Synthetic small molecule analogues of the immunomodulatory Acanthocheilonema viteae product ES-62 promote metabolic homeostasis during obesity in a mouse model

Lumb, Felicity E.; Crowe, Jenny; Doonan, James; Suckling, Colin J.; Selman, Colin; Harnett, Margaret M.; Harnett, William

doi:10.1016/j.molbiopara.2019.111232

Cited by 14 publications

(15 citation statements)

References 42 publications

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“…Male and female C57BL/6J mice (Envigo, UK) were housed (in same sex groups of 2 to 4, randomly allocated on arrival at 4 weeks of age) in the Central Research Facility (University of Glasgow, UK) and maintained, under specific pathogen-free conditions, at 22°C under a 12-h light/dark cycle with ad libitum access to water and Chow (CRM-P) and High Calorie (Western Diet RD) diets from Special Diet Services, UK as described previously ( 11 , 30 ). Briefly, from 4 weeks of age, all mice were fed normal Chow CRM-P diet (comprising Oil, 3.36%; Protein 18.35%; Fibre, 4.23%: Sugar 3.9%; Atwater fuel energy from Oil, 9.08%; Protein, 22.03%: Carbohydrate, 68.9%) plus 150 ppm Fenbendazole.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, from 4 weeks of age, all mice were fed normal Chow CRM-P diet (comprising Oil, 3.36%; Protein 18.35%; Fibre, 4.23%: Sugar 3.9%; Atwater fuel energy from Oil, 9.08%; Protein, 22.03%: Carbohydrate, 68.9%) plus 150 ppm Fenbendazole. Mice were administered PBS, purified endotoxin-free ES-62 (1 μg ( 31 );) or a combination of SMAs 11a plus 12b (both 1 µg ( 32 )) weekly via the subcutaneous route from 9 weeks of age ( 30 , 31 ). At 10 weeks of age, the HCD cohorts received Western Diet RD (Fat, 21.4%; Protein, 17.5%; Fibre, 3.5%; Sucrose 33%; Atwater fuel energy from Fat, 42%; Protein, 15%: Carbohydrate, 43%) plus 150 ppm Fenbendazole.…”

Section: Methodsmentioning

confidence: 99%

“…Flow cytometric analysis was performed as described previously ( 11 , 14 , 30 , 33 ). Briefly, following red cell-lysis (with 0.8% NH 4 Cl buffer), BM, blood, spleen, MLN and adipose tissue cells were suspended in FACS buffer (PBS containing 2.5% BSA and 0.5 mM EDTA) and phenotyped using the following antibodies:…”

Section: Methodsmentioning

confidence: 99%

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The parasitic worm product ES-62 protects the osteoimmunology axis in a mouse model of obesity-accelerated ageing

et al. 2022

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Despite significant increases in human lifespan over the last century, adoption of high calorie diets (HCD) has driven global increases in type-2 diabetes, obesity and cardiovascular disease, disorders precluding corresponding improvements in healthspan. Reflecting that such conditions are associated with chronic systemic inflammation, evidence is emerging that infection with parasitic helminths might protect against obesity-accelerated ageing, by virtue of their evolution of survival-promoting anti-inflammatory molecules. Indeed, ES-62, an anti-inflammatory secreted product of the filarial nematode Acanthocheilonema viteae, improves the healthspan of both male and female C57BL/6J mice undergoing obesity-accelerated ageing and also extends median lifespan in male animals, by positively impacting on inflammatory, adipose metabolic and gut microbiome parameters of ageing. We therefore explored whether ES-62 affects the osteoimmunology axis that integrates environmental signals, such as diet and the gut microbiome to homeostatically regulate haematopoiesis and training of immune responses, which become dysregulated during (obesity-accelerated) ageing. Of note, we find sexual dimorphisms in the decline in bone health, and associated dysregulation of haematopoiesis and consequent peripheral immune responses, during obesity-accelerated ageing, highlighting the importance of developing sex-specific anti-ageing strategies. Related to this, ES-62 protects trabecular bone structure, maintaining bone marrow (BM) niches that counter the ageing-associated decline in haematopoietic stem cell (HSC) functionality highlighted by a bias towards myeloid lineages, in male but not female, HCD-fed mice. This is evidenced by the ability of ES-62 to suppress the adipocyte and megakaryocyte bias and correspondingly promote increases in B lymphocytes in the BM. Furthermore, the consequent prevention of ageing-associated myeloid/lymphoid skewing is associated with reduced accumulation of inflammatory CD11c+ macrophages and IL-1β in adipose tissue, disrupting the perpetuation of inflammation-driven dysregulation of haematopoiesis during obesity-accelerated ageing in male HCD-fed mice. Finally, we report the ability of small drug-like molecule analogues of ES-62 to mimic some of its key actions, particularly in strongly protecting trabecular bone structure, highlighting the translational potential of these studies.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The parasitic worm product ES-62 protects the osteoimmunology axis in a mouse model of obesity-accelerated ageing

