Lone Møller Pedersen:
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besity is a major health problem affecting millions of people world-wide. Obesity is accompanied by serious threats to health such as type 2 diabetes, hypertension, cardiovascular diseases, sleep apnea and certain types of cancer. A better understanding of the molecular mechanisms of fat cell development, also termed adipocyte differentiation, and the role played by adipocytes in whole-body energy metabolism is therefore of utmost importance. Mammals harbour two general types of adipose tissue, white adipose tissue (WAT) and brown adipose tissue (BAT) that carry out essentially opposite functions. WAT is the primary depository for storing excess energy in the form of triglyceride, whereas BAT is able to burn of energy though adrenergic stimulated adaptive thermogenesis and plays an essential role in the protection against cold in rodents. When activated, BAT has the capacity to dissipate substantial amounts of energy by uncoupling oxidative phosphorylation via the mitochondrial protein uncoupling protein 1 (UCP1). An extensive literature has shown BAT to counteract obesity in rodents. With the recent discovery that also adult humans contain active BAT and the recognition of a negative correlation between the amount of BAT and body mass index (BMI) this may be exploited as a potential target in future anti-obesity therapy.
The present thesis consists of three studies dealing with several aspects of adipocyte biology with a special focus on the role of the prostaglandin synthesising enzymes cyclooxygenases (COXs) in energy homeostasis in obesity, but also in the opposite situation during energy deficiency as seen in cancer cachexia.
The first study investigates the effects of polyunsaturated fatty acids (PUFAs) of the n-6 class in obesity development. Depending on the background diet, being either high in carbohydrate or high in protein, differential obesiogenic outcomes of this class of fatty acids are observed. In the context of a protein-enriched diet, which leads to a low insulin/glucagon ratio, elevated cyclic adenosine monophosphate (cAMP) signalling and induction of COX activity, n-6 PUFAs are inhibitory to adipocyte differentiation. Oppositely, on a high carbohydrate diet background these PUFAs will augment fat cell development. Since n-6 PUFAs are prominent fatty acids in western diets, this study points out the significance of the general nutritional background in development of excess fat stores.
The second study demonstrates the importance of COXs in UCP1 induction in WAT. During cold exposure and on a high fat diet (HFD) a recruitment of energy consuming UCP1 expressing brown-like adipocytes, called brite adipocytes, are observed in WAT in rodents. In this study we find COX activity to be pivotal to the induction of UCP1 in brite adipocytes both during cold exposure and on a HFD. Pharmaceutical as well as genetic ablation of COX activity impairs UCP1 induction in WAT and thereby renders these animals sensitive to cold as well as to diet-induced obesity. This report firmly establishes COXs as key enzymes in energy homeostasis and opens up the possibility for COXs being targets in anti-obesity therapy via increasing energy expenditure.
The last study is a work in progress. It is centered on COXs and especially the downstream PGE2 product as potential links between the hyperinflammatory state and the increased energy expenditure observed in cancer-associated cachexia. Screening a cohort of cancer cell lines we have picked a low and a high PGE2 secreting cell line for subcutaneous implantation into nude mice. Initial analysis has shown animals implanted with the high PGE2 secreting cell line to develop cachexia as assessed by decreased mass of both adipose tissue and skeletal muscle, the hallmarks of the wasting syndrome seen in cachexia. Further analysis is needed to explore the mechanisms involved, but very preliminary data could point to a scenario partly dependent on elevated energy expenditure in WAT due to increased thermogenic gene expression.