Injecting engineered anti-inflammatory macrophages therapeutically induces white adipose tissue browning and improves diet-induced insulin resistance

Abstract Background: The obesity epidemic has become a serious public health problem in many countries worldwide. Seaweed has few calories and is rich in active nutritional components necessary for health promotion and disease prevention. The aim of this study was to investigate the effects of the Campylaephora hypnaeoides J. Agardh (C. hypnaeoides), an edible seaweed traditionally eaten in Japan, on high-fat (HF) diet-induced obesity and related metabolic diseases in mice.Methods: Male C57BL/6J mice were randomly divided into the following groups: normal diet group, HF diet group, HF diet supplemented with 2% C. hypnaeoides, and HF diet supplemented with 6% C. hypnaeoides. After 13 weeks of treatment, the weight of the white adipose tissue and liver, and the serum levels of glucose, insulin, adipokines, and lipids were measured. Hepatic levels of adipokines, oxidant markers, and antioxidant markers were also determined. Insulin resistance was assessed by a glucose tolerance test. Polysaccharides of C. hypnaeoides were purified and their molecular weight was determined by high-performance seize exclusion chromatography. The anti-inflammatory effects of purified polysaccharides were evaluated in RAW264.7 cells. Results: Treatment of HF diet-induced obese mice with C. hypnaeoides for 13 weeks suppressed the increase in body weight and white adipose tissue weight. It also ameliorated insulin resistance, diabetes, hepatic steatosis, and hypercholesterolemia. The ingestion of an HF diet increased serum levels of malondialdehyde (MDA), tumor necrosis factor a (TNF-a), and monocyte chemoattractant protein-1 (MCP-1), while it decreased serum adiponectin levels. In the liver, an HF diet markedly increased the MDA, TNF-a, and interleukin-6 (IL-6) levels, while it decreased glutathione (GSH) and superoxide dismutase (SOD). These metabolic changes induced by HF diet feeding were ameliorated by dietary C. hypnaeoides. Purified polysaccharides and ethanol extract from C. hypnaeoides inhibited the lipopolysaccharide-induced overproduction of nitric oxide and TNF-a in macrophage RAW264.7 cells. Conclusions: The present results indicated that C. hypnaeoides was able to alleviate HF diet-induced metabolic disorders, including obesity, diabetes, hepatic steatosis, and hypercholesterolemia by attenuating inflammation and improving the antioxidant capacity in mice. Polysaccharides and polyphenols may be involved in these beneficial effects of C. hypnaeoides.

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Factors controlling insulin resistance in white adipose tissue of lactating rats

Biochemical Society Transactions ◽

10.1042/bst0180492 ◽

1990 ◽

Vol 18 (3) ◽

pp. 492-493 ◽

Cited By ~ 3

Author(s):

MARGARET E. GRAHAM ◽

ERIC FINLEY ◽

RICHARD G. VERNON

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

White Adipose Tissue

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Eplerenone prevented obesity-induced inflammasome activation and glucose intolerance

Journal of Endocrinology ◽

10.1530/joe-17-0351 ◽

2017 ◽

Vol 235 (3) ◽

pp. 179-191 ◽

Cited By ~ 28

Author(s):

Tsutomu Wada ◽

Akari Ishikawa ◽

Eri Watanabe ◽

Yuto Nakamura ◽

Yusuke Aruga ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Glucose Intolerance ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

M2 Macrophage ◽

Expression Levels ◽

Nlrp3 Inflammasome Activation ◽

M1 Macrophage ◽

Anti Inflammatory

Obesity-associated activation of the renin-angiotensin-aldosterone system is implicated in the pathogenesis of insulin resistance; however, influences of mineralocorticoid receptor (MR) inhibition remain unclear. Therefore, we aimed to clarify the anti-inflammatory mechanisms of MR inhibition using eplerenone, a selective MR antagonist, in C57BL/6 mice fed a high-fat diet (HFD) for 12 weeks. Eplerenone prevented excessive body weight gain and fat accumulation, ameliorated glucose intolerance and insulin resistance and enhanced energy metabolism. In the epididymal white adipose tissue (eWAT), eplerenone prevented obesity-induced accumulation of F4/80+CD11c+CD206−-M1-adipose tissue macrophage (ATM) and reduction of F4/80+CD11c−CD206+-M2-ATM. Interestingly, M1-macrophage exhibited lower expression levels of MR, compared with M2-macrophage, in the ATM of eWAT and in vitro-polarized bone marrow-derived macrophages (BMDM). Importantly, eplerenone and MR knockdown attenuated the increase in the expression levels of proIl1b, Il6 and Tnfa, in the eWAT and liver of HFD-fed mice and LPS-stimulated BMDM. Moreover, eplerenone suppressed IL1b secretion from eWAT of HFD-fed mice. To reveal the anti-inflammatory mechanism, we investigated the involvement of NLRP3-inflammasome activation, a key process of IL1b overproduction. Eplerenone suppressed the expression of the inflammasome components, Nlrp3 and Caspase1, in the eWAT and liver. Concerning the second triggering factors, ROS production and ATP- and nigericin-induced IL1b secretion were suppressed by eplerenone in the LPS-primed BMDM. These results indicate that eplerenone inhibited both the priming and triggering signals that promote NLRP3-inflammasome activation. Therefore, we consider MR to be a crucial target to prevent metabolic disorders by suppressing inflammasome-mediated chronic inflammation in the adipose tissue and liver under obese conditions.

