Abstract
Purpose of Review
Obesity is a global health crisis with detrimental effects on all organ systems leading to worsening disease state and rising costs of care. Persons with obesity failing lifestyle therapies need to be escalated to appropriate pharmacological treatment modalities, medical devices, and/or bariatric surgery if criteria are met and more aggressive intervention is needed. The progression of severe obesity in the patient population coupled with related co-morbidities necessitates the development of novel therapies for the treatment of obesity. This development is preceded by increased understanding of the underpinnings of energy regulation and neurohormonal pathways involved in energy homeostasis.
Recent Findings
Though there are approved anti-obesity drugs available in the USA, newer drugs are now in the pipeline for development given the urgent need. This review focuses on anti-obesity drugs in the pipeline including centrally acting agents (setmelanotide, neuropeptide Y antagonist [velneperit], zonisamide-bupropion [Empatic], cannabinoid type-1 receptor blockers), gut hormones and incretin targets (new glucagon-like-peptide-1 [GLP-1] analogues [semaglutide and oral equivalents], amylin mimetics [davalintide, dual amylin and calcitonin receptor agonists], dual action GLP-1/glucagon receptor agonists [oxyntomodulin], triple agonists [tri-agonist 1706], peptide YY, leptin analogues [combination pramlintide-metreleptin]), and other novel targets (methionine aminopeptidase 2 inhibitor [beloranib], lipase inhibitor [cetilistat], triple monoamine reuptake inhibitor [tesofensine], fibroblast growth factor 21), including anti-obesity vaccines (ghrelin, somatostatin, adenovirus36).
Summary
With these new drugs in development, anti-obesity therapeutics have potential to vastly expand allowing better treatment options and personalized approach to obesity care.
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References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Gregg EW, Shaw JE. Global health effects of overweight and obesity. N Engl J Med. 2017;377:80–1. https://doi.org/10.1056/NEJMe1706095.
Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. Trends in obesity among adults in the United States, 2005 to 2014. JAMA. 2016;315:2284–91. https://doi.org/10.1001/jama.2016.6458.
•• Apovian CM, et al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:342–62. https://doi.org/10.1210/jc.2014-3415. Provides current guidelines for clinical application of approved anti-obesity drugs.
Van Gaal LF, Broom JI, Enzi G, Toplak H. Efficacy and tolerability of orlistat in the treatment of obesity: a 6-month dose-ranging study. Orlistat Dose-Ranging Study Group. Eur J Clin Pharmacol. 1998;54:125–32.
James WP, Avenell A, Broom J, Whitehead J. A one-year trial to assess the value of orlistat in the management of obesity. Int J Obes Relat Metab Disord. 1997;21(Suppl 3):S24–30.
Weintraub M, Sundaresan PR, Schuster B, Ginsberg G, Madan M, Balder A, et al. Long-term weight control study. II (weeks 34 to 104). An open-label study of continuous fenfluramine plus phentermine versus targeted intermittent medication as adjuncts to behavior modification, caloric restriction, and exercise. Clin Pharmacol Ther. 1992;51:595–601.
Aronne LJ, et al. Evaluation of phentermine and topiramate versus phentermine/topiramate extended-release in obese adults. Obesity (Silver Spring, Md.). 2013;21:2163–71. https://doi.org/10.1002/oby.20584.
Aronne L, Shanahan W, Fain R, Glicklich A, Soliman W, Li Y, et al. Safety and efficacy of lorcaserin: a combined analysis of the BLOOM and BLOSSOM trials. Postgrad Med. 2014;126:7–18. https://doi.org/10.3810/pgm.2014.10.2817.
Fidler MC, Sanchez M, Raether B, Weissman NJ, Smith SR, Shanahan WR, et al. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab. 2011;96:3067–77. https://doi.org/10.1210/jc.2011-1256.
Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjøth TV, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA. 2015;314:687–99. https://doi.org/10.1001/jama.2015.9676.
Wadden TA, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes. 2015;39:187. https://doi.org/10.1038/ijo.2014.88.
•• Srivastava G, Apovian CM. Current pharmacotherapy for obesity. Nat Rev Endocrinology. 2017; https://doi.org/10.1038/nrendo.2017.122. Most recent review on current anti-obesity drugs in regard to efficacy, safety, and clinical application.
Apovian CM. Naltrexone/bupropion for the treatment of obesity and obesity with type 2 diabetes. Futur Cardiol. 2016;12:129–38. https://doi.org/10.2217/fca.15.79.
Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363:245–56. https://doi.org/10.1056/NEJMoa0909809.
Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95:297–308. https://doi.org/10.3945/ajcn.111.024927.
Kang JG, Park CY. Anti-obesity drugs: a review about their effects and safety. Diabetes Metab J. 2012;36:13–25. https://doi.org/10.4093/dmj.2012.36.1.13.
