The rate of obesity among adults and children is rising, which underlines the need for effective anti-obesity strategies. Multiple promising pharmacotherapies have recently been developed and approved for human use. These focus primarily on reducing energy intake by interfering with satiety and nutrient uptake. Strategies to simultaneously decrease energy intake and increase energy expenditure are an interesting focus for future research. 

Since the (re)discovery of brown adipose tissue (BAT) in adult humans, activation of its unique uncoupling protein 1 (UCP1) has been suggested to enhance energy dissipation to increase energy expenditure. However, the UCP1 knockout (KO) mouse model paradoxically remains lean on a high-fat diet (HFD) in mild cold. This suggests the presence of alternative thermogenic mechanisms, which are of high translational value, as obese individuals typically have little to no BAT and UCP1. It was previously suggested that fibroblast growth factor 21 (FGF21) plays a crucial role in the lean phenotype of UCP1 KO mice by remodeling and transforming the inguinal white adipose tissue (iWAT) towards a more beige phenotype. While BAT is studied intensively, the influence of beige fat on obesity remains unclear, particularly in the context of UCP1. Moreover, the underlying molecular mechanisms by which FGF21 regulates body weight are not yet fully understood.

In Chapter I, we investigate the ability of the over-the-counter drug Ibuprofen to activate UCP1 in UCP1-expressing human embryonic kidney 293 cells and isolated brown fat mitochondria. We show that Ibuprofen is a viable activator, but different variants are needed for improved delivery to activate brown adipocytes in vivo. In Chapter II, we show that overexpression of one key enzyme of the futile lipid cycle, glycerol kinase, did not induce major changes in adipocyte lipid metabolism. However, beta-adrenergic stimulation of these adipocytes may induce increased lipid cycling. Chapter III shows that FGF21 treatment results in immediate weight loss in UCP1 KO mice on HFD, whereas wildtype (WT) mice have a delayed response. We find that the iWAT has increased levels of FGF21-responsive genes only in UCP1 KO mice, which suggests that FGF21 sensitivity in iWAT underlies the body weight loss. In Chapter IV, we show that male UCP1 KO mice are susceptible to diet-induced obesity resistance, whereas female UCP1 KO mice have a similar weight to female WT mice, with a higher food intake. Interestingly, the levels of FGF21 and iWAT browning are similar between sexes. Overall, our results suggest that hyperphagia may counterbalance the beneficial effects of FGF21 on metabolism in female mice. 

Collectively, our results highlight new ways to activate the metabolic capacity of beige adipocytes within iWAT. Furthermore, we demonstrate the importance of iWAT in sustained FGF21 sensitivity and show sex-specific differences in response to high endogenous FGF21 levels.