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Cited by 303Adipokines, Inflammation, and Metabolic DiseasesStress Responses and CortisolCytokine Signaling Pathways and Interactions

Origin and function of stress-induced IL-6 in murine models

Open access
Qing, Hua, Desrouleaux, Reina, Israni-Winger, Kavita, Mineur, Yann S., Fogelman, Nia, Zhang, Cuiling, Rashed, Saleh, Palm, Noah W. +4 more·2020·Cell
DOI 10.1016/j.cell.2020.05.054PMC PMC7384974
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Abstract

Summary Acute psychological stress has long been known to decrease host fitness to inflammation in a wide variety of diseases, but how this occurs is incompletely understood. Using mouse models, we show that IL6 is the dominant cytokine inducible upon acute stress alone. Stress-inducible IL6 is produced from brown adipocytes in a beta-3-adrenergic-receptor-dependent fashion. During stress, endocrine IL6 is the required instructive signal for mediating hyperglycemia through hepatic gluconeogenesis, which is necessary for anticipating and fueling “fight or flight” responses. This adaptation came at the cost of enhancing mortality to a subsequent inflammatory challenge. These findings provide a mechanistic understanding of the ontogeny and adaptive purpose of IL6 as a bona fide stress hormone coordinating systemic immunometabolic reprogramming. This brain-brown fat-liver axis may provide new insights into brown adipose tissue as a stress-responsive endocrine organ and mechanistic insight into targeting this axis in the treatment of inflammatory and neuropsychiatric diseases.

AI snapshot

Written from the paper’s full text.

TL;DR

Acute psychological stress in mice induces endocrine IL-6, produced by brown adipocytes via β3-adrenergic receptor signaling, which drives hepatic gluconeogenesis and stress hyperglycemia but also worsens mortality to subsequent endotoxemia. The paper defines a brain–brown fat–liver axis for stress-induced IL-6 and its adaptive and maladaptive consequences.

Key findings

  • Acute stress alone induced circulating IL-6 in mice; among 32 screened cytokines/chemokines, IL-6 was the most greatly induced and common to two stress models. Stress-induced IL-6 peaked at 4 hours and remained detectable above baseline at 18 hours, unlike corticosterone/noradrenaline, which peaked at 2 hours and returned to baseline by 4 hours. In a human community sample, high-stress individuals had higher IL-6 (74 pg/ml, SE 35) than low-stress individuals (3.9 pg/ml, SE 2.78; t=2.15, p<0.05).
  • Stress-inducible IL-6 came from brown adipocytes, required consciousness and sympathetic outflow, and depended on ADRB3 but not UCP1 or ambient temperature. BAT excision ablated the IL-6 response; Il6f/fΔUCP1 and Adrb3f/fΔUCP1 mice showed attenuated stress-induced IL-6.
  • IL-6 was necessary and sufficient for stress hyperglycemia via hepatic gluconeogenesis. IL6Ra blockade reduced endogenous glucose production and impaired pyruvate conversion to glucose; hepatocyte-specific Il6ra deletion recapitulated these effects and impaired normal light-dark box behavior after stress.
  • Stress-induced BAT-derived IL-6 decreased host tolerance to LPS: stress priming enhanced LPS mortality, ADRB3 agonist or stress-dosed IL-6 was sufficient to potentiate mortality, and Il6f/fΔUCP1 mice were resistant to stress-priming. Stress-primed animals showed more renal damage and a trend toward more cardiac damage, absent in Il6f/fΔUCP1 animals.

