In their Research Article "TRB3 Links the E3 Ubiquitin Ligase COP1 to Lipid Metabolism " (23 June, p. 1763), Ling Qi et al. suggest that the beneficial effects of disrupting insulin signaling in adipose tissue may be linked to the activity of pseudokinase Tribbles 3 (TRB3), a key regulator of lipid metabolism in maintaining energy homeostasis (1). They show evidence that (i) transgenic mice expressing TRB3 in adipose tissue are protected from diet-induced obesity due to enhanced fatty acid oxidation, and (ii) that the phosphorylation and ubiquitination pathways of acetyl–coenzyme A carboxylase (ACC) is the mechanism for the TRB3-dependent insulin resistance in adipose tissue, which may reduce hepatic steatosis as well as systemic insulin resistance.
This paper and studies in lower organisms have pointed to a potential link between TRB3 and the ubiquitin-proteasome machinery (2, 3). The ubiquitin-proteasome pathway is required for activation of nuclear factor kappa B (NFkB), a central transcription factor that regulates inflammatory genes, which occurs through degradation of the inhibitory IkB proteins (4). Thus, despite the beneficial role of TRB3 in promoting lipid metabolism by stimulating the ubiquitin-proteasome system (1), the same machinery may promote inflammation in adipose tissue as well as in systemic insulin resistance and diabetes. In fact, it the ubiquitin-proteasome pathway is up-regulated in diabetic rat muscle (5) and in human diabetic atherosclerotic plaques (6).
Mounting evidence highlights the role of adipose tissue in the development of a systemic inflammatory state that contributes to diabetes-associated vasculopathy and cardiovascular risk (7). In recent years, the concept that activation of the proinflammatory pathway can be a mechanism for obesity-associated insulin resistance and diabetes has emerged. For example, the cytokine tumor necrosis factor (TNF-alpha) is elevated in adipose tissue and blood from obese rodents, and neutralization of TNF-alpha improves insulin sensitivity in these animals (8). It is evident that both TRB3 and inflammation contribute to cell-autonomous insulin resistance. A more 'adipocentric' view holds that inflammation arises initially in adipose tissue, resulting in modulated secretion of free fatty acids and adipokines, which then exert endocrine effects to decrease insulin sensitivity in liver and muscle (9). It is likely that systemic insulin resistance is the result of a combination of the autocrine and paracrine effects of cytokines, adipokines and free fatty acids released from obese adipose tissue. These findings raise interesting questions about the pathogenesis of insulin resistance, diabetes and its complications.
References
1. L. Qi et al., Science 312, 1763 (2006).
2. J. Grosshans, E. Wieschaus, Cell 101, 523 (2000).
3. P. Rorth, K. Szabo, G. Texido, Mol. Cell 6, 23 (2000).
4. V. J. Palombella, O. J. Rando, A. L. Goldberg, T. Maniatis, Cell 78, 773 (1994).
5. S. H. Lecker et al., J. Clin. Invest. 104, 1411 (1999).
6. R. Marfella et al., Diabetes 55, 622 (2006).
7. A. H. Berg, P. E. Scherer, Circulation Research 96, 939 (2005).
8. G. S. Hotamisligil, N. S. Shargill, B. M. Spiegelman, Science 259, 87 (1993).
9. C. de Luca, J. M. Olefsky, Nature Medicine 12, 41 (2006).
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