gms | German Medical Science

Objectives: Recently, our group established a murine model combining traumatic brain injury (TBI) and a femoral fracture (Fx).

Similar to humans, TBI resulted in accelerated fracture healing in this model. Alterations in energy utilization may provide an explanation for this phenomenon, as metabolic changes after TBI are potentially explained by the selfish brain hypothesis: During times of increased stress, the brain increases energy demands and alters metabolic processes and energy flow in the whole organism including bone tissue. Thus, our current study aimed to characterize alterations in metabolic processes during isolated or combined injury.

Methods: Our previously reported trauma model combining TBI and Fx was applied. A total of 72 female C57BL/6J mice were randomly assigned to four groups (control, Fx, TBI, and combined trauma (TBI+Fx)). TBI (controlled impact injury to the parietal cortex) and Fx (femoral osteotomy) stabilized with an external fixator was induced surgically. Tissue sampling was performed during the acute inflammation (day 3 post-injury), the soft callus (d7), and the remodelling stage (d14) of fracture healing. RNA of homogenized tissues was reverse transcribed to cDNA, followed by qPCR analyses using the Δ Δ-CT-method.

Results and conclusion: No major alterations in metabolic markers were observed in bone tissue, with the exception of osteocalcin and the glucose transporter Glut1. These ones were differentially regulated by concomitant TBI in intact bone, but not in fracture callus. In the hypothalamus, expression profiling revealed a specific central regulation of energy homeostasis during combined injury, characterized by alterations of fatty acid (FA) translocase CD36 during acute inflammation and soft callus stage, and decreased expression of glucose transporter Glut3 and leptin receptor at d7 post trauma. In the liver, isolated or combined injury resulted in an increased expression of genes associated with glucose metabolism, leptin receptor, and cAMP downstream effectors. While TBI was associated with an induction of genes involved in FA turnover and glucagon receptor, isolated Fx induced the expression of insulin receptor, Igf1, and lipoprotein receptors. In white adipose tissue (WAT), injury led to nonspecific reduction in leptin expression, while a significantly enhanced expression of UCP1 was detected, indicating browning of WAT especially following combined injury. In turn, combined injury resulted in an activation of brown adipose tissue, evidenced by elevated UCP1 expression and genes associated with fatty acid turnover.

Isolated and combined injuries exert distinct changes in metabolic marker expression in white and brown adipose tissue, indicating the activation of specific metabolic pathways depending on the type of trauma. Specific changes in gene expression suggest the interference of such processes in the hypothalamus, and may provide a mechanistic link between TBI and accelerated bone regeneration in affected patients.