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Toll-like receptor-4 mediated inflammation is involved in the cardiometabolic alterations induced by intermittent hypoxia.

Poulain L, Richard V, Lévy P, Dematteis M, Arnaud C - Mediators Inflamm. (2015)

Bottom Line: The pathophysiology is still poorly understood but there are some similarities with the obesity-associated cardiometabolic complications.As the latter results from inflammation involving toll-like receptor-4 (TLR4) signaling, we assessed this pathway in the cardiometabolic consequences of IH.These results confirm the important role of inflammation in the cardiometabolic consequences of IH and suggest that targeting TLR4/NFκB pathway could represent a further therapeutic option for sleep apnea patients.

View Article: PubMed Central - PubMed

Affiliation: Université Grenoble Alpes, Laboratoire HP2, 38042 Grenoble, France ; INSERM U1042, 38042 Grenoble, France.

ABSTRACT

Objective: Intermittent hypoxia (IH) is a major component of sleep apnea syndrome as its cardiometabolic complications have been mainly attributed to IH. The pathophysiology is still poorly understood but there are some similarities with the obesity-associated cardiometabolic complications. As the latter results from inflammation involving toll-like receptor-4 (TLR4) signaling, we assessed this pathway in the cardiometabolic consequences of IH.

Methods: Lean adult male TLR4-deficient (TLR4(-/-)) mice and their controls (C57BL/6 mice) were exposed to either IH (FiO2 21-5%, 1 min cycle, 8 h/day) or air (normoxic mice) for 4 weeks. Animals were assessed at 1-week exposure for insulin tolerance test and after 4-week exposure for morphological and inflammatory changes of the epididymal fat and thoracic aorta.

Results: IH induced insulin resistance, morphological and inflammatory changes of the epididymal fat (smaller pads and adipocytes, higher release of TNF-α and IL-6) and aorta (larger intima-media thickness and higher NFκB-p50 activity). All these alterations were prevented by TLR4 deletion.

Conclusion: IH induces metabolic and vascular alterations that involve TLR4 mediated inflammation. These results confirm the important role of inflammation in the cardiometabolic consequences of IH and suggest that targeting TLR4/NFκB pathway could represent a further therapeutic option for sleep apnea patients.

No MeSH data available.


Related in: MedlinePlus

TLR4 signaling is involved in IH-induced insulin resistance. Glucose variation during the 90 minutes of the intraperitoneal insulin tolerance test (IpITT) in C57BL/6 or TLR4−/− mice exposed to 1 week of intermittent hypoxia (IH) or normoxia (N) (a). IpITT presented separately for C57BL/6 (b) and TLR4−/− mice (c). For each group, lowest blood glucose level (nadir) during the 90 minutes of the IpITT (d). *P < 0.05 IH/C57BL/6 versus N/C57BL/6, n = 13–15 per group.
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fig2: TLR4 signaling is involved in IH-induced insulin resistance. Glucose variation during the 90 minutes of the intraperitoneal insulin tolerance test (IpITT) in C57BL/6 or TLR4−/− mice exposed to 1 week of intermittent hypoxia (IH) or normoxia (N) (a). IpITT presented separately for C57BL/6 (b) and TLR4−/− mice (c). For each group, lowest blood glucose level (nadir) during the 90 minutes of the IpITT (d). *P < 0.05 IH/C57BL/6 versus N/C57BL/6, n = 13–15 per group.

Mentions: After one-week exposure, the 4 experimental groups were assessed for insulin tolerance test (Figure 2(a)). C57BL/6 mice exposed to IH exhibited a decreased response to insulin as shown by a lower glucose decrement (Figure 2(b)) and a trend for a smaller glucose nadir compared to their normoxic controls (Figure 2(d)). The insulin response was not affected in hypoxic TLR4−/− mice: the response curve was almost superposable with those of the normoxic TLR4−/− animals (Figures 2(c) and 2(d)) and not significantly different from the curve of normoxic C57BL6 animals (Figure 2(a)).


