Effect of a high caloric diet in the expression of Hypoxia- inducible factor-1 (HIF1): Role in obesity through deregulation of pomc gene

Abstract

The balance between food intake and energy expenditure are mainly regulated by hypothalamus. In the last decade, several studies demonstrated that the ingestion of high caloric diets, especially rich in saturated fatty acids, leads to the activation of inflammatory processes in the hypothalamus. Hypothalamic neuroinflammation can produce functional alterations in neurons and consequently contribute to the development of obesity. Neuronal cells exposed to pathogenic inflammatory factors can react through the activation of transcriptional mechanisms that will induce the expression of several proteins involved in the protection of cellular integrity.Hypoxia- inducible factor-1 (HIF1) is a key transcription factor to adapt to hypoxic conditions, and activates many genes involved in angiogenesis, glucose metabolism, cellular growth, and apoptosis in response to hypoxia or other harmful conditions. Recent studies demonstrated thatHIF1 can also be induced by inflammatory stimulus.Our main hypothesis is that the expression of HIF1 in the hypothalamus is modulated by high fat diet leading to changes in the expression of neuronal pomc and consequently to alterations in neuronal pathways that control food intake. To test our hypothesis, we will use Swiss and C57/BL mice fed with high fat diet for different time points as a model of obesity. The effect of high fat diet in the expression and distribution of HIF1 will be measured. Also, we will evaluate how the inhibition of mTOR and ubiquitin-proteasome pathways modulates the expression of HIF1, as well as the role of HIF1 in pomc expression.This study will give important knowledge to understand the pathological mechanisms by which high fat diet induces changes hypothalamic activity leading to dysfunction in energy homeostasis that induce obesity.