Chen KY, Muniyappa R, Abel BS, Mullins KP, Staker P, Brychta RJ, et al. RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals. J Clin Endocrinol Metab. 2015;100:1639–45. https://doi.org/10.1210/jc.2014-4024.
Fani L, Bak S, Delhanty P, van Rossum EF, van den Akker EL. The melanocortin-4 receptor as target for obesity treatment: a systematic review of emerging pharmacological therapeutic options. Int J Obes. 2014;38:163–9. https://doi.org/10.1038/ijo.2013.80.
Kievit P, Halem H, Marks DL, Dong JZ, Glavas MM, Sinnayah P, et al. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes. 2013;62:490–7. https://doi.org/10.2337/db12-0598.
Yukioka H. A potent and selective neuropeptide Y Y5-receptor antagonist, S-2367, as an anti-obesity agent. Nihon yakurigaku zasshi Folia pharmacologica Japonica. 2010;136:270–4.
George M, Rajaram M, Shanmugam E. New and emerging drug molecules against obesity. J Cardiovasc Pharmacol Ther. 2014;19:65–76. https://doi.org/10.1177/1074248413501017.
Powell AG, Apovian CM, Aronne LJ. New drug targets for the treatment of obesity. Clin Pharmacol Ther. 2011;90:40–51. https://doi.org/10.1038/clpt.2011.82.
Gadde KM, Yonish GM, Foust MS, Wagner HR. Combination therapy of zonisamide and bupropion for weight reduction in obese women: a preliminary, randomized, open-label study. J Clin Psychiatry. 2007;68:1226–9.
Release, O. P. I. P. Orexigen (R) Therapeutics phase 2b trial for Empatic(TM) meets primary efficacy endpoint demonstrating significantly greater weight loss versus comparators in obese patients. http://ir.orexigen.com/phoenix.zhtml%3Fc=207034%26p=irol-newsArticle%26ID=1336796%26highlight= Accessed September 13, 2017.
Guide to receptors and channels (GRAC), 4th Edition. Br J Pharmacol 2009;158 Suppl 1, S1–254, doi:https://doi.org/10.1111/j.1476-5381.2009.00499.x.
Jarbe TU, DiPatrizio NV. Delta9-THC induced hyperphagia and tolerance assessment: interactions between the CB1 receptor agonist delta9-THC and the CB1 receptor antagonist SR-141716 (rimonabant) in rats. Behav Pharmacol. 2005;16:373–80.
Salamone JD, McLaughlin PJ, Sink K, Makriyannis A, Parker LA. Cannabinoid CB1 receptor inverse agonists and neutral antagonists: effects on food intake, food-reinforced behavior and food aversions. Physiol Behav. 2007;91:383–8. https://doi.org/10.1016/j.physbeh.2007.04.013.
Colombo G, Agabio R, Diaz G, Lobina C, Reali R, Gessa GL. Appetite suppression and weight loss after the cannabinoid antagonist SR 141716. Life Sci. 1998;63:Pl113–7.
Vickers SP, Webster LJ, Wyatt A, Dourish CT, Kennett GA. Preferential effects of the cannabinoid CB1 receptor antagonist, SR 141716, on food intake and body weight gain of obese (fa/fa) compared to lean Zucker rats. Psychopharmacology. 2003;167:103–11. https://doi.org/10.1007/s00213-002-1384-8.
Hildebrandt AL, Kelly-Sullivan DM, Black SC. Antiobesity effects of chronic cannabinoid CB1 receptor antagonist treatment in diet-induced obese mice. Eur J Pharmacol. 2003;462:125–32.
European Medicines Agency: European Public Assessment Report (EPAR) Acomplia. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000666/WC500021282.pdf Accessed September 27, 2017 (2007).
Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet. 2007;370:1706–13. https://doi.org/10.1016/S0140-6736(07)61721-8.
Mitchell PB, Morris MJ. Depression and anxiety with rimonabant. Lancet. 2007;370:1671–2. https://doi.org/10.1016/S0140-6736(07)61705-X.
• Blundell J, et al. Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes Obes Metab. 2017;19:1242–51. https://doi.org/10.1111/dom.12932. The aim of this trial was to investigate the mechanism of action of body weight loss with semaglutide, a new drug which has shown significant weight loss potential of almost 16% in clinical trials.
Aroda VR, Bain SC, Cariou B, Piletič M, Rose L, Axelsen M, et al. Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. Lancet Diabetes Endocrinol. 2017;5:355–66. https://doi.org/10.1016/S2213-8587(17)30085-2.
Seino Y, Terauchi Y, Osonoi T, Yabe D, Abe N, Nishida T, et al. Safety and efficacy of semaglutide once weekly versus sitagliptin once daily, both as monotherapy in Japanese subjects with type 2 diabetes. Diabetes Obes Metab. 2017;20:378–88. https://doi.org/10.1111/dom.13082.
