Endocrine Abstracts

Disruption of the balance in energy homeostasis and substrate metabolism can lead to obesity and the metabolic syndrome on one hand and body wasting in cachexia associated with cancer and other chronic diseases on the other hand. Indirect evidence suggests that prostaglandins (PGs), products of the cyclooxygenase (COX) pathway, are involved in the regulation of metabolic processes under physiological conditions or during disease, in particular cancer cachexia. However, the direct in vivo effects of PG action on peripheral tissues and the consequences for energy homeostasis have not been elucidated. To examine the effect of PG excess as a single factor on metabolism we analyzed the phenotype of transgenic mice over-expressing COX-2 locally in defined epithelia. These mice displayed increased PG E2 and F2alpha plasma levels, whereas no systemic inflammation could be detected. This was associated with severe wasting of abdominal adipose tissue, a process which developed with age and could be reversed by treatment with a selective COX-2 inhibitor. Interestingly, K5COX2 mice showed improved glucose tolerance and normal insulin sensitivity. Furthermore, the findings that K5COX2 mice were hyperphagic with elevated body temperature and reduced circulating free fatty acid levels suggest that PG-mediated adipose tissue wasting is a consequence of increased substrate utilization coupled to energy dissipation. Phenotypic analysis of adipose tissue in K5COX2 mice for the dissection of the underlying molecular mechanisms is currently underway. Taken together, our results highlight a previously unrecognized ability of PGs to modulate adipose tissue maintenance and energy expenditure in vivo. Modulation of PG-controlled pathways of metabolic regulation could represent an attractive approach applicable not only to the treatment of cachexia symptoms but also to the control of obesity.