Archive for June, 2016

7 June 2016

Clara John about her research

Worldwide 1.7 billion people are affected by supernutrition and its repercussion, outpacing the global burden caused by malnutrition (Haslam and James 2005; Rosen and Spiegelman 2014). In many cases obesity (BMI > 30 kg/m2), a consequence of overnutrition, is accompanied by a disturbance of the cellular and systemic cholesterol homeostasis. According to the National Institute of Health, USA this accounts for one of the ten major risk factors for cardiovascular diseases. One of the causes leading to atherosclerosis involves impairments in vascular metabolism of cholesterol rich lipoproteins (Lewington, Whitlock et al. 2007; Ference, Yoo et al. 2012).

Due to the high metabolic activity of brown adipose tissue (BAT) and the possibility to induce the browning of different white adipose tissue-depots, the activation of BAT is considered as a therapeutic target to treat or prevent metabolic diseases. One of the main functions of BAT is the non-shivering thermogenesis (Cannon and Nedergaard 2004) leading to an increase in energy expenditure, which is paralleled by a robust stimulation of appetite and food intake including cholesterol. Whereas glucose and fatty acids serve as fuels for energy production and can be metabolized directly (Cannon and Nedergaard 2004; Bartelt, Bruns et al. 2011, an excess of cholesterol intake needs to be disposed by alternative routes to avoid the systemic accumulation of potentially cytotoxic cholesterol.

The underlying hypothesis of my work is that cold induced BAT-activation results in a dynamic adaption of vascular lipoprotein- as well as cellular sterol metabolism to maintain the general regulation of systemic cholesterol handling.

Our studies showed that the BAT-activation resulted in an increased HDL-turnover as well as reverse cholesterol transport (RCT), the movement of cholesterol from peripheral tissues back to the liver via HDL. Those results support the‘HDL-Flux-Hypothesis’proposed by Rader and Tall (2012). The hypothesis suggests that therapeutic interventions to promote HDL-mediated cholesterol efflux to the liver will reduce cardiovascular risk, regardless of whether it affects plasma cholesterol levels (Khera, Cuchel et al. 2011; Rohatgi, Khera et al. 2014). Additionally, we could observe that activated BAT induces the hepatobiliary disposal of cholesterol in form of bile acids.

These findings lead to the assumption that the activation of BAT contributes to preserve systemic cholesterol homeostasis. Future studies should therefore address the question of whether the activation of brown and beige adipocytes in humans could serve as a therapeutic target to prevent cardiovascular diseases.