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Role of PGC 1ß co-activator in the brain: energy homeostasis, obesity, ageing and neuronal death

Final Activity Report Summary - PGC1? IN BRAIN (Role of PGC 1? coactivator in the brain: energy homeostasis, obesity, ageing and neuronal death)

The development of obesity requires the existence of positive energy balance and is strongly associated with insulin resistance and diabetes. One of the hypotheses to explain the relation between obesity and diabetes is the concept of lipid induced toxicity or lipotoxicity. Of specific relevance for this project is the role of PGC-1 beta in the lipid homeostasis and its relevance in the lipotoxic damage. One of the mechanisms how lipids can be toxic is through the induction of endoplasmic reticulum (ER) stress response. The term 'ER stress' refers to the perturbation of the protein folding functionality of the ER resulting in apoptotic cell death. ER stress has also been observed in the adipose tissue of obese models in rodents and human biopsies. Thus, we extended the concept of PGC1 beta in the energy homeostasis failure induced by lipotoxicity to the hypothalamus, a region of the CNS specialized in the control of energy balance, and investigated whether hypothalamic ER stress may be the cause, consequence or contribute to maintain a vicious cycle promoting energy deregulation and metabolic derangement. Also, we investigated whether the specific nutrient composition may influence the development of ER stress in the hypothalamus of PGC 1 beta KO and its association with and the severity of metabolic disturbance.

Given the fact that PGC-1ß is involved in the lipid handling under positive energy balance in liver, we wondered whether under physiological conditions the absence of this coactivator may be associated with failure in the brain lipid homeostasis. Hypothalamic gene expression of PGC-1ß KO mice showed a decrease in the gene expression related with lipid metabolism like SREBP1c, LXRbeta and RXRbeta. We wondered whether the failure in lipids handling of PGC-1ß mice may result in physiologically ER stress response. We found a significant increase in the basal XBPs and CHOP gene expression, and upregulation in the basal protein content of GRP78 and CHOP, three genes related with ER stress response. We found also that ER stress pathway activation is disturbed in PGC-1ß KO mice exposed to six months high fat diet. As in vivo, neuronal culture from PGC-1ß KO mice are insensitive to respond to pharmacologic ER stress stimulation by tunicamycin or thapsigargin, compared to WT mice. These experiments provided new information about the role of PGC-1ß in the ER stress response associated to lipid homeostasis and its role in the energy homeostasis.