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Department of Nutrition Sciences University of Alabama at Birmingham Birmingham, Alabama 35294-3360
Address all correspondence and requests for reprints to: W. Timothy Garvey, M.D., Department of Nutrition Sciences, University of Alabama at Birmingham, 1675 University Boulevard, Birmingham, Alabama 35294-3360. E-mail: garveyt{at}uab.edu.
The discovery of uncoupling protein (UCP)2 and UCP3 in 1997 created a great deal of excitement. These proteins were localized to mitochondria and were homologous to UCP1 expressed in rodent brown fat (1). UCP1 localizes to the mitochondrial inner membrane and dissipates the transmembrane potential by transporting protons from the intermembrane space back into the matrix. This reduces the proton motive force that drives ATP formation, and respiration proceeds in the uncoupled mitochondrion, releasing fuel energy only as heat. However, brown fat disappears after infancy in humans, and there is minimal or no detectable UCP1 expression in adults. Thus, there was no identified counterpart that could mediate nonshivering thermogenesis in humans. Notably, the new UCPs were expressed in adult tissues—UCP3 in skeletal muscle and UCP2 widely expressed in multiple tissues. UCP2 and UCP3 were obvious candidate proteins for regulation of energy expenditure in humans with potential roles in the pathogenesis of obesity. However, intensive research over the subsequent 8 yr since the discovery of UCP2 and UCP3 has failed to definitively elucidate their role in metabolism. One thing is clear; these proteins do not function as robust uncouplers of oxidative phosphorylation analogous to UCP1 (2, 3).
Schrauwen et al. (4), in this issue, have reported that UCP3 protein levels in skeletal muscle are diminished in patients with impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) compared with normoglycemic controls, and are increased in T2DM after treatment with the insulin-sensitizing thiazolidinedione rosiglitazone. The authors have correlated muscle content of UCP3 protein with measures of whole-body physiology to gain insight into the functional role of UCP3. Lower levels in IGT and T2DM implicate a role for UCP3 suppression in insulin resistance and defects in carbohydrate and lipid oxidation. The 8-wk course of rosiglitazone increased insulin sensitivity measured as insulin-stimulated glucose uptake during hyperinsulinemic clamps, but this increase did not quite achieve statistical significance. It is possible that this effect would have reached statistical significance with prolongation of rosiglitazone treatment, as it can take up to 3 months to achieve full pharmacological effectiveness. Rosiglitazone therapy did reduce plasma free fatty acids (FFAs) under basal conditions and enhanced insulin’s ability to stimulate glucose oxidation and suppress lipid oxidation. The authors refer to insulin-mediated stimulation of glucose oxidation and concomitant inhibition of lipid oxidation as "metabolic flexibility." This term is probably unnecessary because it reflects a complexity of biochemical events involving multiple organs and cannot be measured in a precise or standardized manner. The stimulation of glucose oxidation together with inhibition of lipid oxidation are well-known actions of insulin, and it will suffice to say that rosiglitazone did enhance the insulin sensitivity of these metabolic pathways. These data implicate a role for muscle UCP3 in insulin sensitivity with respect to stimulation of glucose uptake and regulation of substrate metabolism. The questions remain: 1) whether the down-regulation of muscle UCP3 expression was mechanistically linked with the development of insulin resistance; and 2) what does this tell us about the biochemical action of UCP3 in mitochondria?
Regarding biochemical mechanisms, accumulating data have supported three leading hypotheses for UCP3 action. The first proposal is that UCP3 acts to reduce reactive oxygen species (ROS) formation by mitochondria and so protects cells from their damaging effects (5). ROS are produced in the course of mitochondrial respiration in a manner that is proportional to the transmembrane potential; therefore, this role would require that UCP3 function as a low-grade uncoupler. A second hypothesis is that UCP3 could facilitate lipid oxidation by acting as a FFA anion transporter (6). Entry of long-chain FFA into mitochondria and subsequent oxidation requires carnitine palmitoyltransferase I and esterification to coenzyme A (CoA). However, under conditions of high acyl-CoA flux, accumulation of acyl-CoA would be detrimental to mitochondrial function because these molecules are strong surfactants that could damage membranes. Also, excessive sequestration of CoA in the form of long-chain FFA esters could inhibit ß-oxidation and tricarboxylic acid cycle activity. UCPs are known to be able to export FFA– from the mitochondrial matrix, but this could only help alleviate the accumulation of acyl-CoA if a thioesterase was available to remove CoA from the FFA. In fact, a mitochondrial thioesterase-1 has been identified and was found to be up-regulated in UCP3-hyperexpressing mice (7). Thus, it is feasible to suggest that UCP3 could help sustain increased rates of lipid oxidation via export of FFA–.