Methods

  • Male mice aged 6–8 weeks, largely C57BL/6J, plus genetic models including Il6f/fΔUCP1, Adrb3f/fΔUCP1, Il6raf/fΔAlb, Adrb3 KO, Ucp1 KO, and bone marrow chimeras. Acute stress models included tube restraint, cage switching, social isolation, and retro-orbital bleeding; human subjects were a community sample assessed with the Cumulative Adversity Interview and matched on age, gender, education, and BMI.
  • Main analyses included plasma cytokine arrays and ELISA, qRT-PCR, immunohistochemistry, metabolic tolerance tests (GTT, ITT, PTT), tracer infusions for endogenous glucose production and palmitate turnover, indirect calorimetry, blood pressure telemetry, light-dark box behavior, and LPS endotoxemia survival. Statistics used Prism 8.0 with t tests, one-way/two-way ANOVA, Tukey tests, and log-rank Mantel-Cox tests; p<0.05 considered significant.

Limitations

  • The paper states experiments were performed on mice in a single facility and largely on the C57BL/6J background; microbiota, genetic background, and facility-specific factors are unknown, and animal-facility settings likely affect physiology studies. It also states stress-induced IL-6 likely has additional roles, many open questions remain, and human translatability is to be determined.
  • The paper notes the LPS model may not be generalizable to other models of inflammation, and the precise mechanism by which stress-induced IL-6 primes LPS-mediated mortality remains unclear. It also states the role of BAT in adult humans is controversial and it remains unclear how rodent findings translate to humans.
  • Evident from the text: most mechanistic claims rely on male mice, and the human data are limited to a small high/low stress comparison without the same causal manipulations.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.cell.2020.05.054

Cites

105 of 105 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 70 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    A single conscious retro-orbital bleed induced IL6.

    “Unexpectedly, we found that a single conscious retro-orbital bleed induced IL6 (Figure 1A).”
    • Also stated in: § Acute stress induces endocrine IL6 · boosted
      “demonstrating that conscious bleeding itself increased circulating IL6 and that repeated bleeding sustained high IL6 levels (Figure 1C).”
    Quote in the paperSubstantial claim
  • Findingown data

    Adrenalectomized mice had significantly higher levels of IL6 following stress.

    “We found that adrenalectomized mice had significantly higher levels of IL6 following stress, suggesting that the adrenal gland negatively regulated IL6 (Figure S1B).”
    Quote in the paperSubstantial claim
  • Findingown data

    ADRB3 antagonist applied alongside restraint challenge negated the effects of stress-priming.

    “To test if ADRB3-dependent IL6 was necessary, ADRB3 antagonist was applied alongside the restraint challenge, which negated the effects of stress-priming (Figure 6E).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: LPS-induced mortality is due solely to the inflammatory response without any confounding contribution by pathogens.
  • Findingown data

    Pck1 and G6pc were significantly increased following acute stress.

    “We thus assessed the hepatic transcriptional induction of Pck1, G6pc and other gluconeogenic genes and found that Pck1 and G6pc were significantly increased following acute stress (Figure 4G).”
    Quote in the paperSubstantial claim
  • Findingown data

    Ambient temperature (4°C, 22°C, 32°C) had no effect on stress-induced IL6 induction.

    “We subjected animals placed in standard cold acclimation (4°C), standard (22°C), and thermoneutral (32°C) conditions to bleeding stress, and did not note any effect on IL6 induction (Figure S1K).”
    Quote in the paperSubstantial claim
  • May combine two claims. 41
  • Classified as probably not a substantial claim. 26

  • May combine two claims.

    Findingown data

    ADRB3 agonist CL316,243, but not ADRB1/2 agonist isoproterenol, was sufficient to induce IL6.

    “We thus challenged animals with ADRB agonists and found that the ADRB3 agonist CL316,243, but not the ADRB1/2 agonist isoproterenol, was sufficient to induce IL6 (Figure 3E and F), consistent with previous reports (Kosteli et al., 2010; Zhang et al., 2014).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Kosteli et al., 2010 source

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    • cites Zhang et al., 2014 source

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  • May combine two claims.

    Findingcitation

    The absolute level of IL6 detected fell in the middle range of reported levels in inflammatory contexts and above reported ranges post-exercise and diet-induced obesity.

