Proinflammatory cytokine interleukin-1β suppresses cold-induced thermogenesis in adipocytes

Goto, Tsuyoshi; Naknukool, Supaporn; Yoshitake, Rieko; Hanafusa, Yuki; Tokiwa, Soshi; Li, Yongjia; Sakamoto, Tomoya; Nitta, Takahiro; Kim, Minji; Takahashi, Nobuyuki; Yu, Rina; Daiyasu, Hiromi; Seno, Shigeto; Matsuda, Hideo; Kawada, Teruo

doi:10.1016/j.cyto.2015.11.001

Cited by 101 publications

(66 citation statements)

References 37 publications

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“…This opens the possibility that the observed reduced Ucp1 expression in vivo by LPS is not directly caused by LPS stimulation of adipocytes, but mediated indirectly via LPS stimulation of macrophages within the tissue to release catecholamines [29], a hypothesis that was recently challenged as macrophages seem to lack the rate-limiting enzyme tyrosine hydroxylase [30], or by LPS stimulating the inflammatory tone and, thus, eliciting other cell types, either locally or more distant to release IL1 that subsequently inhibits UCP1 expression. In support of the latter, recent reports have suggested an important role of macrophage-derived IL1β in diminished browning of white adipocytes in an extracellular signal-regulated kinase-dependent manner [31,32]. Our study supports this notion as we found that chronic inflammation by LPS treatment of the mice generally resulted in a decreased expression of the thermogenic genes in subcutaneous WAT and Prdm16 (a marker of browning), indicating that LPS treatment diminish browning of WAT.…”

Section: Discussionsupporting

confidence: 91%

Inflammation Downregulates UCP1 Expression in Brown Adipocytes Potentially via SIRT1 and DBC1 Interaction

Nøhr

Bobba

Richelsen

et al. 2017

IJMS

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Brown adipose tissue thermogenesis at the cost of energy is not only important for the development of obesity, but also possesses great promise in anti-obesity treatment. Uncoupling protein 1 (UCP1) expression has been reported to be under control of the intracellular deacetylase SIRT1. Here, we investigated the effect and mechanism of inflammation and sirtuin-1 (SIRT1) activation on the induction of thermogenic genes in immortalized brown adipocytes incubated with LPS or IL1β and mice with elevated inflammatory tone. In vitro stimulation of brown adipocytes with dibutyryl cyclic adenosine monophosthate (dbcAMP) reduced the expression of deleted in breast cancer-1 (Dbc1) (SIRT1 inhibitor) and increased the Ucp1 expression. Silencing of SIRT1 attenuated dbcAMP induction of Ucp1. In contrast, IL1β increased the expression of Dbc1 and greatly reduced the induction of Ucp1. Similarly, in vivo studies revealed decreased expression of Ucp1 in brown adipose tissue (BAT) in mice chronically infused with LPS. Resveratrol, a known SIRT1 activator, partly rescued the Ucp1 downregulation by inflammation in both the cell cultures and mice. Here, we describe how the expression of Ucp1 in BAT is controlled via SIRT1 and is reduced under inflammation and can be rescued by SIRT1 activation by resveratrol. We suggest the reduced UCP1 expression under inflammation is mediated by the increased expression of DBC1, which inhibits SIRT1 activity.

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Section: Discussionsupporting

confidence: 91%

Inflammation Downregulates UCP1 Expression in Brown Adipocytes Potentially via SIRT1 and DBC1 Interaction

Nøhr

Bobba

Richelsen

et al. 2017

IJMS

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“…In both sWAT and eWAT, LPS treatment upregulated Il6 , Mcp1 , and Tnfa expression, and downregulated Pgc1a expression compared to PBS‐injected mice. Multiple in vitro and in vivo studies have previously reported LPS‐induced suppression of thermogenesis in white adipocytes (Bae et al, ; Goto et al, ; Okla et al, ). In C3H10T1/2 white adipocytes, LPS downregulated Ucp1 and Pgc1a both at mRNA and protein levels (Bae et al, ), and conditioned medium from LPS‐stimulated RAW 264.7 macrophages led to suppression of isoproterenol‐induced Ucp1 upregulation (Goto et al, ).…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide Alters Thermogenic and Inflammatory Genes in White Adipose Tissue in Mice Fed Diets with Distinct 18‐Carbon Fatty‐Acid Composition

