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1.  A New Role for Lipocalin Prostaglandin D Synthase in the Regulation of Brown Adipose Tissue Substrate Utilization 
Diabetes  2012;61(12):3139-3147.
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.
PMCID: PMC3501861  PMID: 22923471
2.  Assessment of brown adipose tissue function 
In this review we discuss practical considerations for the assessment of brown adipose tissue in rodent models, focusing on mice. The central aim of the review is to provide a critical appraisal of the utility of specialized techniques for assessing brown adipose tissue function in vivo. We cover several of the most common specialized methods for analysing brown adipose tissue function in vivo, including assessment of maximal thermogenic capacity by indirect calorimetry and the measurement of sympathetic tone to brown adipose tissue. While these techniques are powerful, they are not readily available to all laboratories; therefore we also cover several simple measurements that, particularly in combination, can be used to determine if a mouse model is likely to have alterations in brown adipose tissue function. Such techniques include: pair feeding, analysis of brown adipose tissue lipid content and mRNA and protein markers of brown adipose tissue activation.
PMCID: PMC3671177  PMID: 23760815
brown adipose tissue; BAT; maximal thermogenic capacity; adipose tissue; energy expenditure; cold exposure
3.  Below Thermoneutrality, Changes in Activity Do Not Drive Changes in Total Daily Energy Expenditure between Groups of Mice 
Cell Metabolism  2012;16(5):665-671.
In this study we investigated the relationship between activity and energy expenditure (EE) in mice. By determining the relationship between activity and EE over a 24 hr period in an individual mouse, activity was calculated to account for 26.6% ± 1.1% of total EE at 30°C. However, when comparing across multiple mice, only 9.53% ± 1.1% of EE from activity appeared to be independent of other components involved in the thermogenic response, suggesting other metabolic processes may mask the contribution of activity to EE. In line with this concept, below thermoneutrality mice still expended a substantial amount of energy on activity; however, at 24°C, 20°C, or 5°C, no independent effect of EE from activity on total daily EE could be detected. Overall these results suggest that when studying mice at temperatures below thermoneutrality, activity is unlikely to explain differences in EE between groups of animals.
► Under standard lab conditions, more-active mice do not expend more energy
PMCID: PMC3556741  PMID: 23140644
4.  Lipocalin Prostaglandin D Synthase and PPARγ2 Coordinate to Regulate Carbohydrate and Lipid Metabolism In Vivo 
PLoS ONE  2012;7(7):e39512.
Mice lacking Peroxisome Proliferator-Activated Receptor γ2 (PPARγ2) have unexpectedly normal glucose tolerance and mild insulin resistance. Mice lacking PPARγ2 were found to have elevated levels of Lipocalin prostaglandin D synthase (L-PGDS) expression in BAT and subcutaneous white adipose tissue (WAT). To determine if induction of L-PGDS was compensating for a lack of PPARγ2, we crossed L-PGDS KO mice to PPARγ2 KO mice to generate Double Knock Out mice (DKO). Using DKO mice we demonstrated a requirement of L-PGDS for maintenance of subcutaneous WAT (scWAT) function. In scWAT, DKO mice had reduced expression of thermogenic genes, the de novo lipogenic program and the lipases ATGL and HSL. Despite the reduction in markers of lipolysis in scWAT, DKO mice had a normal metabolic rate and elevated serum FFA levels compared to L-PGDS KO alone. Analysis of intra-abdominal white adipose tissue (epididymal WAT) showed elevated expression of mRNA and protein markers of lipolysis in DKO mice, suggesting that DKO mice may become more reliant on intra-abdominal WAT to supply lipid for oxidation. This switch in depot utilisation from subcutaneous to epididymal white adipose tissue was associated with a worsening of whole organism metabolic function, with DKO mice being glucose intolerant, and having elevated serum triglyceride levels compared to any other genotype. Overall, L-PGDS and PPARγ2 coordinate to regulate carbohydrate and lipid metabolism.
