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  • 1
    Abstract: Glucagon and thyroid hormone (T3) exhibit therapeutic potential for metabolic disease but also exhibit undesired effects. We achieved synergistic effects of these two hormones and mitigation of their adverse effects by engineering chemical conjugates enabling delivery of both activities within one precisely targeted molecule. Coordinated glucagon and T3 actions synergize to correct hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity in metabolically compromised mice. We demonstrate that each hormonal constituent mutually enriches cellular processes in hepatocytes and adipocytes via enhanced hepatic cholesterol metabolism and white fat browning. Synchronized signaling driven by glucagon and T3 reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T3 action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T3 action. Our findings support the therapeutic utility of integrating these hormones into a single molecular entity that offers unique potential for treatment of obesity, type 2 diabetes, and cardiovascular disease.
    Type of Publication: Journal article published
    PubMed ID: 27720451
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  • 2
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    The American Society for Pharmacology and Experimental Therapeutics (ASPET)
    Publication Date: 2018-08-08
    Description: With their ever-growing prevalence, obesity and diabetes represent major health threats of our society. Based on estimations by the World Health Organization, approximately 300 million people will be obese in 2035. In 2015 alone there were more than 1.6 million fatalities attributable to hyperglycemia and diabetes. In addition, treatment of these diseases places an enormous burden on our health care system. As a result, the development of pharmacotherapies to tackle this life-threatening pandemic is of utmost importance. Since the beginning of the 19th century, a variety of drugs have been evaluated for their ability to decrease body weight and/or to improve deranged glycemic control. The list of evaluated drugs includes, among many others, sheep-derived thyroid extracts, mitochondrial uncouplers, amphetamines, serotonergics, lipase inhibitors, and a variety of hormones produced and secreted by the gastrointestinal tract or adipose tissue. Unfortunately, when used as a single hormone therapy, most of these drugs are underwhelming in their efficacy or safety, and placebo-subtracted weight loss attributed to such therapy is typically not more than 10%. In 2009, the generation of a single molecule with agonism at the receptors for glucagon and the glucagon-like peptide 1 broke new ground in obesity pharmacology. This molecule combined the beneficial anorectic and glycemic effects of glucagon-like peptide 1 with the thermogenic effect of glucagon into a single molecule with enhanced potency and sustained action. Several other unimolecular dual agonists have subsequently been developed, and, based on their preclinical success, these molecules illuminate the path to a new and more fruitful era in obesity pharmacology. In this review, we focus on the historical pharmacological approaches to treat obesity and glucose intolerance and describe how the knowledge obtained by these studies led to the discovery of unimolecular polypharmacology.
    Print ISSN: 0031-6997
    Electronic ISSN: 1521-0081
    Topics: Chemistry and Pharmacology , Medicine
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  • 3
    Publication Date: 2014-03-29
    Description: Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering the potential to reveal new targets for therapeutic intervention. Substantial changes in circulating total bile acids are known to occur after VSG. Moreover, bile acids are known to regulate metabolism by binding to the nuclear receptor FXR (farsenoid-X receptor, also known as NR1H4). We therefore examined the results of VSG surgery applied to mice with diet-induced obesity and targeted genetic disruption of FXR. Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signalling as an important molecular underpinning for the beneficial effects of this weight-loss surgery.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016120/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016120/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ryan, Karen K -- Tremaroli, Valentina -- Clemmensen, Christoffer -- Kovatcheva-Datchary, Petia -- Myronovych, Andriy -- Karns, Rebekah -- Wilson-Perez, Hilary E -- Sandoval, Darleen A -- Kohli, Rohit -- Backhed, Fredrik -- Seeley, Randy J -- DK078392/DK/NIDDK NIH HHS/ -- DK082173/DK/NIDDK NIH HHS/ -- DK093848/DK/NIDDK NIH HHS/ -- HL111319/HL/NHLBI NIH HHS/ -- K08 DK084310/DK/NIDDK NIH HHS/ -- K99 HL111319/HL/NHLBI NIH HHS/ -- P30 DK078392/DK/NIDDK NIH HHS/ -- England -- Nature. 2014 May 8;509(7499):183-8. doi: 10.1038/nature13135. Epub 2014 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, Ohio 45237, USA. ; Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, S-413 45 Gothenburg, Sweden. ; 1] Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, Ohio 45237, USA [2] Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. ; Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. ; Divison of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. ; 1] Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, S-413 45 Gothenburg, Sweden [2] Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670636" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Bariatric Surgery ; Bile Acids and Salts/blood ; Body Composition ; Cecum/microbiology ; Feeding Behavior ; *Gastrectomy ; Glucose Intolerance/surgery ; Glucose Tolerance Test ; Male ; Mice ; Mice, Inbred C57BL ; Obesity/etiology/surgery ; Receptors, Cytoplasmic and Nuclear/deficiency/genetics/*metabolism ; Signal Transduction ; Stomach/metabolism/surgery ; Weight Loss
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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