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1.  Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training 
Comprehensive Physiology  2013;3(1):1-58.
Metabolic syndrome (MS) is a collection of cardiometabolic risk factors that includes obesity, insulin resistance, hypertension, and dyslipidemia. Although there has been significant debate regarding the criteria and concept of the syndrome, this clustering of risk factors is unequivocally linked to an increased risk of developing type 2 diabetes and cardiovascular disease. Regardless of the true definition, based on current population estimates, nearly 100 million have MS. It is often characterized by insulin resistance, which some have suggested is a major underpinning link between physical inactivity and MS. The purpose of this review is to: (i) provide an overview of the history, causes and clinical aspects of MS, (ii) review the molecular mechanisms of insulin action and the causes of insulin resistance, and (iii) discuss the epidemiological and intervention data on the effects of exercise on MS and insulin sensitivity.
doi:10.1002/cphy.c110062
PMCID: PMC4129661  PMID: 23720280
2.  Macrophage PPARγ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones 
Journal of Clinical Investigation  2007;117(6):1658-1669.
PPARγ is required for fat cell development and is the molecular target of antidiabetic thiazolidinediones (TZDs), which exert insulin-sensitizing effects in adipose tissue, skeletal muscle, and liver. Unexpectedly, we found that inactivation of PPARγ in macrophages results in the development of significant glucose intolerance plus skeletal muscle and hepatic insulin resistance in lean mice fed a normal diet. This phenotype was associated with increased expression of inflammatory markers and impaired insulin signaling in adipose tissue, muscle, and liver. PPARγ-deficient macrophages secreted elevated levels of factors that impair insulin responsiveness in muscle cells in a manner that was enhanced by exposure to FFAs. Consistent with this, the relative degree of insulin resistance became more severe in mice lacking macrophage PPARγ following high-fat feeding, and these mice were only partially responsive to TZD treatment. These findings reveal an essential role of PPARγ in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs.
doi:10.1172/JCI31561
PMCID: PMC1868788  PMID: 17525798
3.  Reciprocal Regulation of Hepatic and Adipose Lipogenesis by Liver X Receptors in Obesity and Insulin Resistance 
Cell metabolism  2013;18(1):106-117.
SUMMARY
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.
doi:10.1016/j.cmet.2013.04.021
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
4.  Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice☆ 
Molecular Metabolism  2014;3(2):177-190.
Pairing the selective estrogen receptor modulator bazedoxifene (BZA) with estrogen as a tissue-selective estrogen complex (TSEC) is a novel menopausal therapy. We investigated estrogen, BZA and TSEC effects in preventing diabetisity in ovariectomized mice during high-fat feeding. Estrogen, BZA or TSEC prevented fat accumulation in adipose tissue, liver and skeletal muscle, and improved insulin resistance and glucose intolerance without stimulating uterine growth. Estrogen, BZA and TSEC improved energy homeostasis by increasing lipid oxidation and energy expenditure, and promoted insulin action by enhancing insulin-stimulated glucose disposal and suppressing hepatic glucose production. While estrogen improved metabolic homeostasis, at least partially, by increasing hepatic production of FGF21, BZA increased hepatic expression of Sirtuin1, PPARα and AMPK activity. The metabolic benefits of BZA were lost in estrogen receptor-α deficient mice. Thus, BZA alone or in TSEC produces metabolic signals of fasting and caloric restriction and improves energy and glucose homeostasis in female mice.
doi:10.1016/j.molmet.2013.12.009
PMCID: PMC3953695  PMID: 24634829
Akt, protein kinase B; AMPKα, AMP-activated protein kinase α; AUC, area-under the curve; BAT, brown adipose tissue; BZA, bazedoxifene; CE, conjugated equine estrogens; E2, 17β-estradiol; ER, estrogen receptor; FAS, fatty acid synthase; FGF21, fibroblast growth factor 21; GIR, glucose infusion rate; H&E, hematoxylin and eosin; HFD, high-fat diet; HGP, hepatic glucose production; ITT, insulin tolerance test; Lcn2, lipocalin 2; LPL, lipoprotein lipase; NAFLD, non-alcoholic fatty liver disease; OGTT, oral glucose tolerance test; OVX, ovariectomy; PTT, pyruvate tolerance test; RBP4, retinol binding protein 4; Rd, rate of whole-body glucose disappearance; RER, respiratory exchange ratio; SERM, selective estrogen receptor modulator; TBARS, thiobarbituric acid reactive substances; TG, triacylglycerol; TSEC, tissue-selective estrogen complex; UCPs, uncoupling proteins; VO2, oxygen consumption; WAT, white adipose tissue.; Tissue-selective estrogen complexes; Bazedoxifene; Menopause; Metabolic syndrome; Insulin resistance; Type 2 diabetes
5.  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.
doi:10.1194/jlr.M029355
PMCID: PMC3494265  PMID: 23028113
Nr4a; nuclear receptor; mitochondria
6.  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.
doi:10.1016/j.cmet.2013.01.016
PMCID: PMC3626567  PMID: 23473036
7.  Insulin Resistance and Altered Systemic Glucose Metabolism in Mice Lacking Nur77 
Diabetes  2009;58(12):2788-2796.