Shin

Ajuwon

2018

Lipids

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Fatty acids are involved in the regulation of inflammatory responses in obesity. However, despite being the largest dietary fatty‐acid class, effects of 18‐carbon fatty acids with different degrees of saturation on inflammatory, metabolic, and thermogenic markers have not been well studied. Therefore, the objective of this study was to test if diets with different 18‐carbon fatty‐acid profiles differentially regulate inflammatory and metabolic genes. Male C57BL/6 mice were fed one of the four different diets: a control diet (CON) containing 5.6% kcal fat from lard and 4.4% kcal fat from soybean oil (CON) or three high‐fat diets (HFD) containing 25% kcal fat from lard and 20% kcal fat from either shea butter oil (saturated fatty‐acid‐rich fat; shea butter [SHB]), olive oil (monounsaturated fatty‐acid‐rich fat; olive oil [OO]), or soybean oil (polyunsaturated fatty‐acid‐rich fat; soybean oil [SBO]) ad libitum for 4 weeks with or without a terminal 4‐h lipopolysaccharide (LPS) treatment. Compared to CON, HFD‐fed mice had higher weight gain and fat accumulation. The OO group had the highest brown adipose tissue (BAT) mass while the SBO group had higher Il6 and lower Cpt1a expression in white adipose tissue (WAT) than other HFD groups. Treatment with LPS upregulated expression of proinflammatory cytokines, and this was associated with downregulation of thermogenic gene expression. However, the diets did not have differential effects on inflammatory response to LPS. These data indicate that the saturation degree of 18‐C fatty acids is not an important factor on response to LPS with regard to metabolic and inflammatory indicators.

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“…In white adipocytes, pro-inflammatory cytokines derived from lipopolysaccharide (LPS)- or tumor necrosis factor α (TNF-α)-activated macrophages suppressed the induction of the uncoupling protein 1 (UCP1) promoter activity and mRNA expression via extracellular signal-related kinase (ERK) activation [15]. Furthermore, IL-1β, a typical pro-inflammatory cytokine, suppressed isoproterenol-induced activation of the UCP1 promoter and cold-induced UCP1 expression in mouse adipose tissue [16]. These studies indicate that inflammation links obesity and dysfunctional thermogenesis; however, the nature of the link between obesity-associated chronic immune response and non-shivering thermogenesis is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Effects of Toll-Like Receptor 4, NLRP3 Inflammasome, and Interleukin-1β on White Adipocyte Browning

et al. 2017

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Adipose tissue expansion is accompanied by infiltration and accumulation of pro-inflammatory macrophages, which links obesity to pathologic conditions such as type 2 diabetes. However, little is known regarding the role of pro-inflammatory adipose tissue remodeling in the thermogenic activation of brown/beige fat. Here, we investigated the effect of pattern recognition receptors (PRR) activation in macrophages, especially the toll-like receptor 4 (TLR4) and Nod-like receptor 3 (NLRP3), on white adipocyte browning. We report that TLR4 activation by lipopolysaccharide repressed white adipocyte browning in response to β3-adrenergic receptor activation and caused ROS production and mitochondrial dysfunction, while genetic deletion of TLR4 protected mitochondrial function and thermogenesis. In addition, activation of NLRP3 inflammasome in macrophages attenuated UCP1 induction and mitochondrial respiration in cultures of primary adipocytes, while the absence of NLRP3 protected UCP1 in adipocytes. The effect of NLRP3 inflammasome activation on browning was mediated by IL-1β signaling, as blocking IL-1 receptor in adipocytes protected thermogenesis. We also report that IL-1β interferes with thermogenesis via oxidative stress stimulation and mitochondrial dysfunction as we observed a statistically significant increase in ROS production, decrease in SOD enzyme activity, and increase in mitochondrial depolarization in adipocytes treated with IL-1β. Collectively, we demonstrated that inflammatory response to obesity, such as TLR4 and NLRP3 inflammasome activation as well as IL-1β secretion, attenuates β3-adrenoreceptor-induced beige adipocyte formation via oxidative stress and mitochondrial dysfunction. Our findings provide insights into targeting innate inflammatory system for enhancement of the adaptive thermogenesis against obesity.

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Proinflammatory cytokine interleukin-1β suppresses cold-induced thermogenesis in adipocytes

Cited by 101 publications

References 37 publications

Inflammation Downregulates UCP1 Expression in Brown Adipocytes Potentially via SIRT1 and DBC1 Interaction

Inflammation Downregulates UCP1 Expression in Brown Adipocytes Potentially via SIRT1 and DBC1 Interaction

Lipopolysaccharide Alters Thermogenic and Inflammatory Genes in White Adipose Tissue in Mice Fed Diets with Distinct 18‐Carbon Fatty‐Acid Composition

Inhibitory Effects of Toll-Like Receptor 4, NLRP3 Inflammasome, and Interleukin-1β on White Adipocyte Browning

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