    “The absolute level of IL6 we detected fell in the middle range of reported levels (50 pg/mL to 200 ng/mL) in inflammatory contexts and above reported ranges post-exercise and diet-induced obesity (30-100 pg/mL) (Chowdhury et al.; Gao et al., 2014; Greenhill et al., 2011; Masuda et al., 2013; Osuchowski et al., 2006; Remick et al., 2005; Vida et al.; Wang et al., 2017; Yan et al., 2015).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Gao et al., 2014 source

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    • cites Greenhill et al., 2011 source

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    • cites Masuda et al., 2013 source

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  • May combine two claims.

    Findingown data

    Circulatory cortisol and noradrenaline increased within 15 minutes, peaked at two hours after acute stress, and returned to baseline by four hours.

    “Circulatory cortisol and noradrenaline were increased within 15 minutes, peaked at two hours after acute stress and returned to baseline by four hours; however, IL6, which was significantly increased in blood by two hours, peaked at four hours, and was even detectable above baseline 18 hours after acute stress (Figure 1D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Pre-treatment with pharmacologic inhibitor of ADRB3, but not ADRB1/2, or genetic deletion of Adrb3, abrogated stress-induced IL6.

    “Concordantly, pre-treatment with the pharmacologic inhibitor of ADRB3, but not ADRB1/2 (Figure 3G and Figure S1P) or genetic deletion of Adrb3 (Figure 3H), abrogated stress-induced IL6.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Glucose, but not lipid, was sufficient to prime the LPS response.

    “We also tested if hyperglycemia induced by IL6 during stress was itself sufficient to prime LPS responses, and thus challenged animals to exogenous glucose to achieve stress hyperglycemia or an isocaloric isovolumetric dose of lipid, and found that glucose, but not lipid, was sufficient to prime the LPS response (Figure S5C).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: LPS-induced mortality is due solely to the inflammatory response without any confounding contribution by pathogens.

  • May combine two claims.

    Findingown data

    Stress-priming did not significantly change circulating or tissue inflammatory cytokines, tissue inflammatory transcripts, or body temperature after LPS.

    “We did not detect significant changes in circulating or tissue inflammatory cytokines post-LPS in a variety of experimental settings, nor did we detect any changes in tissue inflammatory transcripts or body temperature (Figure S5D–R, S6D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IL6Ra inhibitor suppressed gluconeogenesis from pyruvate in liver but not in kidney.

    “To directly assess gluconeogenesis in the liver and kidney, we developed a method to assess the contribution of pyruvate to gluconeogenesis in a tissue-specific manner during stress, and found that IL6Ra inhibitor suppressed gluconeogenesis from pyruvate in liver but not in kidney (Figure 5C and D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    6-OHDA treatment significantly attenuated stress-inducible IL6, confirming sympathetic outflow was required.

    “After 6-OHDA treatment, we found that stress-inducible IL6 was significantly attenuated, confirming that sympathetic outflow was required (Figure 3D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No significant changes in canonical stress hormones or stress-induced heart rate or hypertension after acute stress in absence of IL6 function.

    “We did not detect significant changes in the quantity of canonical stress hormones (Figures S1C–D) or stress-induced heart rate or hypertension (Figure S2A) after acute stress in the absence of IL6 function, suggesting that autonomic output was not significantly impacted by IL6.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IL6 was the most greatly induced cytokine and common to two different stress models.

    “IL6 was the most greatly induced cytokine and common to two different stress models (Figure 1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Ucp1-deficient animals showed no differences in endocrine IL6 levels or BAT transcriptional upregulation of Il6.

    “Consistent with a function independent from thermoregulation, we did not note differences in either endocrine IL6 levels or BAT transcriptional upregulation of Il6 (Figure 3A and B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Il6ra was significantly induced in liver but not in kidney.