OBJECTIVE
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.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSIONS
Collectively, these data demonstrate that loss of Nur77 influences systemic glucose metabolism and highlight the physiological contribution of muscle Nur77 to this regulatory pathway.
doi:10.2337/db09-0763
PMCID: PMC2780886  PMID: 19741162
8.  Hypermetabolism, Hyperphagia, and Reduced Adiposity in Tankyrase-Deficient Mice 
Diabetes  2009;58(11):2476-2485.
OBJECTIVE
Tankyrase (TNKS) is a Golgi-associated poly-ADP-ribose polymerase that is implicated in the regulation of GLUT4 trafficking in 3T3-L1 adipocytes. Its chromosomal locus 8p23.1 is linked to monogenic forms of diabetes in certain kindred. We hypothesize that TNKS is involved in energy homeostasis in mammals.
RESEARCH DESIGN AND METHODS
Gene-trap techniques were used to ablate TNKS expression in mice. Homozygous and wild-type littermates maintained on standard chow were compared.
RESULTS
Wild-type mice express the TNKS protein abundantly in adipose tissue, the brain, and the endocrine pancreas but scarcely in the exocrine pancreas and skeletal muscle. TNKS-deficient mice consume increased amounts of food (by 34%) but have decreased plasma leptin levels and a >50% reduction in epididymal and perirenal fat pad size. Their energy expenditure is increased as assessed by metabolic cage studies and core body temperatures. These changes are not attributable to an increase in physical activity or uncoupled respiration (based on oxygraph analyses of mitochondria isolated from brown fat and skeletal muscle). The heightened thermogenesis of TNKS-deficient mice is apparently fueled by increases in both fatty acid oxidation (based on muscle and liver gene expression analyses and plasma ketone levels) and insulin-stimulated glucose utilization (determined by hyperinsulinemic-euglycemic clamps). Although TNKS deficiency does not compromise insulin-stimulated GLUT4 translocation in primary adipocytes, it leads to the post-transcriptional upregulation of GLUT4 and adiponectin in adipocytes and increases plasma adiponectin levels.
CONCLUSIONS
TNKS-deficient mice exhibit increases in energy expenditure, fatty acid oxidation, and insulin-stimulated glucose utilization. Despite excessive food intake, their adiposity is substantially decreased.
doi:10.2337/db08-1781
PMCID: PMC2768175  PMID: 19651815
9.  Sarcopenia Exacerbates Obesity-Associated Insulin Resistance and Dysglycemia: Findings from the National Health and Nutrition Examination Survey III 
PLoS ONE  2010;5(5):e10805.
Background
Sarcopenia often co-exists with obesity, and may have additive effects on insulin resistance. Sarcopenic obese individuals could be at increased risk for type 2 diabetes. We performed a study to determine whether sarcopenia is associated with impairment in insulin sensitivity and glucose homeostasis in obese and non-obese individuals.
Methodology
We performed a cross-sectional analysis of National Health and Nutrition Examination Survey III data utilizing subjects of 20 years or older, non-pregnant (N = 14,528). Sarcopenia was identified from bioelectrical impedance measurement of muscle mass. Obesity was identified from body mass index. Outcomes were homeostasis model assessment of insulin resistance (HOMA IR), glycosylated hemoglobin level (HbA1C), and prevalence of pre-diabetes (6.0≤ HbA1C<6.5 and not on medication) and type 2 diabetes. Covariates in multiple regression were age, educational level, ethnicity and sex.
Principal Findings
Sarcopenia was associated with insulin resistance in non-obese (HOMA IR ratio 1.39, 95% confidence interval (CI) 1.26 to 1.52) and obese individuals (HOMA-IR ratio 1.16, 95% CI 1.12 to 1.18). Sarcopenia was associated with dysglycemia in obese individuals (HbA1C ratio 1.021, 95% CI 1.011 to 1.043) but not in non-obese individuals. Associations were stronger in those under 60 years of age. We acknowledge that the cross-sectional study design limits our ability to draw causal inferences.
Conclusions
Sarcopenia, independent of obesity, is associated with adverse glucose metabolism, and the association is strongest in individuals under 60 years of age, which suggests that low muscle mass may be an early predictor of diabetes susceptibility. Given the increasing prevalence of obesity, further research is urgently needed to develop interventions to prevent sarcopenic obesity and its metabolic consequences.
doi:10.1371/journal.pone.0010805
PMCID: PMC3279294  PMID: 22421977

Results 1-9 (9)