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

Abstract

Severe quantitative and qualitative brown adipocyte defects are common in obesity. To investigate whether aberrant expression of tumor necrosis factor ␣ (TNF-␣) in obesity is involved in functional brown fat atrophy, we have studied genetically obese (ob͞ob) 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 ␤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-␣ function. These results indicate that TNF-␣ plays an important role in multiple aspects of brown adipose tissue biology and mediates the abnormalities that occur at this site in obesity. O besity in experimental models is ubiquitously associated with abnormalities in brown adipose tissue (BAT) (1, 2). In adult obese animals, the amount of thermogenically active BAT as well as the expression of ␤ 3 -adrenoceptors in brown adipocytes are substantially reduced, potentially resulting in alterations of metabolic function and thermoregulation (3-5). The molecular basis of these obesity-related changes is poorly understood. It has been demonstrated that expression of tumor necrosis factor ␣ (TNF-␣) in adipose tissue is elevated in a variety of experimental obesity models (6-9) and obese humans (10, 11). Owing to its ability to inhibit insulin receptor signaling (12-14), TNF-␣ represents a component of obesity-related insulin resistance (15). More recently, TNF-␣ has been shown to induce brown and white adipocyte apoptosis in vitro (16)(17)(18). Interestingly, in genetic models of obesity, the number of apoptotic cells in the brown fat is dramatically higher than that in control animals (16). This leads to reduction in the number of multilocular thermogenically active brown fat cells and therefore causes BAT functional atrophy, which is characterized by defective thermoregulation in both genetic and dietary obesity. In addition, because BAT is an important target for insulin action and other aspects of energy metabolism, its atrophy could further contribute to the abnormal metabolic profile in obesity. Here, we have tested whether abnormal TNF-␣ production in obesity contributes to any of these abnormalities in BAT. Materials and MethodsGeneration of ob͞ob Mice Deficient in TNF Receptors (TNFR). Obese (ob͞ob) mice deficient in TNFR were generated as described (19)(20)(21). Mice with targeted null mutations at both TNFR 1 and 2 loci (p55, respectively) were crossed with Ob͞ob mice, to produce animals heterozygous at the TNFR1, TNFR2, and ob loci (p55, and Ob͞ob). The resulting triple heterozygotes were then crossbred with each other to produce OB͞ob mice wild type at TNFR loci or with homozygous null mutations in each or both TNFR. The subsequent intercrossing of these animals produced control OB͞OB and ob͞ob mice and littermates with m...

Apelin Enhances Brown Adipogenesis and Browning of White Adipocytes

“…Studies also suggest that adipose tissue inflammation (as characterized by accumulation of macrophages and inflammatory cytokines, such as TNF␣) found in obesity may be responsible for reduced brown fat by inhibiting differentiation and inducing apoptosis of brown adipocytes (42)(43)(44)(45). To further investigate this, indirect co-culturing of brown preadipocytes and macrophages (primary rat macrophages) was performed ( Fig.…”

Control of body weight: a physiologic and transgenic perspective

“…Thus, TNF-α could play a role in obesity-related insulin resistance though with the participation of other factors in the development of this syndrome. An unexpected role for TNF-α in thermogenesis control in genetic and dietary models of obesity can be inferred from the findings that in obese mice lacking either TNF-α or its receptors an increase in BAT UCP1 and β 3 -AR expression are observed in association to a rise in multilocular functional brown adipocytes [154].…”

Revisiting the adipocyte: a model for integration of cytokine signaling in the regulation of energy metabolism

“…The presence of their ligands, namely TNF␣, Fas ligand (FAS-L or CD95-L), or TNF-related apoptosis-induced ligand (TRAIL), in adipose tissue is due to their synthesis by adipocytes and adipose tissue-embedded macrophages. TNF␣ is overexpressed in adipose tissue of obese individuals and constitutes a well-known regulator of apoptosis in white and brown adipocytes (134,221,223). Upon binding to TNFR1, TNF␣ triggers caspase-8 cleavage and activation, which further activates caspase-3, leading to adipocyte cell death (268).…”

“…The extrinsic pathway of apoptosis is initiated by the stimulation of death receptors of the TNF receptor superfamily, such as TNF receptor 1 (TNFR1), CD95 (APO-1/Fas), or death receptor 3-6 (DR3-6), during the pathological expansion of adipose tissue in obesity (128,156,213,223). The presence of their ligands, namely TNF␣, Fas ligand (FAS-L or CD95-L), or TNF-related apoptosis-induced ligand (TRAIL), in adipose tissue is due to their synthesis by adipocytes and adipose tissue-embedded macrophages.…”