Tumor necrosis factor alpha mediates apoptosis of brown adipocytes and defective brown adipocyte function in obesity

Severe quantitative and qualitative brown adipocyte defects are common in o besity, To investigate whether aberrant expression of tumor necrosis factor alpha (TNF-alpha) in obesity is involved in functional brown fat atrophy, we have studied genetically obese (ob/ob) mice with targeted null mutations in the genes encoding the two TNF receptors, The absence of both TNF recep tors or p55 receptor alone resulted in a significant reduction in brown adi pocyte apoptosis and an increase in beta(3)-adrenoreceptor and uncoupling p rotein-1 expression in obese mice. Increased numbers of multilocular functi onally active brown adipocytes, and improved thermoregulation was also obse rved in obese animals lacking TNF-alpha function. These results indicate th at TNF-alpha plays an important role in multiple aspects of brown adipose t issue biology and mediates the abnormalities that occur at this site in obe sity.