What is the significance of uncoupling proteins in adipose tissue

Acta , — Mailloux, R. Meirhaeghe, A. An uncoupling protein 3 gene polymorphism associated with a lower risk of developing Type II diabetes and with atherogenic lipid profile in a French cohort.

Diabetologia 43, — Mensink, M. Skeletal muscle uncoupling protein-3 restores upon intervention in the prediabetic and diabetic state: implications for diabetes pathogenesis? Diabetes Obes. Musa, C. Four novel UCP3 gene variants associated with childhood obesity: effect on fatty acid oxidation and on prevention of triglyceride storage. Nabben, M. Significance of uncoupling protein 3 in mitochondrial function upon mid- and long-term dietary high-fat exposure. Nedergaard, J.

Unexpected evidence for active brown adipose tissue in adult humans. Ost, M. Patti, M. The role of mitochondria in the pathogenesis of type 2 diabetes. Peirce, V. Regulation of glucose homoeostasis by brown adipose tissue. Lancet Diabetes Endocrinol. Petrovic, N. Porter, R. Uncoupling protein 1: a short-circuit in the chemiosmotic process. Rolfe, D. Contribution of mitochondrial proton leak to skeletal muscle respiration and to standard metabolic rate.

Saito, M. Brown adipose tissue as a therapeutic target for human obesity. Schrauwen, P. The role of uncoupling protein3 in fatty acid metabolism: protection against lipotoxicity? Oxidative capacity, lipotoxicity, and mitochondrial damage in type 2 diabetes. Diabetes 53, — Uncoupling protein 3 content is decreased in skeletal muscle of patients with type 2 diabetes. Diabetes 50, — Senese, R. Uncoupling protein 3 expression levels influence insulin sensitivity, fatty acid oxidation, and related signaling pathways.

Pflugers Arch. Shabalina, I. Cell Rep. Son, C. Reduction of diet-induced obesity in transgenic mice overexpressing uncoupling protein 3 in skeletal muscle. Diabetologia 47, 47— Cold-activated brown adipose tissue in healthy men. Vidal-Puig, A. Energy metabolism in uncoupling protein 3 gene knockout mice. Vitali, A.

Lipid Res. Wu, J. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell , — Adaptive thermogenesis in adipocytes: is beige the new brown? This study aims to evaluate the long-term effects of diet and exercise on UCP1 and UCP3 levels and energy balance efficiency.

Rats fed with standard or high-sugar HSD diets were simultaneously subjected to running training over an 8-week period. The final destination of the electrons is the generation of molecular oxygen, which is reduced to water by complex IV, in the last step of the MRC.

Therefore, the process of substrate oxidation and oxygen reduction is also called respiration 8. Partial uncoupling of respiration from ATP synthesis, also known as proton leak, can be mediated by UCPs and by other mitochondrial inner membrane proteins, such as adenine nucleotide translocase ANT ; which prevents the inhibition of MRC by excessive levels of ATP 6,9.

ROS correspond to a variety of molecules and free radicals chemical species with one unpaired electron derived from the metabolism of molecular oxygen. Superoxide anion O 2 - is the precursor of most ROS and a mediator in oxidative chain reactions ROS normally exist in all aerobic cells in balance with biochemical antioxidants. Oxidative stress occurs when this critical balance is disrupted because of excess ROS, depletion of antioxidants, or both.

This stress causes damage to cellular macromolecules, such as nucleic acids, proteins, lipids, and structural carbohydrates Moreover, oxidative stress can also lead to cell death by necrosis or apoptosis, mechanisms involved in the pathogenesis of ageing and some disorders, such as DM2 and its chronic complications Uncoupling of the mitochondrial respiratory chain, changes in energy expenditure, and adaptive thermogenesis.

Total body energy expenditure represents the conversion of oxygen and food or storable forms of energy to carbon dioxide, water, heat and "work" on the environment Energy expenditure in humans can be subdivided into: 1 basal energy expenditure or resting metabolic rate RMR , measured under resting conditions and required for normal cell functioning; 2 energy expenditure resulting from physical activity; and 3 energy expenditure attributed to adaptive thermogenesis Figure 2 7, Variations in the RMR are due to several determinants, including body composition fat vs.

It is known that low energy expenditure could predict future weight gain, and that only a slight imbalance between energy intake and energy expenditure is necessary for weight gain, if it persists for several years 10, Thus, increasing the energy expenditure by increasing proton leak in mitochondria has been recognized as an effective way to achieve weight loss 7. Brown adipose tissue BAT is found in newborns, rodents and hibernating mammals, and is the main site of adaptive thermogenesis, which is defined as non-shivering heat production in response to environmental temperature or diet 10, As a result, thermogenesis in BAT has important roles in thermal and energetic balance and, when deficient, may lead to obesity BAT is a metabolically active tissue, which consists of adipocytes rich in mitochondria and numerous small lipid droplets, and is heavily innervated by sympathetic nerves 7.

This tissue differs from the white adipose tissue WAT , which contains large lipid droplets and few mitochondria 7, In fetuses and newborns, BAT has traditionally been regarded as occurring in specific depots, such as axillary, interscapular, perirenal, and periadrenal ones This amount takes care of heat generation for the body when the skeletal muscles are yet not able to make any controlled movements and thus, produce heat Children have highly active functional BAT until years of age; but, until a few years ago, it was thought that the quantity of BAT declined after puberty, and was rare in adults.

