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1.  Reciprocal Regulation of Hepatic and Adipose Lipogenesis by Liver X Receptors in Obesity and Insulin Resistance 
Cell metabolism  2013;18(1):106-117.
Liver X receptors (LXRs) regulate lipogenesis and inflammation, but their contribution to the metabolic syndrome is unclear. We show that LXR signaling is required for key aspects of the metabolic syndrome in obese mice. LXRαβ-deficient-ob/ob (LOKO) mice remain obese, but show reduced hepatic steatosis and improved insulin sensitivity compared to ob/ob mice. Impaired hepatic lipogenesis in LOKO mice is accompanied by reciprocal increases in adipose lipid storage, reflecting tissue-selective effects of LXR on the SREBP, PPARγ, and ChREBP lipogenic pathways. LXRs are essential for obesity-driven SREBP-1c and ChREBP activity in liver, but not fat. Furthermore, loss of LXRs in obesity promotes adipose PPARγ and ChREBP-β activity, leading to improved insulin sensitivity. LOKO mice also exhibit defects in beta-cell mass and proliferation despite improved insulin sensitivity. Our data suggest that sterol sensing by LXRs in obesity is critically linked with lipid and glucose homeostasis and provide insight into complex relationships between LXR and insulin signaling.
PMCID: PMC4089509  PMID: 23823481
Nuclear receptor; liver X receptor (LXR); peroxisome proliferator-activated receptor (PPAR); carbohydrate response element binding protein (ChREBP); insulin resistance; diabetes; obesity; metabolic syndrome; hepatic steatosis; insulin signaling
2.  Skeletal muscle Nur77 expression enhances oxidative metabolism and substrate utilization[S] 
Journal of Lipid Research  2012;53(12):2610-2619.
Mitochondrial dysfunction has been implicated in the pathogenesis of type 2 diabetes. Identifying novel regulators of mitochondrial bioenergetics will broaden our understanding of regulatory checkpoints that coordinate complex metabolic pathways. We previously showed that Nur77, an orphan nuclear receptor of the NR4A family, regulates the expression of genes linked to glucose utilization. Here we demonstrate that expression of Nur77 in skeletal muscle also enhances mitochondrial function. We generated MCK-Nur77 transgenic mice that express wild-type Nur77 specifically in skeletal muscle. Nur77-overexpressing muscle had increased abundance of oxidative muscle fibers and mitochondrial DNA content. Transgenic muscle also exhibited enhanced oxidative metabolism, suggestive of increased mitochondrial activity. Metabolomic analysis confirmed that Nur77 transgenic muscle favored fatty acid oxidation over glucose oxidation, mimicking the metabolic profile of fasting. Nur77 expression also improved the intrinsic respiratory capacity of isolated mitochondria, likely due to the increased abundance of complex I of the electron transport chain. These changes in mitochondrial metabolism translated to improved muscle contractile function ex vivo and improved cold tolerance in vivo. Our studies outline a novel role for Nur77 in the regulation of oxidative metabolism and mitochondrial activity in skeletal muscle.
PMCID: PMC3494265  PMID: 23028113
Nr4a; nuclear receptor; mitochondria
3.  Adipose subtype–selective recruitment of TLE3 or Prdm16 by PPARγ specifies lipid-storage versus thermogenic gene programs 
Cell metabolism  2013;17(3):423-435.
Transcriptional effectors of white adipocyte-selective gene expression have not been described. Here we show that TLE3 is a white-selective cofactor that acts reciprocally with the brown-selective cofactor Prdm16 to specify lipid storage and thermogenic gene programs. Occupancy of TLE3 and Prdm16 on certain promoters is mutually exclusive, due to the ability of TLE3 to disrupt the physical interaction between Prdm16 and PPARγ. When expressed at elevated levels in brown fat, TLE3 counters Prdm16, suppressing brown-selective genes and inducing white-selective genes, resulting in impaired fatty acid oxidation and thermogenesis. Conversely, mice lacking TLE3 in adipose tissue show enhanced thermogenesis in inguinal white adipose depots and are protected from age-dependent deterioration of brown adipose tissue function. Our results suggest that the establishment of distinct adipocyte phenotypes with different capacities for thermogenesis and lipid storage is accomplished in part through the cell type–selective recruitment of TLE3 or Prdm16 to key adipocyte target genes.
PMCID: PMC3626567  PMID: 23473036
4.  Liver X Receptor Signaling is a Determinant of Stellate Cell Activation and Susceptibility to Fibrotic Liver Disease 
Gastroenterology  2010;140(3):1052-1062.
Background & Aims
Liver X receptors (LXRs) are lipid-activated nuclear receptors with important roles in cholesterol transport, lipogenesis, and anti-inflammatory signaling. Hepatic stellate cells (HSCs) activate during chronic liver injury and mediate the fibrotic response. These cells are also major repositories for lipids, but the role of lipid metabolism during stellate cell activation remains unclear. Here we show that LXR signaling is an important determinant of stellate cell activation and susceptibility to fibrotic liver disease.
Immortalized and primary stellate cells purified from mice were treated with highly specific LXR ligands. Carbon tetrachloride (CCl4) and methionine choline deficiency (MCD) were used as chronic liver injury models. Reciprocal bone marrow transplants were performed to test the importance of hematopoietically-derived cells to the fibrotic response.
