Neutrophil aging exacerbates high fat diet induced metabolic alterations

Baragetti, Andrea; Dalt, L. Da; Moregola, A.; Svecla, M.; Terenghi, Ottavia; Mattavelli, Elisa; Gaetano, Lucia Nicolini De; Uboldi, Patrizia; Catapano, Alberico L.; Norata, Giuseppe Danilo

doi:10.1016/j.metabol.2023.155576

Cited by 6 publications

(3 citation statements)

References 33 publications

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“…The glucose tolerance test (GTT) and insulin tolerance test (ITT) were determined as previously described [ 20 ]. In brief, 14-h fasted mice were intraperitoneally injected with glucose (1 gr/kg body weight) for GTT, while 4-h fasted mice were intraperitoneally injected with insulin (0.75 IU/kg body weight, Humulin R, Lilly) for ITT.…”

Section: Methodsmentioning

confidence: 99%

ASGR1 deficiency diverts lipids toward adipose tissue but results in liver damage during obesity

Svecla,

Da Dalt,

Moregola

et al. 2024

Cardiovasc Diabetol

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Background Asialoglycoprotein receptor 1 (ASGR1), primarily expressed on hepatocytes, promotes the clearance and the degradation of glycoproteins, including lipoproteins, from the circulation. In humans, loss-of-function variants of ASGR1 are associated with a favorable metabolic profile and reduced incidence of cardiovascular diseases. The molecular mechanisms by which ASGR1 could affect the onset of metabolic syndrome and obesity are unclear. Therefore, here we investigated the contribution of ASGR1 in the development of metabolic syndrome and obesity. Methods ASGR1 deficient mice (ASGR1−/−) were subjected to a high-fat diet (45% Kcal from fat) for 20 weeks. The systemic metabolic profile, hepatic and visceral adipose tissue were characterized for metabolic and structural alterations, as well as for immune cells infiltration. Results ASGR1−/− mice present a hypertrophic adipose tissue with 41% increase in fat accumulation in visceral adipose tissue (VAT), alongside with alteration in lipid metabolic pathways. Intriguingly, ASGR1−/− mice exhibit a comparable response to an acute glucose and insulin challenge in circulation, coupled with notably decreased in circulating cholesterol levels. Although the liver of ASGR1−/− have similar lipid accumulation to the WT mice, they present elevated levels of liver inflammation and a decrease in mitochondrial function. Conclusion ASGR1 deficiency impacts energetic homeostasis during obesity leading to improved plasma lipid levels but increased VAT lipid accumulation and liver damage.

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Section: Methodsmentioning

confidence: 99%

ASGR1 deficiency diverts lipids toward adipose tissue but results in liver damage during obesity

Svecla,

Da Dalt,

Moregola

et al. 2024

Cardiovasc Diabetol

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“…We conducted enrichment analysis of biological processes with the proteins that emerged as significantly associated with carotid atherosclerosis following in silico strategies, as previously published 27,28 . The DAVID (The Database for Annotation, Visualization, and Integrated Discovery, NIAID, North Bethesda, MD, USA) platform was used for gene ontology (GO) enrichment analyses.…”

Section: Methodsmentioning

confidence: 99%

Plasma proteins identify increased number of carotid plaques and predict occurring atherosclerotic events

