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Origin and Function of Stress-Induced IL-6 in Murine Models
Open accessAbstract
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.
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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.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Results > Acute stress induces endocrine IL6
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Acute stress induces endocrine IL6 · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that adrenalectomized mice had significantly higher levels of IL6 following stress, suggesting that the adrenal gland negatively regulated IL6 (Figure S1B).”
§ Origin and function of stress-induced IL6 in murine models > Results > Acute stress induces endocrine IL6
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Results > ADRB3-dependent IL6 from BAT potentiates lethal endotoxemia secondary to acute stress
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: LPS-induced mortality is due solely to the inflammatory response without any confounding contribution by pathogens.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Results > IL6 is necessary for maintaining hyperglycemia following acute stress
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Results > ADRB3 mediates brown-adipocyte-derived IL6 in response to acute stress independently of thermoregulation
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found significant overall increased IL6 levels in the high [74 pg/ml, SE: 35] versus low [3.9 pg/ml, SE: 2.78] stress groups (t=2.15, p<0.05) (Figure S1E).”
§ Origin and function of stress-induced IL6 in murine models > Results > Acute stress induces endocrine IL6
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that hepatocyte-specific deletion was sufficient to recapitulate the inhibitory effects of systemic IL6Ra blockade on gluconeogenesis after bleeding (Figure 5E) and restraint stress (Figure 5F).”
§ Origin and function of stress-induced IL6 in murine models > Results > IL6Ra in the liver controls stress hyperglycemia through hepatocyte reprogramming
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Here, regardless of stress-priming, animals lacking hepatic IL6 signaling were significantly more sensitive to endotoxemia, suggesting that the hepatic acute phase response was a required adaptation to endotoxemia (Figure S5B), consistent with previous reports (Castell et al., 1989; Wunderlich et al., 2010).”
§ Origin and function of stress-induced IL6 in murine models > Results > ADRB3-dependent IL6 from BAT potentiates lethal endotoxemia secondary to acute stress
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: LPS-induced mortality is due solely to the inflammatory response without any confounding contribution by pathogens.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As expected and consistent with Il6f/fΔUCP1 animals (Figure 2G), stress-inducible IL6 was significantly attenuated in Adrb3f/fΔUCP1 mice (Figure 3I).”
§ Origin and function of stress-induced IL6 in murine models > Results > ADRB3 mediates brown-adipocyte-derived IL6 in response to acute stress independently of thermoregulation
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Consistent with our observations that other acute-phase cytokines were not induced after stress, stress-induced IL6 was present in both gnotobiotic animals and animals deficient in key signaling pathways necessary for detecting bacteria (Figure 2A).”
§ Origin and function of stress-induced IL6 in murine models > Results > Stress-inducible IL6 is produced by brown adipocytes
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- It may state two separate claims as one. 41
- Probably not a substantial claim. 26
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Results > ADRB3 mediates brown-adipocyte-derived IL6 in response to acute stress independently of thermoregulation
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Results > Acute stress induces endocrine IL6
What the sources say
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Results > Acute stress induces endocrine IL6
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Origin and function of stress-induced IL6 in murine models > Results > ADRB3 mediates brown-adipocyte-derived IL6 in response to acute stress independently of thermoregulation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Results > ADRB3-dependent IL6 from BAT potentiates lethal endotoxemia secondary to acute stress
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: LPS-induced mortality is due solely to the inflammatory response without any confounding contribution by pathogens.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Results > ADRB3-dependent IL6 from BAT potentiates lethal endotoxemia secondary to acute stress
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Results > IL6Ra in the liver controls stress hyperglycemia through hepatocyte reprogramming
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“After 6-OHDA treatment, we found that stress-inducible IL6 was significantly attenuated, confirming that sympathetic outflow was required (Figure 3D).”
§ Origin and function of stress-induced IL6 in murine models > Results > ADRB3 mediates brown-adipocyte-derived IL6 in response to acute stress independently of thermoregulation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Origin and function of stress-induced IL6 in murine models > Results > IL6 is necessary for maintaining hyperglycemia following acute stress
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL6 was the most greatly induced cytokine and common to two different stress models (Figure 1B).”
