Lipoxin A4 Attenuates Obesity-Induced Adipose Inflammation and Associated Liver and Kidney Disease

Börgeson, Emma; Johnson, Andrew M.; Lee, Yun Sok; Till, Andreas; Syed, Gulam Hussain; Ali-Shah, Syed Tasadaque; Guiry, Patrick J.; Dalli, Jesmond; Colas, Romain A.; Serhan, Charles N.; Sharma, Kumar; Godson, Catherine

doi:10.1016/j.cmet.2015.05.003

Cited by 188 publications

(175 citation statements)

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“…1a), in accordance with our previous studies [29]. However, HFD-fed Adipoq −/− mice presented with an increased number of F4/80 + macrophages (p < 0.05; Fig.…”

Section: Resultssupporting

confidence: 92%

“…AICAR reduced adipose inflammation in tissue explants obtained from obese human patients WAT inflammation is a key driver of obesity-related pathophysiology [26][27][28][29]. As a proof-of-principle for translating our rodent data to human pathophysiology, we investigated whether AICAR could reduce inflammation and manipulate leucocyte phenotypes in omental WAT explants taken from obese patients undergoing gastric bypass surgery.…”

Section: Resultsmentioning

confidence: 99%

“…Since white adipose tissue (WAT) inflammation is a key driver of obesity-related pathophysiology [25][26][27][28][29], this was characterised in detail. Finally, to translate our rodent data to human pathophysiology, we also investigated whether AICAR could reduce inflammation in omental WAT tissue explants obtained from obese individuals undergoing gastric bypass surgery.…”

Section: Introductionmentioning

confidence: 99%

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AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

et al. 2017

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Aims/hypothesis In this study, we aimed to evaluate the therapeutic potential of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-activated protein kinase, for ameliorating high-fat diet (HFD)-induced pathophysiology in mice. We also aimed to determine whether the beneficial effects of AICAR were dependent on adiponectin. Furthermore, human adipose tissue was used to examine the effect of AICAR ex vivo. Methods Six-week-old male C57BL/6J wild-type and Adipoq −/− mice were fed a standard-fat diet (10% fat) or an HFD (60% fat) for 12 weeks and given vehicle or AICAR (500 μg/g) three times/week from weeks 4-12. Diet-induced pathophysiology was examined in mice after 11 weeks by IPGTT and after 12 weeks by flow cytometry and western blotting. Human adipose tissue biopsies from obese (BMI 35-50 kg/m 2 ) individuals were incubated with vehicle or AICAR (1 mmol/l) for 6 h at 37°C, after which inflammation was characterised by ELISA (TNF-α) and flow cytometry. Results AICAR attenuated adipose inflammation in mice fed an HFD, promoting an M1-to-M2 macrophage phenotype switch, while reducing infiltration of CD8 + T cells. AICAR treatment of mice fed an HFD partially restored glucose tolerance and attenuated hepatic steatosis and kidney disease, as evidenced by reduced albuminuria (p < 0.05), urinary H 2 O 2 (p < 0.05) and renal superoxide levels (p < 0.01) in both wild-type and Adipoq −/− mice. AICAR-mediated protection occurred independently of adiponectin, as similar protection was observed in wild-type and Adipoq −/− mice. In addition, AICAR promoted an M1-to-M2 macrophage phenotype switch and reduced TNF-α production in tissue explants from obese human patients. Conclusions/interpretation AICAR may promote metabolic health and protect against obesity-induced systemic diseases Catherine Godson and Kumar Sharma are joint senior authors.Electronic supplementary material The online version of this article

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“…1a), in accordance with our previous studies [29]. However, HFD-fed Adipoq −/− mice presented with an increased number of F4/80 + macrophages (p < 0.05; Fig.…”

Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

et al. 2017

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“…Treatment with LXA 4 of adipose tissue explants from aging mice-a model of adipose inflammation-leads to a decrease in IL-6 and restoration of GLUT4 and insulin receptor substrate (IRS)1 expression, indicating less inflammation and improved insulin sensitivity (21). In addition, it has recently been reported that treatment of mice with LXA 4 protects against high-fat diet (HFD)-induced adipose inflammation and hepatic lipid deposition without affecting glucose tolerance (22).…”

