Brain Uncoupling Protein 2: Uncoupled Neuronal Mitochondria Predict Thermal Synapses in Homeostatic Centers

Abstract

Distinct brain peptidergic circuits govern peripheral energy homeostasis and related behavior. Here we report that mitochondrial uncoupling protein 2 (UCP2) is expressed discretely in neurons involved in homeostatic regulation. UCP2 protein was associated with the mitochondria of neurons, predominantly in axons and axon terminals. UCP2-producing neurons were found to be the targets of peripheral hormones, including leptin and gonadal steroids, and the presence of UCP2 protein in axonal processes predicted increased local brain mitochondrial uncoupling activity and heat production. In the hypothalamus, perikarya producing corticotropin-releasing factor, vasopressin, oxytocin, and neuropeptide Y also expressed UCP2. Furthermore, axon terminals containing UCP2 innervated diverse hypothalamic neuronal populations. These cells included those producing orexin, melanin-concentrating hormone, and luteinizing hormone-releasing hormone. When c-fos-expressing cells were analyzed in the basal brain after either fasting or cold exposure, it was found that all activated neurons received a robust UCP2 input on their perikarya and proximal dendrites. Thus, our data suggest the novel concept that heat produced by axonal UCP2 modulates neurotransmission in homeostatic centers, thereby coordinating the activity of those brain circuits that regulate daily energy balance and related autonomic and endocrine processes.

Uncoupling proteins-2 and 3 influence obesity and inflammation in transgenic mice

“…[9][10][11]30,31 The contradictory results for effects of UCP2 and 3 on ATP levels in pancreas and skeletal muscle present in the current literature suggest that effects of UCP2 and 3 on ATP levels in any one tissue cannot yet be predicted from effects in other tissues.…”

“…10,23 Body composition Body composition (percent of live weight that is fat or lean mass) was determined as previously described. 26 Adiposity index is summed fat pad weights (gonadal, retroperitoneal, femoral and mesenteric) divided by live weight.…”

“…1,2,8 ) UCP2 is potentially the most interesting of these proteins because it is widely but variably expressed in many tissues including adipose, muscle, spleen, brain, and pituitary, 3,[9][10][11] and thus may influence many physiological processes. For example, obesity is increased in humans with UCP2 alleles that decrease UCP2 transcription.…”

Uncoupling protein-2: evidence for its function as a metabolic regulator

“…Specific regions of the brain, particularly the hypothalamus, are associated with the regulation of peripheral metabolism. In rodents, UCP2 mRNA is found in suprachiasmatic, arcuate and paraventricular nuclei of the hypothalamus and in the dorsomotor nucleus of the vagus nerve [18,120]. In non-human primate hypothalamic centres, UCP2 is co-expressed in neurons producing neuropeptide Y (NPY), corticotrophin-releasing hormone (CRH), oxytocin and vasopressin [19].…”

“…In non-human primate hypothalamic centres, UCP2 is co-expressed in neurons producing neuropeptide Y (NPY), corticotrophin-releasing hormone (CRH), oxytocin and vasopressin [19]. The metabolic importance of neuronal pathways involving NPY and CRH is well-known; thus UCP2 could regulate the signalling of efferent pathways to affect peripheral weight regulation [19,120]. In rats, cold exposure increases spinal cord, but not brain, UCP2 mRNA by about 50 % [121].…”