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The Obesity Problem |
Our Research on Fat Cell Metabolism |
'NOVEL UNCOUPLING PROTEINS' | Publications |
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Obesity in the United States and other industrialized societies is now at epidemic proportions (WHO Report 1997). This is a very serious medical and social issue because being significantly overweight or obese is a risk factor for a number of chronic, debilitating diseases including Type II diabetes, hypertension, atherosclerosis, and certain cancers. Although this syndrome has a complex etiology, efforts to understand fat cell metabolism at the molecular level are one avenue through which we may identify potential points of therapeutic intervention (for related discussion see (1). For many years fat cells were considered to be simply an inert storage depot for excess metabolic fuel. However, with the discovery of leptin (2), a hormone secreted from fat cells that "reports" to the rest of the body on the status of energy reserves, fat tissue is now appreciated as an important "endocrine" organ. In addition to leptin, adipocytes have been known to secrete a number of other small peptide hormones, implicating them as signaling agents for adipocytes. The pace of these discoveries still leaves us with much to be learned concerning the function and regulation of these fat-derived hormones.
Our laboratory is interested in the adrenaline receptors in adipocytes: how they are regulated and how their structural features dictate their signal transduction properties. Activation of the adrenaline receptors, specifically the members of the beta-adrenergic receptor (beta-AR) family, provide the major stimulus for the hydrolysis and release of stored lipids. There are three known beta-AR subtypes, one of which is expressed exclusively in the adipocyte: the beta3-AR (3). A curious phenomenon that we are trying to dissect is the fact that although expression of beta1-AR and beta3-AR in adipocytes is decreased in obesity (4-6), selective beta3-AR agonists can nevertheless prevent or reverse this obesity (5,7-9). This curious effect of beta3-AR agonists may be related to their ability to stimulate a process called "non-shivering thermogenesis" in brown fat, in addition to the lipolytic response they can elicit. Brown adipocytes are specialized cells rich in mitochondria and defined by their ability to express the mitochondrial uncoupling protein, UCP1, which allows the dissipation of the proton gradient in the inner mitochondrial membrane to yield heat at the expense of ATP production (see Figure 1). The expression and activity of UCP1 are under the control of the beta-ARs, which are in turn responsive to the sympathetic nervous system drive to brown fat (it is well innervated). For a more detailed discussion of the structure, function and regulation of UCP1 and the fascinating biology of brown adipose tissue please see "Brown Adipose Tissue" by Trayhurn and Nicholls, 1986, and (10). One of our research projects is directed toward understanding the molecular signals that turn on the beta3-AR selectively in adipocytes. This question is important for several reasons. If we can understand how this gene is activated, we may be able to find ways to increase its expression, in order for drugs that can selectively activate it to be more potent. Moreover, since we have already shown (see Figure 2) that in essentially all laboratory animal models of obesity there is a dramatic loss in expression of the beta3-AR, as well as the beta1-AR in fat cells (4,6), we might be able to reverse this process. A fundamental problem in the field of signal transduction is the molecular mechanisms whereby cell surface receptors that couple to the same signal transduction pathway are able to activate specific responses unique to that receptor subtype. In this way the adipocyte is again an interesting model; not only for the study of obesity and fat