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confidence: 99%

ALOX5AP Overexpression in Adipose Tissue Leads to LXA4 Production and Protection Against Diet-Induced Obesity and Insulin Resistance

et al. 2016

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Eicosanoids, such as leukotriene B4 (LTB4) and lipoxin A4 (LXA4), may play a key role during obesity. While LTB4 is involved in adipose tissue inflammation and insulin resistance, LXA4 may exert anti-inflammatory effects and alleviate hepatic steatosis. Both lipid mediators derive from the same pathway, in which arachidonate 5-lipoxygenase (ALOX5) and its partner, arachidonate 5-lipoxygenase–activating protein (ALOX5AP), are involved. ALOX5 and ALOX5AP expression is increased in humans and rodents with obesity and insulin resistance. We found that transgenic mice overexpressing ALOX5AP in adipose tissue had higher LXA4 rather than higher LTB4 levels, were leaner, and showed increased energy expenditure, partly due to browning of white adipose tissue (WAT). Upregulation of hepatic LXR and Cyp7a1 led to higher bile acid synthesis, which may have contributed to increased thermogenesis. In addition, transgenic mice were protected against diet-induced obesity, insulin resistance, and inflammation. Finally, treatment of C57BL/6J mice with LXA4, which showed browning of WAT, strongly suggests that LXA4 is responsible for the transgenic mice phenotype. Thus, our data support that LXA4 may hold great potential for the future development of therapeutic strategies for obesity and related diseases.

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“…Na verdade, a obesidade e a inflamação estão associadas e apresentam contribuição cíclica no agravamento de ambas. Corroborando diversos autores (133,134,136), nós encontramos aumentado número de macrófagos de perfil M1 nos camundongos obesos e este aumento foi ainda mais expressivo quando avaliamos os camundongos MyD88 KO obesos.…”

Section: Discussionunclassified

MyD88: um modulador do perfil inflamatório e metabólico na obesidade experimental.

Castoldi¹

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RESUMOIntrodução: Nos últimos anos, a ativação de receptores da imunidade inata nas células do sistema imune e no tecido adiposo foi descrita como crucial durante o desenvolvimento da obesidade. Além disso, alterações na microbiota intestinal foram relacionadas aos fenótipos inflamatórios e metabólicos na obesidade através do aumento da permeabilidade intestinal, com elevação dos níveis sistêmicos de endotoxina, que colabora para o aumento da inflamação e o desenvolvimento da resistência à insulina. A complexidade do sistema imune nos permite explorar essas vias de sinalização nos diversos órgãos, tecidos e células. Por isso formulamos a hipótese de que MyD88 regularia o desenvolvimento da obesidade, desempenhando um papel importante no tecido adiposo contribuindo para a resistência à insulina. Nos macrófagos, a sinalização via MyD88 favoreceria um perfil pró-inflamatório, e ainda, regularia alterações na microbiota intestinal que por sua vez estariam contribuindo nesse processo através de alterações na permeabilidade intestinal. Objetivo: Estudar a relação entre a obesidade e inflamação, focando no papel da molécula adaptadora MyD88 e sua importância no tecido adiposo, macrófagos, intestino e na modulação da microbiota intestinal. Métodos: Utilizamos camundongos C57BL/6, deficientes de MyD88 (KO), Adiponectina cre+ MyD88 flox +/+ e Lisozima cre+ MyD88 flox +/+ alimentados com dieta hiperlipídica e avaliamos os perfis metabólicos e inflamatórios, permeabilidade intestinal e alterações na microbiota intestinal. Ainda em um modelo de transplante de microbiota estudamos o possível papel da microbiota no desenvolvimento da obesidade. Resultados: Verificamos que camundongos MyD88 KO ganharam mais peso comparados aos camundongos WT, são mais intolerantes à glicose e resistentes à insulina. Porém, ao analisarmos o perfil inflamatório no tecido adiposo e sistêmico, observamos significativa diminuição de IL-1β, TNF-α e IL-6 bem como diminuição na fosforilação das vias de sinalização pró-inflamatórias nos camundongos MyD88 KO obesos. No tecido adiposo, há um predomínio de macrófagos de perfil M1. Além disso, observamos menor inflamação no intestino, porém, a permeabilidade intestinal estava aumentada. A microbiota dos camundongos MyD88 KO foi capaz de induzir resistência à insulina nos camundongos WT, aumentou a permeabilidade intestinal e inflamação no tecido adiposo. A depleção de MyD88 no tecido adiposo não alterou o perfil metabólico dos camundongos comparados aos controles. No entanto, a depleção de MyD88 nos macrófagos, protegeu os camundongos do ganho de peso, resistência à insulina e do aumento da permeabilidade intestinal. Observamos maior polarização M2 no tecido adiposo desses camundongos. Ainda, camundongos MyD88 KO obesos não foram capazes de montar uma resposta inflamatória em resposta à sepse. No entanto, no tecido adiposo dos camundongos MyD88 KO obesos, observamos um aumento significativo da expressão de Dectina-1 e IFN-β, o que poderia explicar a resistência à insulina com a ausência da inflamação clássi...

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Lipoxin A4 Attenuates Obesity-Induced Adipose Inflammation and Associated Liver and Kidney Disease

Cited by 188 publications

References 62 publications

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

ALOX5AP Overexpression in Adipose Tissue Leads to LXA4 Production and Protection Against Diet-Induced Obesity and Insulin Resistance

MyD88: um modulador do perfil inflamatório e metabólico na obesidade experimental.

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