Baragetti,

Grigore,

Olmastroni

et al. 2023

Preprint

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BackgroundThe number of carotid plaques independently predicts incident atherosclerotic cardiovascular disease (ACVD).However, performing vascular imaging in apparently healthy subjects is challenging, owing organizational/economical barriers. Plasma proteomics can offer an alternative approach to identify individuals with carotid plaques, at high risk of eventually developing ACVD.MethodsIn this observational study, we studied by Normalized Protein eXpression (NPX; OlinkTM), the plasma levels of 368 proteins in 664 subjects from the PLIC study, who were screened by ultrasound for the presence of carotid plaques. We clustered, by artificial intelligence, the proteins that more accurately identified subjects, stratifying them according to the number of plaques they presented with. We also study prediction of occurring events over 22 years.Results299/664 subjects had at least 1 carotid plaque. Among those, 77 subjects presented with only one plaque, 101 with 2 plaques and 121 with ≥3 plaques (3+). The remaining 365 subjects with no plaques acted as controls. The proteins differently expressed versus controls increased as a function of the number of plaques. 32 proteins were shared among the groups of subjects with plaques, but 87, significantly associated with the presence of 3+ plaques, improved the AUC of the ROC, together with the ACVD risk factors, to discriminate subjects with 3+ plaques versus the AUC of the ROC considering the ACVD risk factors only (AUC= 0.918 (0.887-0.943) vs AUC= 0.760 (0.716-0.801) respectively, p<0.001). The ACVD risk factors barely predicted the 198 occurring events (AUC= 0.559 (0.521-0.598)), but proteomics associated with plaques improved the prediction (AUC= 0.739 (0.704-0.773), p<0.001).By analyzing the biological processes, we identified that chemotaxis/migration of leukocytes and the signaling of interleukins/cytokines were the top pathways involved.ConclusionsPlasma proteomics helps to identify apparently healthy subjects with higher number of carotid plaques more accurately and to predict occurring ACVDs in those individuals.

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“…over-expressing CXCR4) and “aged” (CXCR2 bright) becomes critical for the survival of the host. All these processes physiologically occur in neutrophils, following a circadian rhythmicity [ 35 ] that is also finely dictated by factors that are affected by the environmental and dietary exposure of the host, such as the case of gut microbiota [ 36 ]; however, we showed for the first time, that the derailment of the CXCR4/CXCR2 axis also contributes to the metabolic alterations induced by fats-enriched diet [ 37 ], thus extending the relevance of neutrophil aging in the context of chronic diseases.…”

Section: Commentarymentioning

confidence: 99%

The High Fat Diet Impacts the Plasticity between Fresh and Aged Neutrophils

Baragetti,

Norata

2023

J Cell Immunol

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Metabolic alterations induced by unhealthy lifestyles, including obesity and insulin resistance are often associated with increased innate immune response and chronic inflammation. Cholesterol has been identified as a key metabolite driving the activation of the inflammasome and the “epigenetic memory” in long-term living hematopoietic stem cells. In addition to these mechanisms, the physiological aging of short-living neutrophils is a relevant modifier of their immune competency, as while they egress from medullary niches as “fresh”, fully competent, cells, they turn into “aged”, disarmed cells, when they extravasate into peripheral tissues to fight against pathogens or they reach the spleen for disposal. We recently observed that cardio-metabolic alterations induced by a lipid enriched unhealthy diet critically accelerate this process. Indeed, the chronic feeding with a high fat diet (HFD) results in the increase of aged neutrophils in the circulation and their accumulation in liver. This profile is associated with a deteriorated insulin response and obesity. The HFD primes aged, but not fresh neutrophils, to infiltrate in the liver and promotes inflammation coupled to altered cell immune architecture in visceral adipose tissue. Preventing the aging of neutrophils via selective ablation of CXCR2, reduces the development of obesity and improves the sensitivity to insulin. In humans, plasma levels of CXCL1, one of the cytokines binding CXCR2 and promoting neutrophil aging, are directly associated with abdominal adiposity and fatty liver independently of other risk factors. Together these findings point to a direct role of aged neutrophils in the development of metabolic disorders.

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Neutrophil aging exacerbates high fat diet induced metabolic alterations

Cited by 6 publications

References 33 publications

ASGR1 deficiency diverts lipids toward adipose tissue but results in liver damage during obesity

ASGR1 deficiency diverts lipids toward adipose tissue but results in liver damage during obesity

Plasma proteins identify increased number of carotid plaques and predict occurring atherosclerotic events

The High Fat Diet Impacts the Plasticity between Fresh and Aged Neutrophils

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