research International · doi:10.1155/2020/5073762 · Cited by 8
Proarrhythmic Lipid Inflammatory Mediators: Mechanisms in Obesity Arrhythmias
Taqanaki, P. B., Aromolaran, K. A., & Aromolaran, A. S. (2025) · Journal of Cellular Physiology · doi:10.1002/jcp.70012 · Cited by 6
Song, M.-Y., Jeon, Y. G., Yang, J. D., Moon, Y. J., Kim, J. B., Bae, E. J., & Park, B. C. (2026) · Nature Communications · doi:10.1038/s41467-025-66040-z · Cited by 4
“The Olefsky group previously identi fi ed LTB 4 as a potent chemokine for immune cells in obese mice 24,25 .”
Microbiota and Glucidic Metabolism: A Link with Multiple Aspects and Perspectives
Ciarambino, T., Crispino, P., Leto, G., Minervini, G., Para, O., & Giordano, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241210409 · Cited by 4
“Finally, B2 lymphocytes, adipose-resident immune cells, adipocyte mitochondrial dysfunction, and reactive oxygen species (ROS) can increase insulin resistance [49] and contribute to beta-cell impairment [50].”
BackgroundThe Role of B Lymphocyte Subsets in Adipose Tissue Development, Metabolism, and Aging
Fernandez, N. C., & Shinoda, K. (2022) · Comprehensive physiology · doi:10.1002/cphy.c220006 · Cited by 5
Ramalho, T. R. D. O., Pereira, N. F., Brandt, S. L., & Serezani, C. H. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-50621-6_4 · Cited by 3
Interaction between adipocytes and B lymphocytes in human metabolic diseases
Stasevich, E. M., Zheremyan, E. A., Kuprash, D. V., & Schwartz, A. M. (2023) · Biochemistry (Moscow) · doi:10.31857/s0320972523020124 · Cited by 2
Metadata
- Authors
- Ying, W., Wollam, J., Ofrecio, J. M., Bandyopadhyay, G., El Ouarrat, D., Lee, Y. S., Oh, D. Y., Li, P., Osborn, O., & Olefsky, J. M.
- Affiliations
- Tongji University (CN)
- University of California San Diego (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Olefsky, Jerrold M.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2017-02-13
- Volume
- 127
- Issue
- 3
- Pages
- 1019-1030
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5330737
- OpenAlex
- W2587579012
- Cited by
- 128
- References
- 52
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 10 · 2023: 13 · 2022: 10 · 2021: 24 · 2020: 18 · 2019: 7 · 2018: 15 · 2017: 13
- FWCI
- 11.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- American Heart Association (16POST31350039)
- University of California, San Diego (DK063491)
- National Institute of Allergy and Infectious Diseases (P30AI036214)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK063491, DK 074868, DK 033651, R37DK033651, R01DK101395, DK 09062, P01DK074868, F32DK009062, R01DK033651, P30DK063491)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Keywords
- insulin resistance, obesity, leukotriene B4, high-fat diet, tissue inflammation, chemokine signaling, glucose homeostasis, T cells, macrophages, adoptive transfer, B cell-deficient mice
- MeSH terms
- Adipose Tissue, Animals, Dietary Fats, Insulin Resistance, Leukotriene B4, Macrophages, Obesity, T-Lymphocytes, Signal Transduction, B-Lymphocyte Subsets, Receptors, Leukotriene B4, Mice, Knockout, Mice
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