biostudies-literatureTinajero ANIDDK NIH HHSNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthInitiative of The University of Texas SystemNIH HHS2621-2641https://www.ebi.ac.uk/biostudies/studies/S-EPMC12092199biostudies-literatureUnknown182(12)<h4>Background and purpose</h4>Despite the well-known occurrence of hypothermia during sepsis, its underlying biological nature and adaptive value remain debated.<h4>Experimental approach</h4>Using indirect calorimetry, telemetry, thermal gradient studies and pharmacological studies, we examined the thermal and metabolic responses of mice treated with a shock-inducing lethal dose of lipopolysaccharide (LPS).<h4>Key results</h4>We report that LPS-treated mice undergo spontaneous hypothermia, driven by hypometabolism and cold-seeking behaviours, even when animals approach the end of life. Conversely, rewarming LPS-treated mice at 30°C delayed hypothermia but worsened mortality, thus highlighting the adaptive importance of hypothermia. Additionally, we show that LPS-induced hypothermia was partly mediated by peripheral neurotensin expressed in response to vascular toll-like receptor 4 (TLR4) signalling. The administration of a neurotensin analogue (JMV449) induced pharmacological hypothermia and significantly ameliorated the clinical presentation and lethality rates in LPS-treated mice. Moreover, the therapeutic benefits of pharmacological hypothermia were prevented when LPS-treated mice were switched to 30°C. Lastly, these beneficial outcomes were attributed to a reduction in oxygen consumption, metabolic stress and cytopathic hypoxia, rather than the modulation of the cytokine storm.<h4>Conclusion and implications</h4>Collectively, our findings indicate that spontaneous and pharmacologically-induced hypothermia protect against endotoxic shock.British journal of pharmacologySpontaneous and pharmacologically induced hypothermia protect mice against endotoxic shock.PMC12092199S10 OD0216841S10OD021684-011S10OD021684‐01P01 DK119130P30 DK127984TRC4P01DK119130P30DK127984Caron AGautron LMerchant WKhan AReynolds RSurbhiJia LTinajero AfalseSpontaneous and pharmacologically induced hypothermia protect mice against endotoxic shock.<h4>Background and purpose</h4>Despite the well-known occurrence of hypothermia during sepsis, its underlying biological nature and adaptive value remain debated.<h4>Experimental approach</h4>Using indirect calorimetry, telemetry, thermal gradient studies and pharmacological studies, we examined the thermal and metabolic responses of mice treated with a shock-inducing lethal dose of lipopolysaccharide (LPS).<h4>Key results</h4>We report that LPS-treated mice undergo spontaneous hypothermia, driven by hypometabolism and cold-seeking behaviours, even when animals approach the end of life. Conversely, rewarming LPS-treated mice at 30°C delayed hypothermia but worsened mortality, thus highlighting the adaptive importance of hypothermia. Additionally, we show that LPS-induced hypothermia was partly mediated by peripheral neurotensin expressed in response to vascular toll-like receptor 4 (TLR4) signalling. The administration of a neurotensin analogue (JMV449) induced pharmacological hypothermia and significantly ameliorated the clinical presentation and lethality rates in LPS-treated mice. Moreover, the therapeutic benefits of pharmacological hypothermia were prevented when LPS-treated mice were switched to 30°C. Lastly, these beneficial outcomes were attributed to a reduction in oxygen consumption, metabolic stress and cytopathic hypoxia, rather than the modulation of the cytokine storm.<h4>Conclusion and implications</h4>Collectively, our findings indicate that spontaneous and pharmacologically-induced hypothermia protect against endotoxic shock.2025-01-01T00:00:00Z2025 Jun2026-04-26T03:21:09.392Z2026-04-26T03:09:50.695ZS-EPMC120921993998792510.1111/bph.70000