Acute heat stress reprograms the circadian–inflammatory–metabolic axis in Lasiopodomys brandtii

Ongoing climate warming, particularly intensifying heatwaves, imposes substantial physiological stress on small mammals. Although heat-induced responses have been extensively studied in laboratory models, little is known about how wild small mammals respond to acute thermal stress. To address this gap, we investigated the physiological responses of Brandt's voles ( Lasiopodomys brandtii ), a diurnal herbivorous rodent native to typical steppe regions, under acute heat exposure (36 °C). Heat-treated voles showed a 1.4 °C rise in core body temperature and a 37 % reduction in metabolic rate, accompanied by a phase advance in their circadian rhythm and the emergence of an 11.8 h ultradian rhythm. Gene expression profiling revealed upregulation of circadian repressors ( Per2 and Cry1 ) and pro-inflammatory genes ( Nfκb or Il1α ) in the hypothalamus, liver and brown adipose tissue (BAT), and tissue-specific alterations in thermogenic regulators ( Pgc1α ). Concurrent with these changes, serum TNF-α levels elevated, IL-6 reduced, and thyroxine (T4) increased, while serum T3 remained stable. Correlation analyses showed that Per2 and Cry1 expression in the liver, but not in the hypothalamus or BAT, were positively associated with serum TNF-α, whereas in the hypothalamus and BAT, clock genes were primarily linked to local inflammatory markers such as Nfκb and Il1α . Network modeling further identified Per2 and Bmal1 as central hub genes across tissues, orchestrating regulatory interactions with both inflammatory and metabolic genes. These findings suggest that heat-induced circadian disruption involves tissue-specific interactions between clock genes and immune-metabolic signals, underscoring the circadian system's key role in coordinating adaptive responses to acute thermal stress. Proposed mechanism by which acute heat stress reprograms the circadian–inflammatory–metabolic axis in Lasiopodomys brandtii . Acute heat exposure (36 °C for 6 h) induces coordinated transcriptional responses across the hypothalamus, liver, and brown adipose tissue (BAT), including upregulation of circadian repressors ( Per2 , Cry1 ) and pro-inflammatory genes ( Tnfα , Il1α ), along with tissue-specific changes in thermogenic and metabolic regulators such as Ucp1 and Pgc1α . These molecular alterations are accompanied by systemic endocrine and immune changes, including elevated serum TNF-α, reduced IL-6, and increased T4, with stable T3 levels. Core body temperature rhythms remain detectable but display shortened period, phase advance, and increased amplitude, reflecting central clock perturbation. These findings indicate a heat-induced, multi-organ response involving inflammatory, hormonal, and circadian components. Illustration created with BioRender.com . • Brandt's voles exhibited both circadian and ultradian metabolic rhythms. • Acute heat stress led to metabolic suppression and circadian phase reversal of core body temperature. • Acute heat stress induced Per2 and Cry1 upregulation and tissue-specific inflammatory responses. • Per2 and Bmal1 serve as hub genes under thermal stress.