§ Origin and function of stress-induced IL6 in murine models > Results > Acute stress induces endocrine IL6
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Results > ADRB3 mediates brown-adipocyte-derived IL6 in response to acute stress independently of thermoregulation
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Origin and function of stress-induced IL6 in murine models > Results > IL6Ra in the liver controls stress hyperglycemia through hepatocyte reprogramming
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Results > ADRB3-dependent IL6 from BAT potentiates lethal endotoxemia secondary to acute stress
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Results > Acute stress induces endocrine IL6
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Results > ADRB3-dependent IL6 from BAT potentiates lethal endotoxemia secondary to acute stress
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: LPS-induced mortality is due solely to the inflammatory response without any confounding contribution by pathogens.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Results > Stress-inducible IL6 is produced by brown adipocytes
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Results > IL6Ra in the liver controls stress hyperglycemia through hepatocyte reprogramming
What the sources say
- Not checked yetcites Stumvoll et al., 1998
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Origin and function of stress-induced IL6 in murine models > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Likewise, we found that pre-exposure to peak plasma levels of stress-induced IL6 was sufficient to increase end-organ damage and potentiate mortality.”
§ Origin and function of stress-induced IL6 in murine models > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Origin and function of stress-induced IL6 in murine models > Discussion
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None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Introduction
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Introduction
What the sources say
- Not checked yetcites Liu et al., 2002 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These experiments demonstrate that ADRB3 is necessary and sufficient for acute-stress-induced IL6.”
§ Origin and function of stress-induced IL6 in murine models > Results > ADRB3 mediates brown-adipocyte-derived IL6 in response to acute stress independently of thermoregulation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Origin and function of stress-induced IL6 in murine models > Results > Acute stress induces endocrine IL6
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Origin and function of stress-induced IL6 in murine models > Results > IL6 is necessary for maintaining hyperglycemia following acute stress
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Origin and function of stress-induced IL6 in murine models > Results > IL6Ra in the liver controls stress hyperglycemia through hepatocyte reprogramming
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“and by the association of IL6 polymorphisms in individuals with depression (Zhang et al., 2016).”
§ Origin and function of stress-induced IL6 in murine models > Introduction
What the sources say
- Not checked yetcites Zhang et al., 2016 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
§ Origin and function of stress-induced IL6 in murine models > Discussion
What the sources say
- Not checked yetcites Oh et al., 2013
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“Gluconeogenesis is normally not engaged in positive energy balance states, with the exception of forced exercise (Banzet et al., 2009).”
§ Origin and function of stress-induced IL6 in murine models > Discussion
What the sources say
- Not checked yetcites Banzet et al., 2009 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Discussion
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Discussion
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Origin and function of stress-induced IL6 in murine models > Results > ADRB3-dependent IL6 from BAT potentiates lethal endotoxemia secondary to acute stress
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“On the other hand, recent work suggest that BAT of “humanized” mice is notably similar to human BAT (de Jong et al., 2019).”
§ Origin and function of stress-induced IL6 in murine models > Discussion
What the sources say
- Not checked yetcites de Jong et al., 2019 source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“IL6 is generally considered a pro-inflammatory cytokine, which is supported by the efficacy of IL6 blockade in inflammatory diseases (Kotch et al.).”
§ Origin and function of stress-induced IL6 in murine models > Discussion
What the sources say
- Not checked yetcites Kotch et al.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Origin and function of stress-induced IL6 in murine models > Discussion
What the sources say
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Discussion
What the sources say
- Not checked yetcites Abreu-Vieira et al., 2015 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Discussion
What the sources say
- Not checked yetcites Banzet et al., 2009 source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Discussion
What the sources say
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“In this setting, IL6 is derived from myocytes and induces hepatic gluconeogenesis.”
§ Origin and function of stress-induced IL6 in murine models > Discussion
What the sources say
- Not checked yetcites Banzet et al., 2009 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Discussion
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“On the other hand, several studies demonstrate an anti-inflammatory role for IL6 (Mauer et al., 2014; Nandi et al.).”
§ Origin and function of stress-induced IL6 in murine models > Discussion
What the sources say
- Not checked yetcites Mauer et al., 2014 source
- Not checked yetcites Nandi et al.