    “We observed that Il6ra was significantly induced in liver but not in kidney (Figure 5B), suggesting that the liver may be the primary target for IL6 signaling in response to acute stress.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Stress did not produce large differences in maintaining glycemia, fatty acid, or ketone body levels.

    “We also did not find large differences in maintaining glycemia, fatty acid, or ketone body levels (Figure S6I–K), which we had previously shown to be important in host tolerance to LPS (Wang et al., 2016).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IL6 was significantly increased in blood by two hours, peaked at four hours, and was detectable above baseline 18 hours after acute stress.

    “Circulatory cortisol and noradrenaline were increased within 15 minutes, peaked at two hours after acute stress and returned to baseline by four hours; however, IL6, which was significantly increased in blood by two hours, peaked at four hours, and was even detectable above baseline 18 hours after acute stress (Figure 1D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Consciousness was required for the stress-priming effect, an effect that could be bypassed with endogenous administration of IL6.

    “Since stress-induced IL6 required consciousness, we tested whether or not animals anesthetized prior to tube restraint were still more susceptible to LPS-induced mortality, and found that consciousness was required for the stress-priming effect, an effect that could be bypassed with endogenous administration of IL6 (Figure 6D).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: LPS-induced mortality is due solely to the inflammatory response without any confounding contribution by pathogens.

  • May combine two claims.

    Findingown data

    Both glucose and water induced IL6, suggesting that the acute stress of gavaging and bleeding, but not hyperglycemia, was responsible for IL6 induction.

    “To test this, we performed an oral glucose tolerance test four hours post retro-orbital bleeding and found that both glucose and water induced IL6, suggesting that the acute stress of gavaging and bleeding, but not hyperglycemia, was responsible for IL6 induction (Figure S1F and G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Gluconeogenic genes were induced by bleeding stress only in the liver, not in the kidney.

    “Since the liver and kidney are the major glucose-producing organs (Stumvoll et al., 1998), we surveyed the transcriptional induction of gluconeogenic genes in both organs and found that they were induced by bleeding stress only in the liver (Figure 5A and Figure S4A).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Stumvoll et al., 1998

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In our study, we did not observe any IL6 induction in muscle, nor did we observe increased activity after stress.

    “In our study, we did not observe any IL6 induction in muscle, nor did we observe increased activity after stress, and instead found that brown adipocytes were indispensable in the setting of acute stress.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Pre-exposure to peak plasma levels of stress-induced IL6 was sufficient to increase end-organ damage and potentiate mortality.

    “Likewise, we found that pre-exposure to peak plasma levels of stress-induced IL6 was sufficient to increase end-organ damage and potentiate mortality.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the LPS model, stress did not meaningfully increase inflammatory magnitude, hemodynamic or cardiopulmonary parameters, or gross metabolic parameters, but led to measurable worsening of end-organ function and death.

    “In the LPS model, which may not be generalizable to other models of inflammation, we found that while stress did not meaningfully increase inflammatory magnitude, hemodynamic or cardiopulmonary parameters, or gross metabolic parameters, it nonetheless led to measurable worsening of end-organ function, and death.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Glucocorticoids and catecholamines are primarily thought to be immunosuppressive and are used therapeutically for this purpose.

    “However, the well-studied mediators of stress physiology, glucocorticoids and catecholamines, are primarily thought to be immunosuppressive (Russell and Lightman, 2019) and used therapeutically for this purpose, creating a paradox that many have tried to resolve for over 30 years (Frank et al., 2013; Munck et al., 1984).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Russell and Lightman, 2019

      Not checked in the free run.

    • cites Frank et al., 2013 source

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    • cites Munck et al., 1984 source

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  • May combine two claims.

    Premisecitation

    In human studies, stress induces measurable changes in biology, such as in the magnitude of inflammatory cytokines and in functional changes within relevant end-organs.

    “In human studies, stress induces measurable changes in biology, such as in the magnitude of inflammatory cytokines and in functional changes within relevant end-organs, such as in pulmonary function in the case of allergic inflammation (Liu et al., 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Liu et al., 2002 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    ADRB3 is necessary and sufficient for acute-stress-induced IL6.