Toll-like receptor-4 mediated inflammation is involved in the cardiometabolic alterations induced by intermittent hypoxia.

Poulain L, Richard V, Lévy P, Dematteis M, Arnaud C - Mediators Inflamm. (2015)

TLR4 signaling is involved in IH-induced insulin resistance. Glucose variation during the 90 minutes of the intraperitoneal insulin tolerance test (IpITT) in C57BL/6 or TLR4−/− mice exposed to 1 week of intermittent hypoxia (IH) or normoxia (N) (a). IpITT presented separately for C57BL/6 (b) and TLR4−/− mice (c). For each group, lowest blood glucose level (nadir) during the 90 minutes of the IpITT (d). *P < 0.05 IH/C57BL/6 versus N/C57BL/6, n = 13–15 per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4383499&req=5

fig2: TLR4 signaling is involved in IH-induced insulin resistance. Glucose variation during the 90 minutes of the intraperitoneal insulin tolerance test (IpITT) in C57BL/6 or TLR4−/− mice exposed to 1 week of intermittent hypoxia (IH) or normoxia (N) (a). IpITT presented separately for C57BL/6 (b) and TLR4−/− mice (c). For each group, lowest blood glucose level (nadir) during the 90 minutes of the IpITT (d). *P < 0.05 IH/C57BL/6 versus N/C57BL/6, n = 13–15 per group.
Mentions: After one-week exposure, the 4 experimental groups were assessed for insulin tolerance test (Figure 2(a)). C57BL/6 mice exposed to IH exhibited a decreased response to insulin as shown by a lower glucose decrement (Figure 2(b)) and a trend for a smaller glucose nadir compared to their normoxic controls (Figure 2(d)). The insulin response was not affected in hypoxic TLR4−/− mice: the response curve was almost superposable with those of the normoxic TLR4−/− animals (Figures 2(c) and 2(d)) and not significantly different from the curve of normoxic C57BL6 animals (Figure 2(a)).

Bottom Line: The pathophysiology is still poorly understood but there are some similarities with the obesity-associated cardiometabolic complications.As the latter results from inflammation involving toll-like receptor-4 (TLR4) signaling, we assessed this pathway in the cardiometabolic consequences of IH.These results confirm the important role of inflammation in the cardiometabolic consequences of IH and suggest that targeting TLR4/NFκB pathway could represent a further therapeutic option for sleep apnea patients.

View Article: PubMed Central - PubMed

Affiliation: Université Grenoble Alpes, Laboratoire HP2, 38042 Grenoble, France ; INSERM U1042, 38042 Grenoble, France.

ABSTRACT

Objective: Intermittent hypoxia (IH) is a major component of sleep apnea syndrome as its cardiometabolic complications have been mainly attributed to IH. The pathophysiology is still poorly understood but there are some similarities with the obesity-associated cardiometabolic complications. As the latter results from inflammation involving toll-like receptor-4 (TLR4) signaling, we assessed this pathway in the cardiometabolic consequences of IH.

Methods: Lean adult male TLR4-deficient (TLR4(-/-)) mice and their controls (C57BL/6 mice) were exposed to either IH (FiO2 21-5%, 1 min cycle, 8 h/day) or air (normoxic mice) for 4 weeks. Animals were assessed at 1-week exposure for insulin tolerance test and after 4-week exposure for morphological and inflammatory changes of the epididymal fat and thoracic aorta.

Results: IH induced insulin resistance, morphological and inflammatory changes of the epididymal fat (smaller pads and adipocytes, higher release of TNF-α and IL-6) and aorta (larger intima-media thickness and higher NFκB-p50 activity). All these alterations were prevented by TLR4 deletion.

Conclusion: IH induces metabolic and vascular alterations that involve TLR4 mediated inflammation. These results confirm the important role of inflammation in the cardiometabolic consequences of IH and suggest that targeting TLR4/NFκB pathway could represent a further therapeutic option for sleep apnea patients.

No MeSH data available.


Related in: MedlinePlus