Traumatic brain injury induces adipokine gene expression in rat brain

Abstract

Traumatic brain injury (TBI) induces cachexia and neuroinflammation which profoundly impact patient recovery. Adipokine genes such as leptin (ob), resistin (rstn) and fasting-induced adipose factor (fiaf) are implicated in energy metabolism and body weight control and are also associated with chronic low grade inflammation. Since central rstn and fiaf expression was increased following hypoxic/ischemic brain injury, we hypothesized that these genes would also be induced in the rat brain following TBI. Realtime RT-PCR detected a 2-2.5-fold increase in ob mRNA in the ipsilateral cortex and thalamus 12h following lateral fluid percussion (FP)-induced brain injury. Fiaf mRNA was elevated 5-7.5-fold in cortex, hippocampus and thalamus, and modest increases were also detectable in the contralateral brain. Remarkably, rstn mRNA was elevated in ipsilateral (150-fold) and in contralateral (50-fold) hippocampus. To test whether these changes were part of an inflammatory response to TBI we also examined the effects of an intracerebral injection of lipopolysaccharide (LPS). We determined that central injection of LPS produced some, but not all, of the changes seen after TBI. For example, in contrast to the stimulatory influence of TBI, LPS had no effect on ob expression in any brain region, though fiaf and rstn mRNA levels were significantly elevated in both ipsi- and contralateral cortex.

In conclusion: (a) brain-derived adipokines could be involved in the acute pathology of traumatic brain injury partly through modulation of central inflammatory responses, but also via leptin-mediated neuroprotective effects and (b) TBI-induced brain adipokines may induce the metabolic changes observed following neurotrauma.

Fig. 1

The effects of TBI (12 h) on ob, rstn and fiaf mRNA in various rat brain regions. (A–C) Leptin (ob) gene expression was significantly upregulated in the ipsilateral cortex (A, 2.5-fold) and thalamus (C, 2-fold) 12 h following lateral FP-induced brain injury. In contrast ob gene expression was unaffected in the hippocampus (B), or in the contralateral brain tissues. (D–F) Following TBI fiaf was significantly upregulated 6-fold, 7.5-fold and 5-fold in the ipsilateral cortex, hippocampus and thalamus respectively. Fiaf expression was also significantly upregulated in the contralateral tissues, but the increases were smaller (cortex 89%; thalamus 103%; hippocampus 150%). (G and H) TBI increased rstn mRNA in the ipsilateral cortex (G, 128%), but had no effects on the contralateral tissue. In contrast, rstn was detectable at low levels in the hippocampus of sham controls, but was strikingly induced following TBI in the ipsi- and contralateral hippocampus (H, 150-fold and 50-fold, respectively). Fiaf expression was undetectable in thalamic samples. Values are expressed as a percentage of the control ± S.E.M. obtained from duplicate experiments (N = 6−8; *p < 0.05, **p < 0.01 and ***p < 0.001, ****p < 0.0005). White bars represent sham, control rats; shaded bars indicate data from TBI rats.

Fig. 2

The effects of intracerebral injection of LPS on ob, rstn and fiaf mRNA in various rat brain regions, measured 12 h post-injection. (A–C) The intracerebral injection of LPS had no effect on leptin (ob) gene expression in cortex, hippocampus or thalamus. (D–F) Following the central injection of LPS fiaf was upregulated in both the ipsilateral and contralateral cortex, but there was no effect in the thalamus or hippocampus. (G and H) LPS increased rstn mRNA in both the ipsilateral and contralateral cortex and hippocampus. Values are expressed as a percentage of the control ± S.E.M. obtained from duplicate experiments (N = 5−10; *p < 0.05, **p < 0.01 and ***p < 0.001). White bars represent sham, control rats; shaded bars indicate LPS-treated rats.