Diet-induced hypothalamic inflammation, cellular stress and the acute phase response

Obesity has evolved into a serious problem for Western societies since it is related to the development of type 2 diabetes and cardiovascular disease. In addition, obese individuals show increased sensitivity to infection compared to lean. High fat diet was previously associated to low-grade inflammation in the hypothalamus in humans and animals with obesity. In this thesis, we investigated the effect of nutrients (fat and/or sugar) on the gene and protein expression of hypothalamic inflammatory and intracellular stress pathways by either providing rats access to a free choice high-fat high-sugar (fcHFHS) diet or intracarotidly infusing fat and/or sugar towards the rat’s brain. In addition, we aimed to define if diet-induced low-grade hypothalamic inflammation contributes to the aggravated acute phase response observed in obese animals. Activation of hypothalamic inflammatory and cellular stress markers depended on fat and sugar consumption in obese rats after one week on fcHFHS diet. Fat specifically activated hypothalamic inflammatory signaling (during fcHFHS diet) and induced gene expression of the cellular stress marker ATF4 (during fcHFHS diet and after intracrotid infusion). Finally, one-week fcHFHS diet-induced hypothalamic low-grade inflammation did not alter the acute phase response in obese rats upon infection with lipopolysaccharide. We concluded that induction of hypothalamic inflammatory and cellular stress markers during fcHFHS diet are sensitive to fat and sugar consumption at early stages of obesity and can be reversed after fat and sugar restriction. More studies are necessary to determine the mechanisms underlying the altered acute phase response upon infection at later stages of obesity.