The third possible role for UCP3 is favored by Schrauwen et al. (8, 9). This hypothesis states that UCP3 protects mitochondria against lipid-induced damage under conditions where availability of FFA exceeds the capacity for their oxidation resulting in the accumulation of FFA in the sarcoplasm. These FFA enter the mitochondrial matrix via a flip-flop mechanism across the mitochondrial membrane phospholipid bilayer and are susceptible to peroxidation. To prevent formation of damaging lipid peroxides, UCP3 acts as a FFA carrier to extrude FFA out of the matrix. The authors posit that, in untreated T2DM, one would expect to see an increase in UCP3 expression because FFA availability is increased and FFA metabolism is impaired. The authors, however, observed the opposite, namely that UCP3 levels were reduced. The authors suggest that this constitutes a basic defect that is integral to diabetes pathogenesis. The failure to up-regulate UCP3 in T2DM would predictably result in an increase in lipid peroxides and subsequent mitochondrial damage and dysfunction. Treatment with rosiglitazone helps correct this pathological condition by increasing UCP3 expression, even as circulating FFA are suppressed and fat oxidation is enhanced by this therapy. The authors also noted reduced muscle UCP3 levels in patients with IGT, suggesting that this pathological mechanism is operative in prediabetic individuals. Thus, the authors have made a good case in describing how their data are consistent with their hypothesis.
Unfortunately, the data cannot be used to support any one of the three potential mechanisms of action over the others. All three mechanistic scenarios purport that UCP3 protects against mitochondrial damage whether through blunting ROS generation, preventing accumulation of fatty acyl-CoA levels, or reducing formation of lipid peroxides (Fig. 1
). If left unchecked, any of these three processes could damage mitochondria and impair function. An accumulating body of evidence has indicated that mitochondrial dysfunction in skeletal muscle could be a proximal cause of impaired lipid oxidation, leading to accumulation of intramyocellular lipid, and development of insulin resistance (10, 11, 12). Thus, regardless of the mechanism via which UCP3 may prevent mitochondrial damage, decreased expression of UCP3 protein could cause insulin resistance as a consequence of impaired mitochondrial fat oxidation and accumulation of intramyocellular lipid. Treatment with rosiglitazone increases both muscle UCP3 expression, thereby restoring the protective mechanisms guarding against mitochondrial damage, as well as insulin sensitivity. Although these data link UCP3 expression with changes in insulin sensitivity, the authors are correct in acknowledging that these correlative data do not constitute proof of causality.
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For the reasons delineated above, the authors can only provide correlative evidence that UCP3 modulates insulin sensitivity, and the data do not rigorously address biochemical mechanisms of action in mitochondria. These considerations highlight the challenge of investigation in humans, and these challenges place any clinical investigator at risk of overinterpreting the mechanistic significance of their data. At the same time, any mechanistic paradigm must take into account the authors’ important observations linking muscle UCP3 protein levels with changes in insulin sensitivity. Although studies in humans have certain inherent limitations, the study of human subjects will be critical for understanding the role of any molecule in human physiology and disease. Human data constitute an important piece of the puzzle that complement data derived from basic investigations, including molecular and cell biology experiments and metabolic phenotyping of transgenic and knockout mice. Consequently, findings from human experimentation should be valued by those funding and publishing clinical investigation, because all pieces of the puzzle are equally essential for the overall understanding of human disease and the development of optimal therapeutic preventative strategies.
Footnotes
Abbreviations: CoA, Coenzyme A; FFA, free fatty acid; IGT, impaired glucose tolerance; ROS, reactive oxygen species; T2DM, type 2 diabetes; UCP, uncoupling protein.
Received January 20, 2006.
Accepted February 22, 2006.
References
-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273[CrossRef][Medline]This article has been cited by other articles:
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  R. S Bhopal and S. B Rafnsson Could mitochondrial efficiency explain the susceptibility to adiposity, metabolic syndrome, diabetes and cardiovascular diseases in South Asian populations? Int. J. Epidemiol., August 1, 2009; 38(4): 1072 - 1081. [Abstract] [Full Text] [PDF]
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