cell metabolism, but also for understanding basic mechanisms of transmembrane signaling (see Figure 3). We reported recently that the beta3-AR in fat cells is dually coupled to Gas and Gai, leading to the simultaneous activation of the PKA pathway and the ERK arm of the MAP kinase pathway, respectively (11,12) (Cao et al submitted). We postulate that the unique physiologic effects of beta3-AR-selective drugs to elicit anti-obesity and anti-diabetic effects may result from the ability to simultaneously initiate these two signaling cascades. (This dual signaling concept is akin to the manner in which two keys are required to open a safe deposit box.) Our current efforts are focused upon two fronts: first, unraveling the importance of certain interesting structural and regulatory features of the beta3-AR to couple to these two pathways, and second, what are the intracellular targets of these two kinase cascades (see Figure 4). Sporadic observations that the brown fat UCP could be detected (primarily when using antisera to measure protein levels) in other tissues such as muscle (13), led Ricquier and colleagues to search for homologues of the UCP. In 1997, Fleury et al (14) reported the cloning of UCP2. In addition to significant homology (59%) with the brown fat UCP (now named "UCP1") and the ability to uncouple respiration as efficiently as UCP1 in model systems, we found that UCP2 was broadly expressed in many tissues. This led to the hypothesis that UCP2 was the long-sought explanation for the relative inefficiency of oxidative respiration seen in most cell types. We also noted that the UCP2 gene resides in a chromosomal location on distal mouse chromosome 7 that is coincident with a quantitative trait locus (QTL) linkage to hyperinsulinemia and high plasma leptin levels (reflective of body fat stores). In addition, we showed that the expression of UCP2 was specifically elevated in white adipose tissue in strains of mice that are relatively resistant to the development of diet-induced obesity and diabetes, but not in obesity-prone mice (14,15). Other groups subsequently reported the discovery of UCP3, expressed predominantly in skeletal muscle and brown fat, and to a lesser extent in heart (16,17). The structural homology between these UCPs and basic features about their regulation and expression in various rodent models and human populations have been recently reviewed (18-20). The UCP3 gene is also located 8-10 kb 5' to the UCP2 gene in both the mouse and human genomes (15,21). While this close linkage relationship means that either or both of these UCPs could be related to this QTL, we could not find evidence for changes in expression of UCP3 in the mouse models that originally defined this QTL (15). It should be noted that increased expression of UCP2 in brown fat of UCP1 -/- animals was observed (22), but it is not yet clear whether this increase is related to the maintenance of normal body weight in these animals. Although it has been shown in various model systems that upregulation of UCP2 may have some uncoupling effects and can alter ATP/ADP ratio (23,24), newly emerging data suggest that we may not really know what the role and mechanism of these novel UCPs are. The studies of Dulloo and colleagues were pivotal in ultimately persuading the majority of investigators to conclude that, at least in peripheral tissues, these novel UCPs must be participating in the metabolic adaptations required during the fasted stated, which requires a switch from predominantly glucose to predominantly fatty acids as a fuel source. They showed that blockade of the fasting-induced rise in free fatty acids completely prevented the increase in UCP2 and UCP3 mRNA (25-27). Recently, targeted disruption of the UCP3 gene was reported (28,29) and these animals display no signs of significantly disturbed fuel metabolism, obesity or sensitivity to cold temperature exposure. We should soon learn about the consequences of similar targeted disruption of the UCP2 gene.
