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A new role for lipocalin prostaglandin d synthase in the regulation of brown adipose tissue substrate utilization
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Virtue, Sam, Feldmann, Helena, Christian, Mark, Tan, Chong Yew, Masoodi, Mojgan, Dale, Martin, Lelliott, Chris, Burling, Keith, Campbell, Mark, Eguchi, Naomi, Voshol, Peter, Sethi, Jaswinder K., Parker, Malcolm G., Urade, Yoshihiro, Griffin, Julian L., Cannon, Barbara and Vidal-Puig, Antonio (2012) A new role for lipocalin prostaglandin d synthase in the regulation of brown adipose tissue substrate utilization. Diabetes, 61 (12). pp. 3139-3147. doi:10.2337/db12-0015 ISSN 0012-1797.
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Official URL: http://dx.doi.org/10.2337/db12-0015
Abstract
In this study, we define a new role for lipocalin prostaglandin D synthase (L-PGDS) in the control of metabolic fuel utilization by brown adipose tissue (BAT). We demonstrate that L-PGDS expression in BAT is positively correlated with BAT activity, upregulated by peroxisome proliferator–activated receptor γ coactivator 1α or 1β and repressed by receptor-interacting protein 140. Under cold-acclimated conditions, mice lacking L-PGDS had elevated reliance on carbohydrate to provide fuel for thermogenesis and had increased expression of genes regulating glycolysis and de novo lipogenesis in BAT. These transcriptional differences were associated with increased lipid content in BAT and a BAT lipid composition enriched with de novo synthesized lipids. Consistent with the concept that lack of L-PGDS increases glucose utilization, mice lacking L-PGDS had improved glucose tolerance after high-fat feeding. The improved glucose tolerance appeared to be independent of changes in insulin sensitivity, as insulin levels during the glucose tolerance test and insulin, leptin, and adiponectin levels were unchanged. Moreover, L-PGDS knockout mice exhibited increased expression of genes involved in thermogenesis and increased norepinephrine-stimulated glucose uptake to BAT, suggesting that sympathetically mediated changes in glucose uptake may have improved glucose tolerance. Taken together, these results suggest that L-PGDS plays an important role in the regulation of glucose utilization in vivo.
Obesity is a chronic illness that is associated with multiple secondary diseases, including diabetes and cardiovascular disease. Although many ideas have been put forward to explain mechanistically how obesity leads to metabolic complications, this still remains an area of considerable controversy. We and others have suggested that alterations in how lipids are stored and handled may link obesity to metabolic complications through defects in adipose tissue expansion and functional capacity and the process of lipotoxicity (1,2).
An important aspect of appropriate lipid handling is the ability of tissues to switch between carbohydrate and lipid as their major metabolic substrates. Under normal physiological conditions, humans switch from using high levels of carbohydrate during the postprandial state to predominantly utilizing stored lipids during the fasted state. The process of switching from fed to fasted states requires adipose tissue to play an important role in lipid buffering. During the fed state, net lipid flux into adipose tissue increases, whereas in the fasted state net lipid efflux predominates (3). Under pathological conditions where adipose tissue becomes insulin resistant, however, the appropriate fluxes into and out of adipose tissue are blunted (4–6).
The process of being able to switch between using metabolic substrates is termed metabolic flexibility and can be measured by assessing the change in respiratory quotient between fed and fasted states. A reduction in metabolic flexibility has been suggested to be a primary defect leading to insulin resistance. When fed a high-fat diet for 3 days, subjects with a family history of type 2 diabetes showed a lower change in respiratory quotient between fasted and fed states than did subjects without a family history of type 2 diabetes (7). The fact that impairments in metabolic substrate utilization may be a primary cause of insulin resistance suggests the possibility of a direct regulatory mechanism controlling this process; however, what form this mechanism takes is poorly understood.
In addition to the known roles for white adipose tissue (WAT) depots in metabolic health, interest in the role of brown adipose tissue (BAT) in adult humans has recently experienced a resurgence through studies with fluorodeoxyglucose positron emission tomography (8–13). BAT has been demonstrated, at least in rodents, to have a very high capacity for both lipid and glucose uptake and oxidation. In small mammals, such as mice, BAT may be responsible for the oxidation of as much as 90% of the total daily fuel intake. In addition to its high rate of lipid and glucose oxidation, BAT also has very high rates of de novo lipogenesis, suggested to account for as much as 40% of all de novo lipogenesis in a cold-exposed rats (14). Given BAT’s very high metabolic rate, its high levels of lipid and glucose oxidation, and its substantial lipid synthesis, elucidation of how fuel utilization is regulated within BAT is an important question, particularly if it is ever to be used efficiently as a therapy to treat human metabolic disease. In this study we investigate the role of lipocalin prostaglandin D synthase (L-PGDS) in the regulation of carbohydrate and lipid utilization by BAT.
L-PGDS has at least two known functions. It is capable of synthesizing D-series prostaglandins, and it also can act as a carrier of lipophilic molecules (15). It has been reported to have a protective role in the development of atherosclerosis (16). Reports regarding the role of L-PGDS in insulin sensitivity, however, are unclear. One report stated that lack of L-PGDS causes glucose intolerance, whereas a second report demonstrated that mice lacking L-PGDS had greater adiposity but unaltered glucose tolerance—suggesting that L-PGDS knockout (KO) mice may be disproportionately glucose tolerant for their degree of adiposity (16,17).
In this study we demonstrated that L-PGDS is highly regulated in BAT. To investigate a putative role for L-PGDS in BAT function, L-PGDS KO mice were cold acclimated. Cold acclimation causes a substantial increase in whole-organism metabolic rate and demands large alterations in carbohydrate and lipid metabolism, particularly in BAT. Mice lacking L-PGDS had lower basal metabolic rates, although they were still able to achieve the same maximal thermogenic capacity as wild-type mice. Crucially, L-PGDS KO mice had reduced lipid and increased carbohydrate utilization, appearing to meet increased demand for oxidative capacity from carbohydrate, either directly or by de novo synthesis of lipids and their subsequent oxidation, rather than from utilization of dietary lipids. Consistent with the concept that a lack of L-PGDS increases net glucose utilization, we showed that mice lacking L-PGDS had improved glucose tolerance when fed a high-fat diet. Overall, we have defined a role for L-PGDS in the control of fuel utilization by BAT.
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