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 obesity. 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 receptors or p55 receptor alone resulted in a significant reduction in brown adipocyte apoptosis and an increase in beta(3)-adrenoreceptor and uncoupling protein-1 expression in obese mice. Increased numbers of multilocular functionally active brown adipocytes, and improved thermoregulation was also observed in obese animals lacking TNF-alpha function. These results indicate that TNF-alpha plays an important role in multiple aspects of brown adipose tissue biology and mediates the abnormalities that occur at this site in obesity.
Nisoli
E
E
Center for Study and Research on Obesity, LITA Vialba, L. Sacco Hospital, University of Milan, Via G.B. Grassi 74, 20157 Milan, Italy.
Briscini
L
L
Giordano
A
A
Tonello
C
C
Wiesbrock
S M
SM
Uysal
K T
KT
Cinti
S
S
Carruba
M O
MO
Hotamisligil
G S
GS
D000222:Adaptation, Physiological; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects*; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000187:drug effects*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D017209:Apoptosis; D001831:Body Temperature; D002352:Carrier Proteins / Q000378:metabolism; D003080:Cold Temperature; D000242:Cyclic AMP / Q000096:biosynthesis; D020287:In Situ Nick-End Labeling; D007473:Ion Channels; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D024101:Mitochondrial Proteins; D009154:Mutation; D009765:Obesity / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D022702:Receptors, Adrenergic, beta-3; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014475:Uncoupling Agents / Q000378:metabolism; D000071256:Uncoupling Protein 1
D015703:Antigens, CD; D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; C000604372:Ucp1 protein, mouse; D014475:Uncoupling Agents; D000071256:Uncoupling Protein 1; D000242:Cyclic AMP