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Adipose tissue: Target and toolbox for the treatment of metabolic disease

PhD ceremony:Ms V.J.M. (Vera) Nies
When:May 24, 2017
Start:12:45
Supervisors:prof. dr. J.W. (Hans) Jonker, prof. dr. H.J. (Henkjan) Verkade
Where:Academy building RUG
Faculty:Medical Sciences / UMCG
Adipose tissue: Target and toolbox for the treatment of metabolic
disease

Due to recent societal changes the prevalence of obesity and obesity-associated chronic metabolic diseases such as type 2 diabetes has increased tremendously. Although several treatment options are available to combat the hyperglycemia that is typical for type 2 diabetes, none of the currently available drugs is ideal, and there is still room for improvement. In this thesis we investigated the mechanisms by which FGF1 controls glucose homeostasis. FGF1 is a paracrine hormone under transcriptional control of PPARĪ³, the master regulator of fat metabolism and the target of the TZD class of anti-diabetic drugs. While TZDs are very effective in improving blood glucose levels, they also induce various adverse effects. Previously, our group found that endogenous FGF1 plays a role in the maintenance of glycemic control during cycles of feeding and fasting, and that pharmacologically administered FGF1 improves blood glucose levels of obese mice. The mechanisms, however, by which (both endogenous and pharmacologically administered) FGF1 regulates glucose homeostasis are largely elusive. In this thesis we investigated how FGF1 affects glucose balance in vitro and in vivo. We found that FGF1 stimulates glucose uptake into adipocytes in vitro. When FGF1 is administered to obese, hyperglycemic mice, FGF1 improves glucose uptake into the muscle and stimulates the secretion of lipids from the liver. These two effects are mediated via different intracellular signaling pathways. Despite its spectacular effects in insulin-resistant mice, FGF1 did not improve glycemic control in insulin-sensitive mice. This indicates that FGF1 alleviates insulin resistance. FGF1 effectively lowers blood glucose levels similar to TZDs, but does not elicit the adverse effects that are associated with TZD treatment. Therefore, FGF1 is an interesting drug with the potential to improve glycemic control in type 2 diabetes patients.