1. Recruitment of brown adipose tissue as a therapy for obesity-associated diseases.

    Frontiers in Endocrinology 3:14 (2012) PMID 22654854 PMCID PMC3356088

    Brown adipose tissue (BAT) has been recognized for more than 20 years to play a key role in cold-induced non-shivering thermogenesis (CIT, NST), and body weight homeostasis in animals. BAT is a flexible tissue that can be recruited by stimuli (including small molecules in animals), and atrophies...
  2. Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP.

    Genes & Development 24(13):1403 (2010) PMID 20595232 PMCID PMC2895199

    The sterol regulatory element-binding protein (SREBP) transcription factor family is a critical regulator of lipid and sterol homeostasis in eukaryotes. In mammals, SREBPs are highly active in the fed state to promote the expression of lipogenic and cholesterogenic genes and facilitate fat stora...
  3. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo.

    BMC Systems Biology 3:31 (2009) PMID 19284563 PMCID PMC2660283

    Calorie restriction (CR) produces a number of health benefits and ameliorates diseases of aging such as type 2 diabetes. The components of the pathways downstream of CR may provide intervention points for developing therapeutics for treating diseases of aging. The NAD+-dependent protein deacetyl...
  4. Sirtuins--novel therapeutic targets to treat age-associated diseases.

    Nature Reviews: Drug Discovery 7(10):841 (2008) PMID 18827827

    Sirtuins post-translationally modulate the function of many cellular proteins that undergo reversible acetylation-deacetylation cycles, affecting physiological responses that have implications for treating diseases of ageing. Potent small-molecule modulators of sirtuins have shown efficacy in pr...
  5. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.

    Nature 450(7170):712 (2007) PMID 18046409 PMCID PMC2753457

    Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeost...
  6. Targeting PGC-1 alpha to control energy homeostasis.

    Expert Opinion on Therapeutic Targets 11(10):1329 (2007) PMID 17907962

    The prevalence of Type 2 diabetes is increasing at an alarming rate in most parts of the world. Effective therapeutic drugs are urgently needed, not only to control the disease but also to prevent or delay its progression. Therapies that target the underlying pathogenesis could, in theory, hold ...
  7. The obesity epidemic: current and future pharmacological treatments.

    Pharmacology and Toxicology 47:565 (2007) PMID 17002599

    The unabated rise in the prevalence of obesity is a challenge for global health care systems. Efforts to reverse this trend by dietary or behavioral counseling have not been successful, which has stimulated efforts to find a role for pharmacotherapy. Currently only a small number of antiobesity ...
  8. Resveratrol improves health and survival of mice on a high-calorie diet.

    Nature 444(7117):337 (2006) PMID 17086191

    Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects...
  9. A role for skeletal muscle stearoyl-CoA desaturase 1 in control of thermogenesis.

    FASEB Journal 20(10):1751 (2006) PMID 16809433

    An enhanced metabolic efficiency for accelerating the recovery of fat mass (or catch-up fat) is a characteristic feature of body weight regulation after weight loss or growth retardation and is the outcome of an "adipose-specific" suppression of thermogenesis, i.e., a feedback control system in ...
  10. Serotonin reciprocally regulates melanocortin neurons to modulate food intake.

    Neuron 51(2):239 (2006) PMID 16846858

    The neural pathways through which central serotonergic systems regulate food intake and body weight remain to be fully elucidated. We report that serotonin, via action at serotonin1B receptors (5-HT1BRs), modulates the endogenous release of both agonists and antagonists of the melanocortin recep...
  11. Adipose targets for obesity drug development.

    Expert Opinion on Therapeutic Targets 10(1):119 (2006) PMID 16441232

    The prevalence of obesity is increasing rapidly in most parts of the world and effective therapeutic drugs are urgently needed. The discovery of leptin in 1994 initiated a new understanding of adipose tissue function, and adipose tissue is now known to not only store and release fatty acids, but...
  12. Serotonin Reciprocally Regulates Melanocortin Neurons to Modulate Food Intake

    Neuron 51(2):239 (2006)

    The neural pathways through which central serotonergic systems regulate food intake and body weight remain to be fully elucidated. We report that serotonin, via action at serotonin1B receptors (5-HT 1BRs), modulates the endogenous release of both agonists and antagonists of the melano...
  13. Divergence of Melanocortin Pathways in the Control of Food Intake and Energy Expenditure

    Cell 123(3):493 (2005) PMID 16269339

    Activation of melanocortin-4-receptors (MC4Rs) reduces body fat stores by decreasing food intake and increasing energy expenditure. MC4Rs are expressed in multiple CNS sites, any number of which could mediate these effects. To identify the functionally relevant sites of MC4R expression, we ...
  14. GLUT4 glucose transporter deficiency increases hepatic lipid production and peripheral lipid utilization.

    Journal of Clinical Investigation 114(11):1666 (2004) PMID 15578099 PMCID PMC529279

    A critical defect in type 2 diabetes is impaired insulin-stimulated glucose transport and metabolism in muscle and adipocytes. To understand the metabolic adaptations this elicits, we generated mice with targeted disruption of the GLUT4 glucose transporter in both adipocytes and muscle (AMG4KO)....
  15. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres.

    Nature 418(6899):797 (2002) PMID 12181572

    The biochemical basis for the regulation of fibre-type determination in skeletal muscle is not well understood. In addition to the expression of particular myofibrillar proteins, type I (slow-twitch) fibres are much higher in mitochondrial content and are more dependent on oxidative metabolism t...
  16. Leptin directly stimulates thermogenesis in skeletal muscle.

    FEBS Letters 515(1-3):109 (2002) PMID 11943204

    Using a method involving repeated oxygen uptake (MO(2)) determinations in skeletal muscle ex vivo, the addition of leptin was found to increase MO(2) in soleus muscles from lean mice. These effects were found to be inhibited by phosphatidylinositol 3-kinase inhibitors, absent in muscles from obe...
  17. Leptin directly stimulates thermogenesis in skeletal muscle

    FEBS Letters 515(1):109 (2002)

    Using a method involving repeated oxygen uptake (MO 2) determinations in skeletal muscle ex vivo, the addition of leptin was found to increase MO 2 in soleus muscles from lean mice. These effects were found to be inhibited by phosphatidylinositol 3-kinase inhibitors, absent in m...
  18. Uncoupling Protein-2 Negatively Regulates Insulin Secretion and Is a Major Link between Obesity, β Cell Dysfunction, and Type 2 Diabetes

    Cell 105(6):745 (2001)

    β cells sense glucose through its metabolism and the resulting increase in ATP, which subsequently stimulates insulin secretion. Uncoupling protein-2 (UCP2) mediates mitochondrial proton leak, decreasing ATP production. In the present study, we assessed UCP2's role in regulating insulin sec...
  19. Role of the β3-Adrenergic Receptor and/or a Putative β4-Adrenergic Receptor on the Expression of Uncoupling Proteins and Peroxisome Proliferator-Activated Receptor-γ Coactivator-1

    Biochemical and Biophysical Research Communicat... 261(3):870 (1999)

    Administration of β-adrenergic receptor (β-AR) agonists, especially β 3-AR agonists, is well known to increase thermogenesis in rodents and humans. In this work we studied the role of the β 3-AR in regulating mRNA expression of genes involved in thermogenesis, i.e., mitochondria...
  20. Uncoupling protein-3 expression in skeletal muscle and free fatty acids in obesity

    The Lancet 351(9120):1933 (1998) PMID 9654269