Nevertheless, nowadays it is known that BAT can be found in adults in the presence of catecholamine-secreting tumors, such as pheochromocytomas and paragangliomas Besides, some recent studies have shown that BAT in adults is highly active both functionally and metabolically, especially after chronic exposure to cold In , Himms-Hagen and Desautels 15 showed that BAT metabolism played a role in the development of obesity, and that obese mice had a defect in the mechanisms necessary for the activation of BAT thermogenesis.

After this pioneering work, many studies have also shown that defective BAT thermogenesis is involved in the development of obesity in most rodent models, and activation of BAT thermogenesis reduces weight gain in these animals 7, It has been suggested that development of ectopic BAT within the WAT may play an important role in preventing obesity 9.

In agreement with this hypothesis, transgenic mice overexpressing UCP1 in their skeletal muscle or WAT develop a resistance to diet-induced obesity and DM2, and have a marked stimulation of fatty acid oxidation in muscles 7. In addition, Tiraby and cols.

Changes in the expression of other genes were also consistent with brown adipocyte mRNA expression profile. The authors concluded that human white adipocytes can therefore acquire typical features of brown fat cells following proper stimulation These data indicate that moderate induction of UCP1 in WAT may be used to increase metabolic energy expenditure in obese subjects. Thus, specific uncoupling of adipocyte mitochondria remains an attractive target for the development of anti-obesity drugs 6,9.

UCPs 1, 2, 3, 4, and 5 are members of an anion-carrier protein family, and are located in the inner mitochondrial membrane These proteins have similarities in their structures, but different tissue expression in mammals. Over the last few years, several studies have shown that UCPs decrease metabolic efficiency by uncoupling substrate oxidation in mitochondria from ATP synthesis by the MRC.

This is thought to be accomplished by promoting net translocation of protons from the intermembrane space, across the inner mitochondrial membrane, to the mitochondrial matrix, thereby dissipating the potential energy available for ATP synthesis, and consequently, decreasing ATP production 6,8. The UCP1 gene covers a 9kb region on chromosome 4 region 4qq31 , and contains 6 exons and 5 introns Figure 3 7.

Moreover, uncoupling of the MRC by means of UCP1 action is only observed when cells are properly stimulated, for example, by norepinephrine 6, The uncoupling activity of UCP1 is explained by its ability to transport protons across the inner mitochondrial membrane, in particular when FFAs bind to the protein.

However, although CoQ has been described as a cofactor essential for its activity, the precise mechanism by which FFAs regulate transport through UCP1 is still a matter of intense debate 6,9. The main proposed mechanisms include the fatty acids protonophore or flip-flop model, and the channel or proton buffering model. In the flip-flop model, UCP1 is a carrier of fatty acid anions, which are transported by this protein from the matrix side to the intermembrane space.

In this model, each fatty acid anion combines with a proton, becomes electrically neutral and flips back through the membrane, releasing the proton in the matrix 6. The channel model predicts a two-domain structure of UCP1 with a pore domain and a gating domain, which allows protons to pass through the UCP1. The arguments for and against each model were reviewed by Brand and cols.

UCP2 knockout mice show increased insulin sensitivity and are protected against dietary fat induced insulin resistance [ 53 ]. Conversely, data from in vitro studies in L6 muscle cells suggest that UCP3 functions to facilitate fatty acid oxidation and minimize mitochondrial ROS production, perhaps thereby reducing muscle insulin resistance [ 54 ].

The data presently available suggest that UCP2 up-regulation has opposing effects on different components of type-2 diabetes. Thus, UCP2 is proposed as a diabetes gene [ 55 ]. Increased UCP3 may, on the other hand, reduce muscle insulin resistance. UCP2 protects against atherosclerosis in animal models [ 56 ] potentially through inhibition of ROS production in endothelial cells [ 57 ] and inhibition of monocyte accumulation in the artery wall [ 58 ].

A common variant in the UCP2 gene is associated with cardiovascular risk in healthy men and with oxidative stress in diabetic men [ 59 ]. Biochem Soc Trans. Nat Genet. FEBS Lett. Biochem Biophys Res Commun. Pros and cons for suggested functions. Exp Physiol. Nat Rev Mol Cell Biol. PubMed: [ www. Cell Metab. Biochim Biophys Acta. Antioxid Redox Signal.

Schrauwen P, Hesselink MK: The role of uncoupling protein 3 in fatty acid metabolism: protection against lipotoxicity?. Proc Nutr Soc.

J Biol Chem. Vidal-Puig AJ: Uncoupling expectations. J Appl Physiol. CAS Google Scholar. Horvath TL, Diano S, Barnstable C: Mitochondrial uncoupling protein 2 in the central nervous system: neuromodulator and neuroprotector. Biochem Pharmacol. J Neurosci. J Clin Invest. Nat Med. J Neurochem. Exp Biol Med Maywood. Faseb J. Samec S, Seydoux J, Dulloo AG: Post-starvation gene expression of skeletal muscle uncoupling protein 2 and uncoupling protein 3 in response to dietary fat levels and fatty acid composition: a link with insulin resistance.

Ann Neurol. J Bioenerg Biomembr. Berentzen T, Dalgaard LT, Petersen L, Pedersen O, Sorensen TI: Interactions between physical activity and variants of the genes encoding uncoupling proteins -2 and -3 in relation to body weight changes during a y follow-up.

Int J Obes Lond.