    “These experiments demonstrate that ADRB3 is necessary and sufficient for acute-stress-induced IL6.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    IL6 is an endocrine hormone inducible by acute stress alone, with different kinetics than the canonical stress hormones corticosterone and noradrenaline.

    “Taken together, these data indicate that IL6 is an endocrine hormone inducible by acute stress alone, with different kinetics than the canonical stress hormones, corticosterone and noradrenaline.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    IL6 was both necessary and sufficient to induce stress-hyperglycemia at four hours after acute stress.

    “A single bolus of stress-dosed IL6 was also sufficient to recapitulate the effects of acute stress (Figure S2C), indicating that IL6 was both necessary and sufficient to induce stress-hyperglycemia at this time point.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Stress-induced IL6 mediates stress-hyperglycemia through hepatic IL6Ra signaling in positive energy balance states and hepatic IL6Ra is necessary for a normal behavioral response to acute stress.

    “Taken in aggregate, we demonstrate that stress-induced IL6 mediates stress-hyperglycemia through hepatic IL6Ra signaling in positive energy balance states and that hepatic IL6Ra is necessary for a normal behavioral response to acute stress.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    IL6 polymorphisms are associated with depression.

    “and by the association of IL6 polymorphisms in individuals with depression (Zhang et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zhang et al., 2016 source

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  • Classified as probably not a substantial claim.

    Premisecitation

    During fasting, ketogenic diets, or other hypoglycemic states, gluconeogenesis programs are mediated primarily by CREB/FoxO1 programs, which are responsive to low energy states.

    “Unlike during fasting, ketogenic diets, or other hypoglycemic states where gluconeogenesis programs are mediated primarily by CREB/FoxO1 programs (Oh et al., 2013), which are responsive to low energy states, stress induces gluconeogenesis even in net positive energy balance states.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Oh et al., 2013

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    Premisecitation

    Gluconeogenesis is normally not engaged in positive energy balance states, with the exception of forced exercise.

    “Gluconeogenesis is normally not engaged in positive energy balance states, with the exception of forced exercise (Banzet et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Banzet et al., 2009 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In contexts of chronically increased IL6 such as obesity or rheumatoid arthritis, IL6 has been shown to induce insulin resistance.

    “In contexts of chronically increased IL6 such as obesity or rheumatoid arthritis, IL6 has been shown to induce insulin resistance (Castaneda et al., 2019; Kim et al., 2004; Perry et al., 2015).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Castaneda et al., 2019

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    • cites Kim et al., 2004 source

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    • cites Perry et al., 2015 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In these same contexts, others have shown that IL6 induces insulin sensitivity, while IL6 has been shown to be insulin sensitizing in exercise.

    “On the other hand, in these same contexts, others have shown that IL6 induces insulin sensitivity (Carey et al., 2006; Findeisen et al., 2019; Matthews et al., 2010; Mauer et al., 2014; Steensberg et al., 2003; Timper et al., 2017), while IL6 has been shown to be insulin sensitizing in exercise (Benrick et al., 2012).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Carey et al., 2006 source

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    • cites Findeisen et al., 2019 source

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    • cites Matthews et al., 2010 source

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  • May combine two claims.

    Interpretationown data

    We propose a model wherein IL6 is a necessary signal that instructs gluconeogenesis in net energy positive states as an anticipatory response to impending increase in glucose demand, as opposed to responsive adaptation.

    “Thus, we propose a model wherein IL6 is a necessary signal that instructs gluconeogenesis in net energy positive states as an anticipatory, (impending increase in glucose demand), as opposed to responsive adaptation (Figure 7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Stress-induced IL6, while adaptive for supporting fight-or-flight physiology, comes at the cost of decreasing host fitness to endotoxemia-induced inflammation.