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Aging-related inflammation driven by cellular senescence enhances NAD consumption via activation of CD38+pro-inflammatory macrophages

10.1101/609438 ◽

2019 ◽

Cited By ~ 7

Author(s):

Anthony J. Covarrubias ◽

Abhijit Kale ◽

Rosalba Perrone ◽

Jose Alberto Lopez-Dominguez ◽

Angela Oliveira Pisco ◽

...

Keyword(s):

Adipose Tissue ◽

Inflammatory Cytokines ◽

Cellular Senescence ◽

White Adipose Tissue ◽

Causal Link ◽

Secretory Proteins ◽

M2 Macrophages ◽

Therapeutic Opportunity ◽

Inflammatory Macrophages ◽

Novel Therapeutic

SummaryDecline in tissue NAD levels during aging is linked to aging and its associated diseases. However, the mechanism for aging-associated NAD decline remains unclear. Here we report that pro-inflammatory M1-like macrophages, but not naïve or M2 macrophages, accumulate in metabolic tissues including visceral white adipose tissue and the liver during aging. Remarkably, these M1-like macrophages highly express the NAD consuming enzyme CD38 and have enhanced CD38-dependent NADase activity. We also find that senescent cells progressively accumulate in visceral white adipose tissue during aging and that inflammatory cytokines found in the supernatant from senescent cells (Senescence associated secretory proteins, SASP) induce macrophages to proliferate and to express CD38. These results highlight a new causal link between visceral tissue senescence and tissue NAD decline during aging and represent a novel therapeutic opportunity targeting maintenance of NAD levels during aging.

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Homeobox a5 Promotes White Adipose Tissue Browning Through Inhibition of the Tenascin C/Toll-Like Receptor 4/Nuclear Factor Kappa B Inflammatory Signaling in Mice

Frontiers in Immunology ◽

10.3389/fimmu.2018.00647 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 15

Author(s):

Weina Cao ◽

Hongtao Huang ◽

Tianyu Xia ◽

Chenlong Liu ◽

Saeed Muhammad ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Nuclear Factor Kappa B ◽

Nuclear Factor ◽

Toll Like Receptor ◽

Inflammatory Signaling ◽

Toll Like Receptor 4 ◽

Tenascin C ◽

Nuclear Factor Kappa ◽

Tissue Browning

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Treatment with atrial natriuretic peptide induces adipose tissue browning and exerts thermogenic actions in vivo

Scientific Reports ◽

10.1038/s41598-021-96970-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Haruka Kimura ◽

Tomohisa Nagoshi ◽

Yuhei Oi ◽

Akira Yoshii ◽

Yoshiro Tanaka ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Hepatic Steatosis ◽

Cold Exposure ◽

Lipid Droplets ◽

Adipose Tissues ◽

Brown Adipose ◽

Ucp1 Expression ◽

Tissue Browning

AbstractIncreasing evidence suggests natriuretic peptides (NPs) coordinate inter-organ metabolic crosstalk with adipose tissues and play a critical role in energy metabolism. We recently reported A-type NP (ANP) raises intracellular temperature in cultured adipocytes in a low-temperature-sensitive manner. We herein investigated whether exogenous ANP-treatment exerts a significant impact on adipose tissues in vivo. Mice fed a high-fat-diet (HFD) or normal-fat-diet (NFD) for 13 weeks were treated with or without ANP infusion subcutaneously for another 3 weeks. ANP-treatment significantly ameliorated HFD-induced insulin resistance. HFD increased brown adipose tissue (BAT) cell size with the accumulation of lipid droplets (whitening), which was suppressed by ANP-treatment (re-browning). Furthermore, HFD induced enlarged lipid droplets in inguinal white adipose tissue (iWAT), crown-like structures in epididymal WAT, and hepatic steatosis, all of which were substantially attenuated by ANP-treatment. Likewise, ANP-treatment markedly increased UCP1 expression, a specific marker of BAT, in iWAT (browning). ANP also further increased UCP1 expression in BAT with NFD. Accordingly, cold tolerance test demonstrated ANP-treated mice were tolerant to cold exposure. In summary, exogenous ANP administration ameliorates HFD-induced insulin resistance by attenuating hepatic steatosis and by inducing adipose tissue browning (activation of the adipose tissue thermogenic program), leading to in vivo thermogenesis during cold exposure.

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