Recruitment of brown adipose tissue as a therapy for obesity-associated diseases.
Frontiers in Endocrinology 3:14 (2012)
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...
Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP.
Genes & Development 24(13):1403 (2010)
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...
Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo.
BMC Systems Biology 3:31 (2009)
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...
Sirtuins--novel therapeutic targets to treat age-associated diseases.
Nature Reviews: Drug Discovery 7(10):841 (2008)
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...
Targeting PGC-1 alpha to control energy homeostasis.
Expert Opinion on Therapeutic Targets 11(10):1329 (2007)
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 ...
The obesity epidemic: current and future pharmacological treatments.
Pharmacology and Toxicology 47:565 (2007)
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 ...
Resveratrol improves health and survival of mice on a high-calorie diet.
Nature 444(7117):337 (2006)
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...
A role for skeletal muscle stearoyl-CoA desaturase 1 in control of thermogenesis.
FASEB Journal 20(10):1751 (2006)
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 ...
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-HT1BRs), modulates the endogenous release of both agonists and antagonists of the melanocortin recep...
Adipose targets for obesity drug development.
Expert Opinion on Therapeutic Targets 10(1):119 (2006)
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...
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...
Divergence of melanocortin pathways in the control of food intake and energy expenditure.
Cell 123(3):493 (2005)
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 gener...
GLUT4 glucose transporter deficiency increases hepatic lipid production and peripheral lipid utilization.
Journal of Clinical Investigation 114(11):1666 (2004)
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)....
Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres.
Nature 418(6899):797 (2002)
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...
Leptin directly stimulates thermogenesis in skeletal muscle.
FEBS Letters 515(1-3):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 muscles from obe...
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...
Differential Regulation of Uncoupling Proteins by Chronic Treatments with β3-Adrenergic Agonist BRL 35135 and Metformin in Obesefa/faZucker Rats
Biochemical and Biophysical Research Communicat... 246(3):899 (1998)
The expressions of uncoupling proteins 2 and 3 (UCP2; UCP3) mRNA were studied in obese (fa/fa) Zucker rats treated with two weight gain reducing agents for three weeks. The specific β3-adrenoceptor agonist BRL 35135 (0.5 mg/kg/day orally) increased the expression of UCP3 mRNA by 3.8-fo...
Genomic Structure of Uncoupling Protein-3 (UCP3) and Its Assignment to Chromosome 11q13
Genomics 47(3):425 (1998)
Tissue-dependent upregulation of rat uncoupling protein-2 expression in response to fasting or cold
FEBS Letters 412(1):111 (1997)
The control of uncoupling protein-2 (UCP2) mRNA expression in rat brown adipose tissue (BAT), heart and skeletal muscles was examined. Cold exposure (48 h) increased UCP2 mRNA in BAT, heart and soleus muscle by 2.4-, 4.3- and 2.6-fold, respectively. Fasting (48 h) had no effect on UCP2 mRNA...