et al. 2022

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“…ES-62 was shown to protect against ageing-related liver fibrosis, with collagen deposition severely limited in both male and female ES-62-mice up to 500 days of age. Treatment with a combined dose of SMAs 11a and 12b also showed protection against liver fibrosis, particularly in female mice, whilst male mice were noted to experience reduced metabolic dysregulation over a time course of some 340 days (90). Interestingly, in male, but not female mice, treatment with ES-62 extended the median lifespan, inhibited late-ageing weight loss, and significantly reduced age-related ileal and colonic erosion, whilst normalising gut microbiota.…”

Section: Obesity-accelerated Ageingmentioning

confidence: 96%

Mini Review: Structure and Function of Nematode Phosphorylcholine-Containing Glycoconjugates

et al. 2021

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An unusual aspect of the biology of nematodes is the covalent attachment of phosphorylcholine (PC) to carbohydrate in glycoconjugates. Investigation of the structure of these molecules by ever-increasingly sophisticated analytical procedures has revealed that PC is generally in phosphodiester linkage with C6 of N-acetylglucosamine (GlcNAc) in both N-type glycans and glycosphingolipids. Up to five PC groups have been detected in the former, being located on both antenna and core GlcNAc. The PC donor for transfer to carbohydrate appears to be phosphatidylcholine but the enzyme responsible for transfer remains to be identified. Work primarily involving the PC-containing Acanthocheilonema viteae secreted product ES-62, has shown that the PC attached to nematode N-glycans possesses a range of immunomodulatory properties, subverting for example, pro-inflammatory signalling in various immune system cell-types including lymphocytes, mast cells, dendritic cells and macrophages. This has led to the generation of PC-based ES-62 small molecule analogues (SMAs), which mirror the parent molecule in preventing the initiation or progression of disease in mouse models of a number of human conditions associated with aberrant inflammatory responses. These include rheumatoid arthritis, systemic lupus erythematosus and lung and skin allergy such that the SMAs are considered to have widespread therapeutic potential.

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“…More recently, ES-62, a glycoprotein of Acanthocheilonema vitae , was also shown to improve metabolic health ( 230 ). Importantly, small-molecule analogues still possess anti-inflammatory properties ( 231 ). With regard to the variety of helminth-derived products and their immunomodulatory functions (reviewed in ( 232 )), many of these may be able to modulate Th2 cell function during obesity and thus may improve diabetes or even counteract weight gain.…”

Section: Th2 Cell Function During Obesity and Malnutritionmentioning

confidence: 99%

Obesity-Mediated Immune Modulation: One Step Forward, (Th)2 Steps Back

et al. 2022

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Over the past decades, the relationship between the immune system and metabolism has become a major research focus. In this arena of immunometabolism the capacity of adipose tissue to secrete immunomodulatory molecules, including adipokines, within the underlying low-grade inflammation during obesity brought attention to the impact obesity has on the immune system. Adipokines, such as leptin and adiponectin, influence T cell differentiation into different T helper subsets and their activation during immune responses. Furthermore, within the cellular milieu of adipose tissue nutrient availability regulates differentiation and activation of T cells and changes in cellular metabolic pathways. Upon activation, T cells shift from oxidative phosphorylation to oxidative glycolysis, while the differential signaling of the kinase mammalian target of rapamycin (mTOR) and the nuclear receptor PPARγ, amongst others, drive the subsequent T cell differentiation. While the mechanisms leading to a shift from the typical type 2-dominated milieu in lean people to a Th1-biased pro-inflammatory environment during obesity are the subject of extensive research, insights on its impact on peripheral Th2-dominated immune responses become more evident. In this review, we will summarize recent findings of how Th2 cells are metabolically regulated during obesity and malnutrition, and how these states affect local and systemic Th2-biased immune responses.

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Synthetic small molecule analogues of the immunomodulatory Acanthocheilonema viteae product ES-62 promote metabolic homeostasis during obesity in a mouse model

Abstract: Enlighten -Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Synthetic small molecule analogues of the immunomodulatory Acanthocheilonema viteae product ES-62 promote metabolic homeostasis during obesity in a mouse model

Cited by 14 publications

References 42 publications

The parasitic worm product ES-62 protects the osteoimmunology axis in a mouse model of obesity-accelerated ageing

The parasitic worm product ES-62 protects the osteoimmunology axis in a mouse model of obesity-accelerated ageing

Mini Review: Structure and Function of Nematode Phosphorylcholine-Containing Glycoconjugates

Obesity-Mediated Immune Modulation: One Step Forward, (Th)2 Steps Back

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