PMCID: PMC3390315  PMID: 22792179
5.  Dact1, a Nutritionally Regulated Preadipocyte Gene, Controls Adipogenesis by Coordinating the Wnt/β-Catenin Signaling Network 
Diabetes  2009;58(3):609-619.
OBJECTIVE—Wnt signaling inhibits adipogenesis, but its regulation, physiological relevance, and molecular effectors are poorly understood. Here, we identify the Wnt modulator Dapper1/Frodo1 (Dact1) as a new preadipocyte gene involved in the regulation of murine and human adipogenesis.
RESEARCH DESIGN AND METHODS—Changes in Dact1 expression were investigated in three in vitro models of adipogenesis. In vitro gain- and loss-of-function studies were used to investigate the mechanism of Dact1 action during adipogenesis. The in vivo regulation of Dact1 and Wnt/β-catenin signaling were investigated in murine models of altered nutritional status, of pharmacological stimulation of in vivo adipogenesis, and during the development of dietary and genetic obesity.
RESULTS—Dact1 is a preadipocyte gene that decreases during adipogenesis. However, Dact1 knockdown impairs adipogenesis through activation of the Wnt/β-catenin signaling pathway, and this is reversed by treatment with the secreted Wnt antagonist, secreted Frizzled-related protein 1 (Sfrp1). In contrast, constitutive Dact1 overexpression promotes adipogenesis and confers resistance to Wnt ligand-induced antiadipogenesis through increased expression of endogenous Sfrps and reduced expression of Wnts. In vivo, in white adipose tissue, Dact1 and Wnt/β-catenin signaling also exhibit coordinated expression profiles in response to altered nutritional status, in response to pharmacological stimulation of in vivo adipogenesis, and during the development of dietary and genetic obesity.
CONCLUSIONS—Dact1 regulates adipogenesis through coordinated effects on gene expression that selectively alter intracellular and paracrine/autocrine components of the Wnt/β-catenin signaling pathway. These novel insights into the molecular mechanisms controlling adipose tissue plasticity provide a functional network with therapeutic potential against diseases, such as obesity and associated metabolic disorders.
PMCID: PMC2646059  PMID: 19073771
6.  The Human Lipodystrophy Gene BSCL2/Seipin May Be Essential for Normal Adipocyte Differentiation 
Diabetes  2008;57(8):2055-2060.
OBJECTIVE—Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is a recessive disorder featuring near complete absence of adipose tissue. Remarkably, although the causative gene, BSCL2, has been known for several years, its molecular function and its role in adipose tissue development have not been elucidated. Therefore, we examined whether BSCL2 is involved in the regulation of adipocyte differentiation and the mechanism whereby pathogenic mutations in BSCL2 cause lipodystrophy.
RESEARCH DESIGN AND METHODS—Following the characterization of BSCL2 expression in developing adipocytes, C3H10T1/2 mesenchymal stem cells were generated in which BSCL2 expression was knocked down using short hairpin RNA (shRNA). These cells were used to investigate whether BSCL2 is required for adipogenesis. BSCL2 constructs harboring pathogenic mutations known to cause lipodystrophy were also generated and characterized.
RESULTS—BSCL2 expression was strongly induced during adipocyte differentiation, and the induction of BSCL2 expression was essential for adipogenesis to occur. The initial induction of key adipogenic transcription factors, including peroxisome proliferator–activated receptor (PPAR)γ and CAAT/enhancer-binding protein-α, was preserved in cells lacking BSCL2. However, the expression of these critical factors was not sustained, suggesting that the activity of PPARγ was impaired. Moreover, expression of key genes mediating triglyceride synthesis, including AGPAT2, lipin 1, and DGAT2, was persistently reduced and lipid accumulation was inhibited. Analysis of pathogenic missense mutants of BSCL2 revealed that the amino acid substitution A212P causes aberrant targeting of BSCL2 within the cell, suggesting that subcellular localization of BSCL2 may be critical to its function.