    “Taken together, our studies suggest that stress-induced IL6, while adaptive for supporting fight-or-flight physiology, comes at the cost of decreasing host fitness to endotoxemia-induced inflammation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recent work suggests that BAT of humanized mice is notably similar to human BAT.

    “On the other hand, recent work suggest that BAT of “humanized” mice is notably similar to human BAT (de Jong et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites de Jong et al., 2019 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    IL6 is generally considered a pro-inflammatory cytokine, supported by the efficacy of IL6 blockade in inflammatory diseases.

    “IL6 is generally considered a pro-inflammatory cytokine, which is supported by the efficacy of IL6 blockade in inflammatory diseases (Kotch et al.).”
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    • cites Kotch et al.

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    Premisecitation

    Signaling on ADRB2 in immune cells has largely been shown to be anti-inflammatory.

    “While signaling on ADRB2 in immune cells has largely been shown to be anti-inflammatory (Agac et al., 2018; Nance and Sanders, 2007), our study suggests that ADRB3 activation after acute stress exposure may be detrimental for adaptation to a subsequent inflammatory challenge.”
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    • cites Agac et al., 2018 source

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    • cites Nance and Sanders, 2007 source

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    Premisecitation

    BAT hyperemia and thermogenesis can be decoupled.

    “Interestingly, BAT hyperemia and thermogenesis can be decoupled, suggesting that there could be scenarios were uncoupled respiration is not necessary for hyperemia (Abreu-Vieira et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Abreu-Vieira et al., 2015 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Other studies demonstrate STAT3 regulation of the same gluconeogenic genes such as Pck1 and G6pc and a role for IL6 in exercise-mediated hepatic gluconeogenesis.

    “While IL6 does not appear to increase gluconeogenesis at rest (Steensberg et al., 2003), our studies resonate well with other studies demonstrating STAT3 regulation of the same gluconeogenic genes such as Pck1 and G6pc and by studies demonstrating a role for IL6 in exercise-mediated hepatic gluconeogenesis (Banzet et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Banzet et al., 2009 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Psychological stress has been known to induce endocrine IL6 for nearly 30 years and has been shown in multiple species, including rats, mice, and humans.

    “Psychological stress has been known to induce endocrine IL6 for nearly 30 years and has been shown in multiple species, including rats, mice, and humans (Cheng et al., 2015; LeMay et al., 1990; Maes et al., 1998).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Cheng et al., 2015 source

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    • cites LeMay et al., 1990 source

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    • cites Maes et al., 1998 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In forced exercise, IL6 is derived from myocytes and induces hepatic gluconeogenesis.

    “In this setting, IL6 is derived from myocytes and induces hepatic gluconeogenesis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Banzet et al., 2009 source

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    Premisecitation

    The role of BAT in adult humans is controversial since its detection is dependent upon the approach employed.

    “The role of BAT in adult humans is controversial since its detection is dependent upon the approach employed (Leitner et al., 2017; Porter et al., 2016; van Marken Lichtenbelt et al., 2009).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Leitner et al., 2017 source

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    • cites Porter et al., 2016 source

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    • cites van Marken Lichtenbelt et al., 2009 source

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    Premisecitation

    Several studies demonstrate an anti-inflammatory role for IL6.

    “On the other hand, several studies demonstrate an anti-inflammatory role for IL6 (Mauer et al., 2014; Nandi et al.).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Mauer et al., 2014 source

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    • cites Nandi et al.

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    Study design and conductcitation

    A community sample of individuals signed written informed consent for research approved by the Yale Institutional Review Board and was carefully assessed for high and low stress using a structured cumulative stress and adversity interview.