1. Wu, Z., Puigserver, P., and Spiegelman, B. M. (1999) Curr Opin Cell Biol 11(6), 689-94 2. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., and Friedman, J. M. (1994) Nature 372(6505), 425-432 3. Strosberg, A. (1997) Ann. Rev. Pharmacol. Toxicol. 37, 421-450 4. Collins, S., Daniel, K. W., Rohlfs, E. M., Ramkumar, V., Taylor, I. L., and Gettys, T. W. (1994) Molecular Endocrinology 8(4), 518-527 5. Collins, S., Daniel, K. W., Petro, A. E., and Surwit, R. S. (1997) Endocrinology 138, 405-413 6. Collins, S., Daniel, K. W., and Rohlfs, E. M. (1999) International Journal of Obesity 23, 669-677 7. Arch, J. R. S., Ainsworth, A. T., Cawthorne, M. A., Piercy, V., Sennitt, M. V., Thody, V. E., Wilson, C., and Wilson, S. (1984) Nature 309, 163-165 8. Himms-Hagen, J., Cui, J., Danforth, E., Jr., Taatjes, D. J., Lang, S. S., Waters, B. L., and Claus, T. H. (1994) Am. J. Physiol. 266, R1371-R1382 9. Sasaki, N., Uchida, E., Niiyama, M., Yoshida, T., and Saito, M. (1998) Journal of Veterinary Medical Science 60(4), 465-469 10. Ricquier, D., and Bouillaud, F. (2000) Biochem J 345 Pt 2, 161-79 11. Soeder, K. S., Snedden, S. K., Cao, W., Della Rocca, G. J., Daniel, K. W., Luttrell, L. M., and Collins, S. (1999) J. Biol. Chem. 274(no.17), 12017-12022 12. Collins, S., Cao, W., Soeder, K. J., and Snedden, S. K. (2000) in Adipocyte Biology and Hormone Signaling (Ntambi, J. M., ed) Vol. 37, pp. 51-62, IOS Press, Washington, D.C. 13. Yoshida, T., Sakane, N., Wakabayashi, Y., Umekawa, T., and Kondo, M. (1994) Life Sciences 54, 491-498 14. Fleury, C., Neverova, M., Collins, S., Raimbault, S., Champigny, O., Levi-Meyrueis, C., Bouillaud, F., Seldin, M. F., Surwit, R. S., Ricquier, D., and Warden, C. H. (1997) Nature Genetics 15(March), 269-272 15. Surwit, R. S., Wang, S., Petro, A. E., Sanchis, D., Raimbault, S., Ricquier, D., and Collins, S. (1998) Proceedings of the National Academy of Sciences, U.S.A. 95, 4061-4065 16. Boss, O., Samec, S., Paoloni-Giacobino, A., Rossier, C., Dulloo, A., Seydoux, J., Muzzin, P., and Giacobino, J.-P. (1997) FEBS Letters 408, 39-42 17. Vidal-Puig, A., Solanes, G., Grujic, D., Flier, J. S., and Lowell, B. B. (1997) Biochemical and Biophysical Research Comm 235, no. 1(June), 79-82 18. Fleury, C., and Sanchis, D. (1999) Int J Biochem Cell Biol 31(11), 1261-78 19. Boss, O., Muzzin, P., and Giacobino, J. P. (1998) Eur J Endocrinol 139(1), 1-9 20. Ricquier, D., Fleury, C., Larose, M., Sanchis, D., Pecqueur, C., Raimbault, S., Gelly, C., Vacher, D., Cassard-Doulcier, A. M., Levi-Meyrueis, C., Champigny, O., Miroux, B., and Bouillaud, F. (1999) J Intern Med 245(6), 637-42 21. Solanes, G., Vidal-Puig, A., Grujic, D., Flier, J. S., and Lowell, B. B. (1997) J. Biol. Chem. 272(41), 25433-25436 22. Enerback, S., Jacobsson, A., Simpson, E. M., Guerra, C., Yamashita, H., Harper, M., and Kozak, L. P. (1997) Nature 387, 90-94 23. Wang, M. Y., Shimabukuro, M., Lee, Y., Trinh, K. Y., Chen, J. L., Newgard, C. B., and Unger, R. H. (1999) Diabetes 48(5), 1020-5 24. Wu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., Troy, A., Cinti, S., Lowell, B., Scarpulla, R. C., and Spiegelman, B. M. (1999) Cell 98(1), 115-24 25. Samec, S., Seydoux, J., and Dulloo, A. G. (1998) Faseb J 12(9), 715-24 26. Samec, S., Seydoux, J., and Dulloo, A. G. (1999) Pflugers Arch 438(4), 452-7 27. Cadenas, S., Buckingham, J. A., Samec, S., Seydoux, J., Din, N., Dulloo, A. G., and Brand, M. D. (1999) FEBS Lett 462(3), 257-60 28. Vidal-Puig, A. J., Grujic, D., Zhang, C. Y., Hagen, T., Boss, O., Ido, Y., Szczepanik, A., Wade, J., Mootha, V., Cortright, R., Muoio, D. M., and Lowell, B. B. (2000) J Biol Chem 275(21), 16258-16266 29. Gong, D. W., Monemdjou, S., Gavrilova, O., Leon, L. R., Marcus-Samuels, B., Chou, C. J., Everett, C., Kozak, L. P., Li, C., Deng, C., Harper, M. E., and Reitman, M. L. (2000) J Biol Chem 275(21), 16251-16257 |
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THE OBESITY PROBLEM.