Cold exposure stress causes hypothermia, cognitive impairment, liver injury, and cardiovascular diseases, thereby increasing morbidity and mortality. Paradoxically, cold acclimation is believed to confer metabolic improvement to allow individuals to adapt to cold, harsh conditions and to protect them from cold stress-induced diseases. However, the therapeutic strategy to enhance cold acclimation remains less studied. Here, we demonstrate that the mitochondrial-derived peptide MOTS-c efficiently promotes cold adaptation. Following cold exposure, the improvement of adipose non-shivering thermogenesis facilitated cold adaptation. MOTS-c, a newly identified peptide, is secreted by mitochondria. In this study, we observed that the level of MOTS-c in serum decreased after cold stress. MOTS-c treatment enhanced cold tolerance and reduced lipid trafficking to the liver. In addition, MOTS-c dramatically upregulated brown adipose tissue (BAT) thermogenic gene expression and increased white fat “browning”. This effect might have been mediated by MOTS-c-activated phosphorylation of the ERK signaling pathway. The inhibition of ERK signaling disturbed the up-regulatory effect of MOTS-c on thermogenesis. In summary, our results indicate that MOTS-c treatment is a potential therapeutic strategy for defending against cold stress by increasing the adipose thermogenesis via the ERK pathway.

Macrophages dynamically reprogram their metabolic states in response to environmental stimuli, thereby exerting distinct immune functions. In our preliminary study, a gut microbiota-derived metabolite, 3-hydroxypropionic acid (3-HPA), is increased in chronic inflammation and generates cysteine carboxyethylated neoantigens. However, the role of such metabolite-induced modification in regulating the function of macrophages remains obscure. Here, we show that 3-HPA alleviates inflammation in a mouse model of sepsis and inhibits the macrophage inflammatory response. Mechanistically, 3-HPA induces glyceraldehyde-3-phosphate dehydrogenase (GAPDH) carboxyethylation, which promotes GAPDH degradation via the ubiquitin-proteasome pathway, thereby suppressing its enzymatic activity and expression to inhibit glycolysis. Concomitantly, reduced GAPDH activity elevates the NAD⁺/NADH ratio, which enhances mitochondrial oxidation by upregulating arginine biosynthesis and the TCA cycle pathway. Overall, our research reveals the mechanism by which GAPDH carboxyethylation mediates metabolic reprogramming and regulates inflammation during inflammatory macrophage activation.

Environmental factors play a crucial role in the onset and progression of negative mood. Low temperature, an important environmental factor, acutely induces negative mood and increases depression risk. However, mechanisms underlying low temperature-induced negative mood and its prevention remain unclear. Here, we report acute cold exposure-induced depression-like behaviors in a mouse model; these behaviors were alleviated under prolonged cold exposure. Plasma-targeted fatty acid analysis revealed a significant correlation between changes in depression-like behaviors and plasma octanoic acid (OA) levels, indicating a potential role for OA in cold-induced depression-like behaviors. OA supplementation effectively alleviated depression-like behaviors and acute cold-induced neuroinflammation. Additionally, OA significantly attenuated lipopolysaccharide-induced depression-like behaviors and neuroinflammation. Mechanistically, OA inhibited microglial activation by targeting the aldo-keto reductase family 1 member B1-prostaglandin F2α pathway, thereby suppressing p65 nuclear translocation and reducing neuroinflammation. This study elucidated a potential OA target in neuroinflammatory response modulation, providing an effective strategy for preventing negative mood and maintaining emotional homeostasis.