    “A community sample of individuals signed written informed consent for research approved by the Yale Institutional Review Board and was carefully assessed for high and low stress using a structured cumulative stress and adversity interview that assessed recent and past life events (Cumulative Adversity Interview (CAI), (Ansell et al., 2012; Seo et al., 2014; Turner and Lloyd, 1995)).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Ansell et al., 2012 source

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    • cites Seo et al., 2014 source

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    • cites Turner and Lloyd, 1995 source

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    Interpretationreasoning

    The impact of the microbiota, genetic background, and facility-specific factors are unknown, and the unnatural settings in animal facilities likely affect the results and interpretation of physiology studies, including this one.

    “The impact of the microbiota, genetic background, and facility-specific factors are unknown, and the unnatural settings in animal facilities likely affect the results and interpretation of physiology studies, including this one.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The high and low groups were group matched on age, gender, education and body mass index (BMI).

    “The high and low groups were group matched on age, gender, education and body mass index (BMI).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    It is likely that stress-induced IL6 plays additional roles besides those described in our studies.

    “It is likely that stress-induced IL6 plays additional roles besides those described in our studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    This study identifies a brain-BAT-liver axis in mice whereby IL6 modulates glucose metabolism under conditions of acute stress and suggests that there is an adaptive purpose for inducing IL6 in acute stress.

    “In summary, this study identifies a brain-BAT-liver axis in mice whereby IL6 modulates glucose metabolism under conditions of acute stress and suggests that there is an adaptive purpose for inducing IL6 in acute stress.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Aerobic exercise, which also induces IL6, is highly associated with improved outcomes in depression and anxiety.

    “On the other hand, aerobic exercise, which also induces IL6 (Benrick et al., 2012; Pedersen and Febbraio, 2008; Reza et al., 2017), is highly associated with improved outcomes in depression and anxiety.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Benrick et al., 2012 source

      Not checked in the free run.

    • cites Pedersen and Febbraio, 2008 source

      Not checked in the free run.

    • cites Reza et al., 2017 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All animal experiments were performed according to institutional regulations upon review and approval of Yale University's Institutional Animal Care and Use Committee.

    “All animal experiments were performed according to institutional regulations upon review and approval of Yale University’s Institutional Animal Care and Use Committee.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Numerous studies have reported that intracranial IL6 and IL6 signaling using non-canonical trans-signaling modalities impact behavior.

    “Numerous studies have reported that intracranial IL6 and IL6 signaling using non-canonical trans-signaling modalities impact behavior (Rothaug et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rothaug et al., 2016 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Should this brain-BAT-liver axis also be relevant in humans, our findings have implications for the pathogenesis of psychiatric diseases such as seasonal affective disorder, and implicate ADRB3 and IL6 as potential therapeutic targets for preventing disease flares in conditions of pathologic inflammation.

    “Should this brain-BAT-liver axis also be relevant in humans, our findings have implications for the pathogenesis of psychiatric diseases such as seasonal affective disorder, where depression occurs primarily as a function of cold and dark seasons, and also implicate ADRB3 and IL6 as potential therapeutic targets for preventing disease flares in conditions of pathologic inflammation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    These experiments were performed on mice in a single facility and largely on the C57BL/6J genetic background.

    “These experiments were performed on mice in a single facility and largely on the C57BL/6J genetic background.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Change from baseline values were computed to assess baseline adjusted values and reduce variability across subjects.

    “Change from baseline values were computed to assess baseline adjusted values and reduce variability across subjects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The light-dark box paradigm is commonly used in depression and anxiety studies, and IL6 has been implicated in depression for many years.

    “Indeed, the light-dark box paradigm we utilized in this study is commonly used in depression and anxiety studies, and IL6 has been implicated in depression for many years (Kappelmann et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kappelmann et al., 2018 source

      Not checked in the free run.

54 of 54

  • The paper relies on this without support.

    LPS-induced mortality is due solely to the inflammatory response without any confounding contribution by pathogens.

    “We decided to use the lipopolysaccharide (LPS) model of inflammation, since in this model, mortality is due solely to the inflammatory response without any confounding contribution by pathogens.”

  • The paper relies on this without support.

