Blockade of 4-1BB and 4-1BBL Interaction Reduces Obesity-Induced Skeletal Muscle Inflammation

Le, Ngoc Hoan; Kim, Chu Sook; Tu, Thai Hien; Choi, Hye-Seon; Kim, Byung Sam; Kawada, Teruo; Goto, Tsuyoshi; Park, Tae Sun; Park, Jung Han Yoon; Yu, Rina

doi:10.1155/2013/865159

Cited by 16 publications

(22 citation statements)

References 32 publications

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“…Skeletal muscle transcript and protein levels of F4/80 and CD68, which were higher in the HFD-fed mice than in the RD-fed mice, were also reduced by quercetin in a dose-dependent manner (Figures 1(c) and 1(d) ). Subsequently, we examined the effect of quercetin on inflammatory receptors such as TNF receptor superfamily member 9 (4-1BB) and toll-like receptor 4 (TLR4), which are known to promote obesity-induced inflammatory responses in skeletal muscle [ 17 , 18 ]. Transcript levels of the inflammatory receptors were lower in the skeletal muscle of the HFD/Q0.05- and HFD/Q0.1-fed mice than in that of the HFD-fed mice ( Figure 1(e) ).…”

Section: Resultsmentioning

confidence: 99%

“…We confirmed that quercetin supplementation markedly reduced transcript and protein levels of the macrophage-specific markers CD68 and F4/80 in the skeletal muscle of HFD-fed obese mice, indicating that it prevented macrophage accumulation, which is in line with our in vitro observation that inhibits the chemotactic activity of macrophages [ 13 ]. Thus, the reduced macrophage infiltration by quercetin may decrease the cross-talk between macrophages/muscle cells, which promotes their inflammatory responses [ 7 , 17 ], and this may be favorable for the reduction of skeletal muscle inflammation.…”

Section: Discussionmentioning

confidence: 99%

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Quercetin Protects against Obesity-Induced Skeletal Muscle Inflammation and Atrophy

Kim

Park

et al. 2014

Mediators of Inflammation

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127

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Skeletal muscle inflammation and atrophy are closely associated with metabolic impairment such as insulin resistance. Quercetin, a natural polyphenol flavonoid, is known to elicit anti-inflammatory and antioxidant activities. In this study, we investigated its effect on obesity-induced skeletal muscle inflammation and atrophy in mice. Male C57BL/6 mice were fed a regular diet, a high-fat diet (HFD), and an HFD supplemented with quercetin for nine weeks. Quercetin reduced levels of inflammatory cytokines and macrophage accumulation in the skeletal muscle of the HFD-fed obese mice. It also reduced transcript and protein levels of the specific atrophic factors, Atrogin-1 and MuRF1, in the skeletal muscle of the HFD-fed obese mice, and protected against the reduction of muscle mass and muscle fiber size. In vitro, quercetin markedly diminished transcript levels of inflammatory receptors and activation of their signaling molecules (ERK, p38 MAPK, and NF-κB) in cocultured myotubes/macrophages, and this was accompanied by reduced expression of the atrophic factors. Together, these findings suggest that quercetin reduces obesity-induced skeletal muscle atrophy by inhibiting inflammatory receptors and their signaling pathway. Quercetin may be useful for preventing obesity-induced muscle inflammation and sarcopenia.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Quercetin Protects against Obesity-Induced Skeletal Muscle Inflammation and Atrophy

Kim

Park

et al. 2014

Mediators of Inflammation

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127

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“…Obesity-induced inflammation increases the risk for development of metabolic complications such as insulin resistance, type 2 diabetes and neurodegenerative diseases. Obesity-induced inflammation initially occurs in metabolically active peripheral organs (e.g., adipose tissue, liver, and skeletal muscle) [1][2][3][4][5]. For example, under obese/diabetic conditions, adipose tissue releases free fatty acid (FFA) and various secretory proteins, including inflammatory cytokines such as TNFa, IL-6, and MCP-1, which then play a crucial role by promoting macrophage infiltration and activation, leading to chronic low-grade systemic inflammation [6][7][8].…”

