Leptin directly promotes T‐cell glycolytic metabolism to drive effector T‐cell differentiation in a mouse model of autoimmunity

Gerriets, Valerie A.; Danzaki, Keiko; Kishton, Rigel J.; Eisner, William; Nichols, Amanda; Saucillo, Donte C.; Shinohara, Mari L.; MacIver, Nancie J.

doi:10.1002/eji.201545861

Cited by 100 publications

(121 citation statements)

References 49 publications

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“…Leptin supresses regulatory T cell differentiation and is a key regulator of T effector cells differentiation, such as Th17. Leptin is necessary for HIF‐1α expression, which is important for the up‐regulation of glycolytic metabolism in effector T cells …”

Section: Adipose Tissue Resident Mϕs In Obesitymentioning

confidence: 99%

Leptin in the regulation of the immunometabolism of adipose tissue-macrophages

Monteiro

Pereira

Palhinha

et al. 2019

Journal of Leukocyte Biology

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Obesity is a pandemic disease affecting around 15% of the global population. Obesity is a major risk factor for other conditions, such as type 2 diabetes and cardiovascular diseases. The adipose tissue is the main secretor of leptin, an adipokine responsible for the regulation of food intake and energy expenditure. Obese individuals become hyperleptinemic due to increased adipogenesis. Leptin acts through the leptin receptor and induces several immunometabolic changes in different cell types, including adipocytes and Mϕs. Adipose tissue resident Mϕs (ATMs) are the largest leukocyte population in the adipose tissue and these ATMs are in constant contact with the excessive leptin levels secreted in obese conditions. Leptin activates both the JAK2‐STAT3 and the PI3K‐AKT‐mTOR pathways. The activation of these pathways leads to intracellular metabolic changes, with increased glucose uptake, upregulation of glycolytic enzymes, and disruption of mitochondrial function, as well as immunologic alterations, such as increased phagocytic activity and proinflammatory cytokines secretion. Here, we discuss the immunometabolic effects of leptin in Mϕs and how hyperleptinemia can contribute to the low‐grade systemic inflammation in obesity.

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Section: Adipose Tissue Resident Mϕs In Obesitymentioning

confidence: 99%

Leptin in the regulation of the immunometabolism of adipose tissue-macrophages

Monteiro

Pereira

Palhinha

et al. 2019

Journal of Leukocyte Biology

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“…Aerobic glycolysis and the induction of one or more PDKs has also emerged as potential therapeutic targets for DCA in chronic inflammatory states associated with autoimmune disease (Gerriets, et al, 2016; Gerriets, et al, 2015), obstructive pulmonary disease (Calvert, et al, 2008; Mercken, et al, 2009; Ostroukhova, et al, 2012), coronary artery restenosis (Deuse, et al, 2014) and amyotrophic lateral sclerosis (ALS) (Miquel, et al, 2012; Palamiuc, et al, 2015; Valbuena, et al, 2016). Mouse models of ALS, due to mutations in Cu/Zn superoxide dismutase (SOD), have described the occurrence of a metabolic shift towards aerobic glycolysis, with upregulation of PDK and phosphorylation of PDC.…”

Section: Therapeutic Uses Of Dcamentioning

confidence: 99%

Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

James

Jahn

Zhong

et al. 2017

Pharmacology & Therapeutics

106

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Dichloroacetate (DCA) has several therapeutic applications based on its pharmacological property of inhibiting pyruvate dehydrogenase kinase. DCA has been used to treat inherited mitochondrial disorders that result in lactic acidosis, as well as pulmonary hypertension and several different solid tumors, the latter through its ability to reverse the Warburg effect in cancer cells and restore aerobic glycolysis. The main clinically limiting toxicity is reversible peripheral neuropathy. Although administration of high doses to rodents can result in liver cancer, there is no evidence that DCA is a human carcinogen. In all studied species, including humans, DCA has the interesting property of inhibiting its own metabolism upon repeat dosing, resulting in alteration of its pharmacokinetics. The first step in DCA metabolism is conversion to glyoxylate catalyzed by glutathione transferase zeta 1 (GSTZ1), for which DCA is a mechanism-based inactivator. The rate of GSTZ1 inactivation by DCA is influenced by age, GSTZ1 haplotype and cellular concentrations of chloride. The effect of DCA on its own metabolism complicates the selection of an effective dose with minimal side effects.

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“…Recent studies have confirmed a direct role for leptin in Teff‐cell function and differentiation. T cell‐specific leptin receptor knockout mice have now been shown by two groups to be critical for T‐cell polarization into pro‐inflammatory Th1 and Th17 subsets which secrete inflammatory cytokines IFN‐γ and IL‐17, respectively . Indeed, Gerriets et al.…”

Section: T‐cell Dysfunction In Malnutritionmentioning

confidence: 99%

“…Indeed, Gerriets et al. demonstrated that both malnutrition‐associated hypoleptinemia and T cell‐specific leptin receptor knockout suppressed Th1 or Th17‐cell number and function . Moreover, both Reis et al.…”

Section: T‐cell Dysfunction In Malnutritionmentioning

confidence: 99%

Nutritional effects on T‐cell immunometabolism

2017

Self Cite

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T cells are highly influenced by nutrient uptake from their environment, and changes in overall nutritional status, such as malnutrition or obesity, can result in altered T-cell metabolism and behavior. In states of severe malnutrition or starvation, T-cell survival, proliferation, and inflammatory cytokine production are all decreased, as is T-cell glucose uptake and metabolism. The altered T-cell function and metabolism seen in malnutrition is associated with altered adipokine levels, most particularly decreased leptin. Circulating leptin levels are low in malnutrition, and leptin has been shown to be a key link between nutrition and immunity. The current view is that leptin signaling is required to upregulate activated T-cell glucose metabolism and thereby fuel T-cell activation. In the setting of obesity, T cells have been found to have a key role in promoting the recruitment of inflammatory macrophages to adipose depots along with the production of inflammatory cytokines that promote the development of insulin resistance leading to diabetes. Deletion of T cells, key T-cell transcription factors, or pro-inflammatory T-cell cytokines prevents insulin resistance in obesity and underscores the importance of T cells in obesity-associated inflammation and metabolic disease. Altogether, T cells have a critical role in nutritional immunometabolism.

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Leptin directly promotes T‐cell glycolytic metabolism to drive effector T‐cell differentiation in a mouse model of autoimmunity

Cited by 100 publications

References 49 publications

Leptin in the regulation of the immunometabolism of adipose tissue-macrophages

Leptin in the regulation of the immunometabolism of adipose tissue-macrophages

Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

Nutritional effects on T‐cell immunometabolism

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