Invited review: Metabolic and immune disturbances in transition cows-Roles of lipid mobilization, inflammation, and milking management.

The transition period is a critical phase of the dairy cow production cycle characterized by profound metabolic, hormonal, and immunological adaptations and an increased incidence of infectious and metabolic disorders. The temporal overlap of negative energy balance, systemic inflammation, and immune disturbances suggests that these processes are mechanistically interconnected. Lipid mobilization and the resulting increase in circulating nonesterified fatty acids (NEFA) have long been considered central to these disturbances. More recently, inflammation-potentially driven by endotoxin translocation-has emerged as an additional explanatory framework. However, the relative contributions and interactions of these processes remain incompletely understood. Emerging evidence indicates that elevated NEFA can directly activate inflammatory pathways, whereas inflammatory responses are often interpreted as evidence of endotoxin exposure in the absence of consistent detection of circulating lipopolysaccharide. These observations suggest that lipid mobilization and inflammation are closely intertwined and may converge on shared signaling pathways rather than represent independent mechanisms. This review critically examines the roles of lipid mobilization and inflammation in the development of metabolic and immune disturbances during the transition period and highlights key limitations in current interpretations. Finally, we discuss how this mechanistic framework informs management strategies, with emphasis on milking practices aimed at limiting excessive lipid mobilization during early lactation. In particular, incomplete milking during the first week of lactation emerges as a promising approach to mitigate metabolic and immune disturbances without compromising subsequent lactational performance. More broadly, findings presented in this review highlight that managing metabolic demand, in addition to nutrient supply, may be a key principle for improving health and robustness in modern high-producing dairy cows.