Inter-organ crosstalk in fructose-induced metabolic dysfunction
Sugar and high fructose consumption have been shown to play a role in the obesity epidemic. As such, fructose specifically is shown to be an underlying factor in 3 key features of metabolic syndrome that often occur in parallel –non-alcoholic fatty liver disease (NAFLD), hypertensive heart disease and neurodegenerative disease. The effects of fructose intake on the organs of the body are not directly due to fructose but the consequence of fructose metabolism and metabolic stress in the liver. Recent studies have demonstrated an association between fatty liver and cardiovascular disease suggesting that metabolic stress in the liver may directly contribute to hypertension and heart failure, as well as cognitive decline, but these mechanisms remain unclear. Moreover, women are at higher risk for the development of NAFLD following menopause, increasing their risk of death from cardiovascular disease. Experimental aims in the present application are to identify inter-organ crosstalk and mechanistic links between metabolically-induced liver stress (by fructose), cognitive decline and cardiac disease and study the differences between males, females and ovariectomized females. Our focus will be on fructose-induced changes in the tissues and to identify potential inter-organ signaling (e.g FGF21).
This rat model will provide new information on the role of fructose in the progression of metabolic and cardiovascular disease and the potential signaling pathways activated by metabolic stress in the liver that are linked to cognitive function and cardiac disease. We will study the effects of the liver hormone FGF21 in the brain and heart, as well as its potential protective role in these organs during metabolic disease.
The 15% fructose solution is shown to be well-tolerated by rats. It may lead to metabolic dysregulation, fatty liver, increased blood pressure, cardiac remodeling, activation of inflammatory pathways and more, however rats will not experience clinical symptoms associated with heart failure within the time frame of the study. All rats will undergo procedures conducted by trained researchers that may cause mild, short-term stress. In-vivo monitoring of blood pressure, echocardiography and memory testing will follow established protocols that ensure animal welfare. One group (n=12) will undergo ovariectomy under surgical anesthesia and appropriate post-surgical analgesia before fructose exposure and one group (n=12) will undergo sham surgery. In these groups, severity is regarded as moderate cf. 2c annex B.
The present application is for 170 rats (male, female and ovariectomized females) so as to ensure an adequate group size for all comparisons.
The intact animal is essential to evaluate the inter-organ interaction following high-fructose feeding and to obtain tissue for molecular analysis. However, use of in-vivo techniques to evaluate cardiac function allows for multiple evaluations in the same animal. Some of these procedures such as blood pressure measurements (tail-cuff) and memory testing require habituation to the test but that help to reduce overall stress for the animal and improved reproducibility of results. The overall severity of procedures included here are considered to be mild with the exception of 2 groups of rats that will undergo surgery and where severity is moderate.
This rat model will provide new information on the role of fructose in the progression of metabolic and cardiovascular disease and the potential signaling pathways activated by metabolic stress in the liver that are linked to cognitive function and cardiac disease. We will study the effects of the liver hormone FGF21 in the brain and heart, as well as its potential protective role in these organs during metabolic disease.
The 15% fructose solution is shown to be well-tolerated by rats. It may lead to metabolic dysregulation, fatty liver, increased blood pressure, cardiac remodeling, activation of inflammatory pathways and more, however rats will not experience clinical symptoms associated with heart failure within the time frame of the study. All rats will undergo procedures conducted by trained researchers that may cause mild, short-term stress. In-vivo monitoring of blood pressure, echocardiography and memory testing will follow established protocols that ensure animal welfare. One group (n=12) will undergo ovariectomy under surgical anesthesia and appropriate post-surgical analgesia before fructose exposure and one group (n=12) will undergo sham surgery. In these groups, severity is regarded as moderate cf. 2c annex B.
The present application is for 170 rats (male, female and ovariectomized females) so as to ensure an adequate group size for all comparisons.
The intact animal is essential to evaluate the inter-organ interaction following high-fructose feeding and to obtain tissue for molecular analysis. However, use of in-vivo techniques to evaluate cardiac function allows for multiple evaluations in the same animal. Some of these procedures such as blood pressure measurements (tail-cuff) and memory testing require habituation to the test but that help to reduce overall stress for the animal and improved reproducibility of results. The overall severity of procedures included here are considered to be mild with the exception of 2 groups of rats that will undergo surgery and where severity is moderate.