LXR ligands suppressed markers of fibrosis and stellate cell activation in primary mouse stellate cells. Lxrαβ −/− stellate cells produce increased levels of inflammatory mediators and conditioned media from Lxrαβ−/− cells increases the fibrogenic program of wild-type cells. Furthermore, Lxrαβ−/− stellate cells exhibit altered lipid morphology and increased expression of fibrogenic genes, suggesting they are primed for activation. In vivo, Lxrαβ−/− mice have marked susceptibility to fibrosis in two injury models. Bone marrow transplants point to altered stellate cell function, rather than hematopoietic cell inflammation, as the primary basis for the Lxrαβ−/− phenotype.
These results reveal an unexpected role for LXR signaling and lipid metabolism in the modulation of hepatic stellate cell function.
PMCID: PMC3049833  PMID: 21134374
Nuclear receptors; LXRs; hepatic stellate cells; liver fibrosis
5.  TLE3 is a dual function transcriptional coregulator of adipogenesis 
Cell metabolism  2011;13(4):413-427.
PPARγ and Wnt signaling are central positive and negative regulators of adipogenesis, respectively. Here we identify the groucho family member TLE3 as a transcriptional integrator of the PPARγ and Wnt pathways. TLE3 is a direct target of PPARγ that participates in a feed-forward loop during adipocyte differentiation. TLE3 enhances PPARγ activity and functions synergistically with PPARγ on its target promoters to stimulate adipogenesis. At the same time, induction of TLE3 during differentiation provides a mechanism for termination of Wnt signaling. TLE3 antagonizes TCF4 activation by β-catenin in preadipocytes, thereby inhibiting Wnt target gene expression and reversing β-catenin-dependent repression of adipocyte gene expression. Transgenic expression of TLE3 in adipose tissue in vivo mimics the effects of PPARγ agonist and ameliorates high fat diet-induced insulin resistance. Our data suggest that TLE3 acts as a dual function switch, driving the formation of both active and repressive transcriptional complexes that facilitate the adipogenic program.
PMCID: PMC3089971  PMID: 21459326
6.  Insulin Resistance and Altered Systemic Glucose Metabolism in Mice Lacking Nur77 
Diabetes  2009;58(12):2788-2796.
Nur77 is an orphan nuclear receptor with pleotropic functions. Previous studies have identified Nur77 as a transcriptional regulator of glucose utilization genes in skeletal muscle and gluconeogenesis in liver. However, the net functional impact of these pathways is unknown. To examine the consequence of Nur77 signaling for glucose metabolism in vivo, we challenged Nur77 null mice with high-fat feeding.
Wild-type and Nur77 null mice were fed a high-fat diet (60% calories from fat) for 3 months. We determined glucose tolerance, tissue-specific insulin sensitivity, oxygen consumption, muscle and liver lipid content, muscle insulin signaling, and expression of glucose and lipid metabolism genes.
Mice with genetic deletion of Nur77 exhibited increased susceptibility to diet-induced obesity and insulin resistance. Hyperinsulinemic-euglycemic clamp studies revealed greater high-fat diet–induced insulin resistance in both skeletal muscle and liver of Nur77 null mice compared with controls. Loss of Nur77 expression in skeletal muscle impaired insulin signaling and markedly reduced GLUT4 protein expression. Muscles lacking Nur77 also exhibited increased triglyceride content and accumulation of multiple even-chained acylcarnitine species. In the liver, Nur77 deletion led to hepatic steatosis and enhanced expression of lipogenic genes, likely reflecting the lipogenic effect of hyperinsulinemia.
Collectively, these data demonstrate that loss of Nur77 influences systemic glucose metabolism and highlight the physiological contribution of muscle Nur77 to this regulatory pathway.
PMCID: PMC2780886  PMID: 19741162
7.  Inhibition of adipocyte differentiation by Nur77, Nurr1 and Nor1 
Members of the NR4A subgroup of nuclear receptors have been implicated in the regulation of glucose and lipid metabolism in insulin-sensitive tissues such as liver and skeletal muscle. However, their function in adipocytes is not well defined. Previous studies have reported that these receptors are rapidly upregulated following treatment of 3T3-L1 preadipocytes with an adipogenic cocktail. We show here that although Nur77 expression is acutely induced by cAMP agonists in 3T3-L1 cells, it is not induced by other adipogenic stimuli, such as PPARγ ligands, nor is it induced during the differentiation of 3T3-F442A preadipocytes, suggesting that Nur77 induction is not an obligatory feature of preadipocyte differentiation. We further demonstrate that inflammatory signals that antagonize differentiation, such as TNFα and lipopolysaccharide, acutely induce Nur77 expression both in vitro and in vivo. We also show that NR4A expression in adipose tissue is responsive to fasting/refeeding. Retroviral transduction of each of the NR4A receptors (Nur77, Nurr1 and NOR1) into either 3T3-L1 or 3T3-F442A preadipocytes potently inhibits adipogenesis. Interestingly, NR4A-mediated inhibition of adipogenesis cannot not be rescued by PPARγ overexpression or activation. Transcriptional profiling of Nur77-expressing preadipocytes led to the identification of gap-junction protein alpha 1 (Gja1) and tolloid-like 1 (Tll1) as Nur77-responsive genes. Remarkably, retroviral expression of either Gja1 or Tll1 in 3T3-L1 preadipocytes also inhibited adipocyte differentiation, implicating these genes as potential mediators of Nur77’s effects on adipogenesis. Finally, we show that Nur77 expression inhibits mitotic clonal expansion of preadipocytes, providing an additional mechanism by which Nur77 may inhibit adipogenesis.
PMCID: PMC2610364  PMID: 18945812
Nuclear Receptor; Nur77; adipogenesis; differentiation

Results 1-7 (7)