CONCLUSIONS—This study demonstrates that BSCL2 is an essential, cell-autonomous regulator of adipogenesis.
PMCID: PMC2494687  PMID: 18458148
7.  Orexin expression is regulated by alpha-melanocyte stimulating hormone 
Journal of neuroendocrinology  2007;19(9):703-707.
The hypothalamic melanocortin system plays a fundamental role in the regulation of energy homeostasis. Orexins (hypocretins) are also involved in a diverse range of physiological processes, including food intake. Previous evidence has suggested that hypothalamic orexin expression may be influenced by the central melanocortin system. Here, we studied orexin mRNA levels in Pomc−/− mice, a mouse model lacking all endogenously produced melanocortin peptides. Orexin expression in the lateral hypothalamus was significantly increased in corticosterone deficient Pomc−/− mice. Further, when circulating glucocorticoids were restored to levels within the physiological range, orexin expression remained elevated. However, ICV administration of the melanocortin α-MSH to Pomc−/− mice reduced orexin expression back down to WT levels. This was independent of the effects of α-MSH on food intake as in Pomc−/− mice pair-fed to α-MSH-treated animals elevated orexin expression persisted. These data indicate that α-MSH may play a role in the regulation of orexin expression in Pomc−/−, with an elevation in orexin levels contributing to the hyperphagia seen in these animals.
PMCID: PMC2637479  PMID: 17680885
Food intake; glucocorticoids; hypothalamus; melanocortins; orexins; proopiomelanocortin
8.  PPAR gamma 2 Prevents Lipotoxicity by Controlling Adipose Tissue Expandability and Peripheral Lipid Metabolism 
PLoS Genetics  2007;3(4):e64.
Peroxisome proliferator activated receptor gamma 2 (PPARg2) is the nutritionally regulated isoform of PPARg. Ablation of PPARg2 in the ob/ob background, PPARg2−/− Lepob/Lepob (POKO mouse), resulted in decreased fat mass, severe insulin resistance, β-cell failure, and dyslipidaemia. Our results indicate that the PPARg2 isoform plays an important role, mediating adipose tissue expansion in response to positive energy balance. Lipidomic analyses suggest that PPARg2 plays an important antilipotoxic role when induced ectopically in liver and muscle by facilitating deposition of fat as relatively harmless triacylglycerol species and thus preventing accumulation of reactive lipid species. Our data also indicate that PPARg2 may be required for the β-cell hypertrophic adaptive response to insulin resistance. In summary, the PPARg2 isoform prevents lipotoxicity by (a) promoting adipose tissue expansion, (b) increasing the lipid-buffering capacity of peripheral organs, and (c) facilitating the adaptive proliferative response of β-cells to insulin resistance.
Author Summary
It is known that obesity is linked to type 2 diabetes, however how obesity causes insulin resistance and diabetes is not well understood. Some extremely obese people are not diabetic, while other less obese people develop severe insulin resistance and diabetes. We believe diabetes occurs when adipose tissue becomes “full,” and fat overflows into other organs such as liver, pancreas, and muscle, causing insulin resistance and diabetes. Peroxisome proliferator activated receptor gamma (PPARg) is essential for the development of adipose tissue and control of insulin sensitivity. PPARg2 is the isoform of PPARg regulated by nutrition. Here we investigate the role of PPARg2 under conditions of excess nutrients by removing the PPARg2 isoform in genetically obese mice, the POKO mouse. We report that removing PPARg2 decreases adipose tissue's capacity to expand and prevents the mouse from making as much fat as a normal obese mouse, despite eating similarly. Our studies suggest that PPARg plays an important antitoxic role when it is induced in liver, muscle, and beta cells by facilitating deposition of fat as relatively harmless lipids and thus prevents accumulation of toxic lipid species. We also show that PPARg2 may be involved in the adaptive response of beta cells to insulin resistance.
PMCID: PMC1857730  PMID: 17465682

Results 1-8 (8)