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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)).”
§ Origin and function of stress-induced IL6 in murine models > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
What the sources say
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Origin and function of stress-induced IL6 in murine models > Limitations, Caveats and Open Questions
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The high and low groups were group matched on age, gender, education and body mass index (BMI).”
§ Origin and function of stress-induced IL6 in murine models > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is likely that stress-induced IL6 plays additional roles besides those described in our studies.”
§ Origin and function of stress-induced IL6 in murine models > Limitations, Caveats and Open Questions
Strength:hedged· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Origin and function of stress-induced IL6 in murine models > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Origin and function of stress-induced IL6 in murine models > Discussion
What the sources say
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All animal experiments were performed according to institutional regulations upon review and approval of Yale University’s Institutional Animal Care and Use Committee.”
§ Origin and function of stress-induced IL6 in murine models > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Numerous studies have reported that intracranial IL6 and IL6 signaling using non-canonical trans-signaling modalities impact behavior (Rothaug et al., 2016).”
§ Origin and function of stress-induced IL6 in murine models > Discussion
What the sources say
- Not checked yetcites Rothaug et al., 2016 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Origin and function of stress-induced IL6 in murine models > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“These experiments were performed on mice in a single facility and largely on the C57BL/6J genetic background.”
§ Origin and function of stress-induced IL6 in murine models > Limitations, Caveats and Open Questions
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Change from baseline values were computed to assess baseline adjusted values and reduce variability across subjects.”
§ Origin and function of stress-induced IL6 in murine models > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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).”
§ Origin and function of stress-induced IL6 in murine models > Discussion
What the sources say
- Not checked yetcites Kappelmann et al., 2018 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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.”
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?
The cited source says what the claim attributes to it.
In the citing paper
“work demonstrating that IL-6 receptor signaling on hepatocytes promotes hepatic gluconeogenesis in mouse models of acute stress 67”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [67]
In the citing paper
“The plasma level of epinephrine reaches its peak from 30 min to 90 min after the onset of immobilization stress (Jeong et al., 2000; Kvetnansky et al., 2006; Qing et al., 2020).”
From Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells (2021) · cites this paper as Qing et al., 2020
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
MinorThe results state that acute stress decreased circulating triglycerides, but the same paragraph later refers to stress-induced hypertriglyceridemia.
“Acute stress decreased circulating triglyceride (TG) levels (Figure S3C)”
“stress-induced hypertriglyceridemia did trend lower in IL6Ra antagonized animals (Figure S3F)”
IL6 administration is called endogenous despite being injected
MinorThe LPS results say that endogenous administration of IL6 bypassed the need for consciousness, but the described intervention was an injection of recombinant IL6.
“an effect that could be bypassed with endogenous administration of IL6 (Figure 6D)”
“recombinant mouse IL6 (406-ML-025/CF, R&D) or PBS control was intravenously injected one hour before experiment”
Reported stress hormone differs from the hormone assayed
MinorThe results describe a time course for circulating cortisol, whereas the methods specify an assay for corticosterone, not cortisol.
“Circulatory cortisol and noradrenaline were increased within 15 minutes, peaked at two hours after acute stress and returned to baseline by four hours”
“Plasma levels of corticosterone (Enzo Life Sciences), insulin (Crystal Chem), and noradrenaline (Eagle Biosciences) were measured using kits according to the manufacturer’s protocols.”
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Interleukin-6 Is a Novel Factor Mediating Glucose Homeostasis During Skeletal Muscle Contraction
Febbraio, M. A., Hiscock, N., Sacchetti, M., Fischer, C. P., & Pedersen, B. K. (2004) · Diabetes · doi:10.2337/diabetes.53.7.1643 · Cited by 455
Association between stressful life events and exacerbation in multiple sclerosis: a meta-analysis
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“To address previous reports of cross-talk between IL6 and adrenal hormones (Bethin et al., 2000; Path et al., 2000), we utilized an antagonistic anti-IL6Ra antibody and found that inhibition of IL6 signaling did not change circulating levels of corticosterone or noradrenaline after acute stress…”
Batty, G. D., Russ, T. C., Stamatakis, E., & Kivimäki, M. (2017) · BMJ · doi:10.1136/bmj.j108 · Cited by 377
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Self-citationSickle Hemoglobin Confers Tolerance to Plasmodium Infection
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“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.”
Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance
Matthews, V. B., Allen, T. L., Risis, S., Chan, M. H. S., Henstridge, D. C., Watson, N., Zaffino, L. A., Babb, J. R., Boon, J., Meikle, P. J., et al. (2010) · Diabetologia · doi:10.1007/s00125-010-1865-y · Cited by 334
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“The mechanism underlying this phenomenon is unclear, but likely is a result of stressinduced IL6-dependent metabolic re-programming similar to that which has been previously published by our group and others (Ganeshan et al., 2019; Luan et al., 2019; Wang et al., 2016; Wang A, 2019; Weis et al., 2017).”
IL-6 Trans-Signaling Modulates TLR4-Dependent Inflammatory Responses via STAT3
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IL-6 Improves Energy and Glucose Homeostasis in Obesity via Enhanced Central IL-6 trans-Signaling
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CREB and FoxO1: two transcription factors for the regulation of hepatic gluconeogenesis
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“Here, regardless of stress-priming, animals lacking hepatic IL6 signaling were significantly more sensitive to endotoxemia, suggesting that the hepatic acute phase response was a required adaptation to endotoxemia (Figure S5B), consistent with previous reports (Castell et al., 1989; Wunderlich et al., 2010).”
Arid5a controls IL-6 mRNA stability, which contributes to elevation of IL-6 level in vivo
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The β2-adrenergic receptor controls inflammation by driving rapid IL-10 secretion
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Interleukin-6 does/does not have a beneficial role in insulin sensitivity and glucose homeostasis
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Human kidney and liver gluconeogenesis: evidence for organ substrate selectivity
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Leptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation
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Human and Mouse Brown Adipose Tissue Mitochondria Have Comparable UCP1 Function
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Muscle-derived interleukin 6 increases exercise capacity by signaling in osteoblasts
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“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; R…”
Cumulative adversity sensitizes neural response to acute stress: association with health symptoms
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Self-citationTreatment of type 2 diabetes with the designer cytokine IC7Fc
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“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.”
Adipocyte lipolysis-stimulated interleukin-6 production requires sphingosine kinase 1 activity
Zhang, W., Mottillo, E. P., Zhao, J., Gartung, A., VanHecke, G. C., Lee, J.-F., Maddipati, K. R., Xu, H., Ahn, Y.-H., Proia, R. L., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.601096 · Cited by 80
The role of interleukin‐6 in the human adrenal gland
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Self-citationIL-6 Strikes a Balance in Metabolic Inflammation
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Interleukin-6 mediates exercise-induced increase in insulin sensitivity in mice
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“Gluconeogenic capacity is mediated by key rate-limiting enzymes, many of which have been shown to be sensitive to IL6 signaling via STAT3 regulatory elements (Banzet et al., 2009).”
InfluentialCold-sensing TRPM8 channel participates in circadian control of the brown adipose tissue
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IL-6 in inflammation, autoimmunity and cancer
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“Additionally, it was shown that acute stress induces a systemic increase of IL-6 secreted from brown adipocytes in a beta-3-adrenergic-receptor-dependent manner in mouse models (290).”
BackgroundMajor depressive disorder: hypothesis, mechanism, prevention and treatment
Cui, L., Li, S., Wang, S., Wu, X., Liu, Y., Yu, W., Wang, Y., Tang, Y., Xia, M., & Li, B. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01738-y · Cited by 1,244
“232 The HPA axis is a crucial endocrine system that orchestrates this response.”
BackgroundPathophysiology of obesity and its associated diseases
Jin, X., Qiu, T., Li, L., Yu, R., Chen, X., Li, C., Proud, C. G., & Jiang, T. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.01.012 · Cited by 603
Tissue homeostasis and inflammation
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The enteric nervous system relays psychological stress to intestinal inflammation
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Metadata
- 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)
- 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
- bronze
- doi.org
- 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 › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Immunology and Microbiology › Immunology › 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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