    The role that IL6 plays in the acute stress response is unclear.

    “The role that IL6 plays in the acute stress response, also referred to as the “fight or flight” response, is unclear.”

  • The paper relies on this without support.

    The possibility that stress-inducible cytokines underlie how stress leads to poorer outcomes in inflammatory diseases has not been explored in depth.

    “The possibility that stress-inducible cytokines, as opposed to glucocorticoids or catecholamines, underlie how stress leads to poorer outcomes in inflammatory diseases has not been explored in depth.”

  • The paper relies on this without support.

    How acute psychological stress decreases host fitness to inflammation is incompletely understood.

    “Acute psychological stress has long been known to decrease host fitness to inflammation in a wide variety of diseases, but how this occurs is incompletely understood.”

  • The paper relies on this without support.

    A normal adaptive response in the light-dark box is to spend more time in the dark enclosure.

    “A normal adaptive response is to spend more time in the dark enclosure.”

  • The paper relies on this without support.

    Mechanistic understanding for stress-induced endocrine IL6 had not been addressed.

    “However, mechanistic understanding for this phenomenon has not been addressed.”

  • The paper relies on this without support.

    The evolutionary basis for IL6 induction during acute stress was unknown, and how this may connect to stress, metabolism, and inflammation was unclear.

    “The evolutionary basis for IL6 induction during acute stress was unknown, and how this may connect to the long-observed connection between stress, metabolism, and inflammation was also unclear.”

  • The paper relies on this without support.

    BAT is highly enriched in ADRB3.

    “Finally, BAT is highly enriched in ADRB3.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Stress is described as both lowering and raising triglycerides

    Minor

    The results state that acute stress decreased circulating triglycerides, but the same paragraph later refers to stress-induced hypertriglyceridemia.

  • IL6 administration is called endogenous despite being injected

    Minor

    The LPS results say that endogenous administration of IL6 bypassed the need for consciousness, but the described intervention was an injection of recombinant IL6.

  • Reported stress hormone differs from the hormone assayed

    Minor

    The results describe a time course for circulating cortisol, whereas the methods specify an assay for corticosterone, not cortisol.

3 of 3

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Authors
Qing, H., Desrouleaux, R., Israni-Winger, K., Mineur, Y. S., Fogelman, N., Zhang, C., Rashed, S., Palm, N. W., Sinha, R., Picciotto, M. R., Perry, R. J., & Wang, A.
Affiliations
Yale University (US)
Corresponding author
Wang, Andrew
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2020-07
Volume
182
Issue
2
Pages
372-387.e14
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2020.05.054
PMC
PMC7384974
OpenAlex
W3038243707
Semantic Scholar
765cc7d927337ef7a578b54719124f52b784ea7c
Cited by
303
References
104
Citations by year
2026: 35 · 2025: 52 · 2024: 54 · 2023: 58 · 2022: 55 · 2021: 43 · 2020: 6
FWCI
29.05
Type
journal article
Language
en
Update notices
erratum (2020-09-17)
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (DA14241, DA050986, R01-DK099039, MH077681, P30-DK079310, K99/R00 CA215315, K08AI128745)
  • Gruber Foundation
Topics
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
interleukin-6, acute psychological stress, brown adipose tissue, beta3-adrenergic receptor, hepatic gluconeogenesis, hyperglycemia, stress hormones, immunometabolic reprogramming, inflammation, cytokine induction, fight-or-flight response
MeSH terms
Uncoupling Protein 1, Animals, Bone Marrow Cells, Brain, Adipose Tissue, Brown, Disease Models, Animal, Gluconeogenesis, Hyperglycemia, Liver, Male, Mice, Inbred C57BL, Stress, Psychological, Interleukin-6, Bone Marrow Transplantation, Cytokines, Mice, Knockout, Chemokines, Receptors, Interleukin-6, Receptors, Adrenergic, beta-3, Mice

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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