Section: Abstract: Astrocyte; Hypothalamus; Inflammation; Obesitymentioning

confidence: 99%

“…Obesity-induced inflammation initially occurs in metabolically active peripheral organs (e.g., adipose tissue, liver, and skeletal muscle) [1][2][3][4][5]. Obesity-induced inflammation initially occurs in metabolically active peripheral organs (e.g., adipose tissue, liver, and skeletal muscle) [1][2][3][4][5].…”

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confidence: 99%

Hypothalamic lipid‐laden astrocytes induce microglia migration and activation

Kwon

Kim

et al. 2017

FEBS Letters

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Obesity-induced hypothalamic inflammation is closely associated with various metabolic complications and neurodegenerative disorders. Astrocytes, the most abundant glial cells in the central nervous system, play a crucial role in pathological hypothalamic inflammatory processes. Here, we demonstrate that hypothalamic astrocytes accumulate lipid droplets under saturated fatty acid-rich conditions, such as obese environment, and that the lipid-laden astrocytes increase astrogliosis markers and inflammatory cytokines (TNFα, IL-1β, IL-6, MCP-1) at the transcript and/or protein level. Medium conditioned by the lipid-laden astrocytes stimulate microglial chemotactic activity and upregulate transcripts of the microglia activation marker Iba-1 and inflammatory cytokines. These findings indicate that the lipid-laden astrocytes formed in free fatty acid-rich obese condition may participate in obesity-induced hypothalamic inflammation through promoting microglia migration and activation.

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“…Hence, it is conceivable that 4-1BB/4-1BBL may participate in glial cell-mediated hypothalamic inflammation. Of note, our previous study demonstrated that 4-1BB and/or 4-1BBL enhance obesity-induced peripheral inflammation such as adipose tissue (adipocytes/macrophages) and skeletal muscle (myotubes/macrophages) by providing a bidirectional inflammatory signal [17,19]. However, the association of these molecules with obesityinduced hypothalamic inflammation remains completely unknown.…”

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confidence: 98%

The involvement of 4‐1BB/4‐1BBL signaling in glial cell‐mediated hypothalamic inflammation in obesity

et al. 2018

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Obesity‐induced inflammation occurs not only in peripheral tissues but also in areas of the central nervous system. Glial cells such as astrocytes and microglia play crucial roles in obesity‐related hypothalamic inflammation, leading to the derangement of energy metabolism and neurodegenerative pathologies. Here, we show that the interaction of 4‐1 BB /4‐1 BBL between lipid‐laden astrocytes/microglia promotes hypothalamic inflammation in obesity. Stimulation of 4‐1 BB , a member of the TNF receptor superfamily, and/or its ligand 4‐1 BBL on astrocytes and/or microglia with a specific agonist resulted in activation of the inflammatory signaling pathway and enhanced production of inflammatory mediators. Contact coculture of lipid‐laden astrocytes and microglia increased the production of inflammatory mediators, and blockade of the 4‐1 BB /4‐1 BBL interaction reduced the inflammatory response. Moreover, deficiency of 4‐1 BB reduced hypothalamic inflammation in obese mice fed an high‐fat diet. These findings suggest that 4‐1 BBL /4‐1 BB signaling enhances the glial cell‐mediated inflammatory cross talk and participates in obesity‐induced hypothalamic inflammation.

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Blockade of 4-1BB and 4-1BBL Interaction Reduces Obesity-Induced Skeletal Muscle Inflammation

Cited by 16 publications

References 32 publications

Quercetin Protects against Obesity-Induced Skeletal Muscle Inflammation and Atrophy

Quercetin Protects against Obesity-Induced Skeletal Muscle Inflammation and Atrophy

Hypothalamic lipid‐laden astrocytes induce microglia migration and activation

The involvement of 4‐1BB/4‐1BBL signaling in glial cell‐mediated hypothalamic inflammation in obesity

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