Ahren B, et al. Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial. Lancet Diabetes Endocrinol. 2017;5:341–54. https://doi.org/10.1016/S2213-8587(17)30092-X.
Lutz TA. Control of food intake and energy expenditure by amylin-therapeutic implications. Int J Obes (Lond). 2009;33(Suppl 1):S24–7. https://doi.org/10.1038/ijo.2009.13.
Wilson JL, Enriori PJ. A talk between fat tissue, gut, pancreas and brain to control body weight. Mol Cell Endocrinol. 2015;418(Pt 2):108–19. https://doi.org/10.1016/j.mce.2015.08.022.
Bailey RJ, Walker CS, Ferner AH, Loomes KM, Prijic G, Halim A, et al. Pharmacological characterization of rat amylin receptors: implications for the identification of amylin receptor subtypes. Br J Pharmacol. 2012;166:151–67. https://doi.org/10.1111/j.1476-5381.2011.01717.x.
Mack CM, Soares CJ, Wilson JK, Athanacio JR, Turek VF, Trevaskis JL, et al. Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight. Int J Obes. 2010;34:385–95. https://doi.org/10.1038/ijo.2009.238.
Mack CM, Smith PA, Athanacio JR, Xu K, Wilson JK, Reynolds JM, et al. Glucoregulatory effects and prolonged duration of action of davalintide: a novel amylinomimetic peptide. Diabetes Obes Metab. 2011;13:1105–13. https://doi.org/10.1111/j.1463-1326.2011.01465.x.
Gydesen S, Andreassen KV, Hjuler ST, Christensen JM, Karsdal MA, Henriksen K. KBP-088, a novel DACRA with prolonged receptor activation, is superior to davalintide in terms of efficacy on body weight. Am J Physiol Endocrinol Metab. 2016;310:E821–7. https://doi.org/10.1152/ajpendo.00514.2015.
Hjuler ST, Andreassen KV, Gydesen S, Karsdal MA, Henriksen K. KBP-042 improves bodyweight and glucose homeostasis with indices of increased insulin sensitivity irrespective of route of administration. Eur J Pharmacol. 2015;762:229–38. https://doi.org/10.1016/j.ejphar.2015.05.051.
Hjuler ST, Gydesen S, Andreassen KV, Karsdal MA, Henriksen K. The dual amylin- and calcitonin-receptor agonist KBP-042 works as adjunct to metformin on fasting hyperglycemia and HbA1c in a rat model of type 2 diabetes. J Pharmacol Exp Ther. 2017;362:24–30. https://doi.org/10.1124/jpet.117.241281.
Hjuler ST, et al. The dual amylin- and calcitonin-receptor agonist KBP-042 increases insulin sensitivity and induces weight loss in rats with obesity. Obesity (Silver Spring). 2016;24:1712–22. https://doi.org/10.1002/oby.21563.
Norregaard PK, et al. A novel GIP analogue, ZP4165, enhances glucagon-like peptide-1-induced body weight loss and improves glycaemic control in rodents. Diabetes Obes Metab. 2017;20:60–8. https://doi.org/10.1111/dom.13034.
Parker JA, McCullough KA, Field BCT, Minnion JS, Martin NM, Ghatei MA, et al. Glucagon and GLP-1 inhibit food intake and increase c-fos expression in similar appetite regulating centres in the brainstem and amygdala. Int J Obes. 2013;37:1391–8. https://doi.org/10.1038/ijo.2012.227.
Pocai A. Action and therapeutic potential of oxyntomodulin. Mol Metab. 2014;3:241–51. https://doi.org/10.1016/j.molmet.2013.12.001.
Cohen MA, Ellis SM, le Roux CW, Batterham RL, Park A, Patterson M, et al. Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab. 2003;88:4696–701. https://doi.org/10.1210/jc.2003-030421.
Wynne K, Park AJ, Small CJ, Patterson M, Ellis SM, Murphy KG, et al. Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial. Diabetes. 2005;54:2390–5.
R&D Pipeline. https://www.novonordisk.com/rnd/rd-pipeline.html Novo Nordisk Accessed August 28, 2017 (2017).
Steinert RE, Feinle-Bisset C, Asarian L, Horowitz M, Beglinger C, Geary N. Ghrelin, CCK, GLP-1, and PYY(3-36): secretory controls and physiological roles in eating and glycemia in health, obesity, and after RYGB. Physiol Rev. 2017;97:411–63. https://doi.org/10.1152/physrev.00031.2014.
Murphy KG, Bloom SR. Gut hormones and the regulation of energy homeostasis. Nature. 2006;444:854–9. https://doi.org/10.1038/nature05484.
Batterham RL, Cohen MA, Ellis SM, le Roux CW, Withers DJ, Frost GS, et al. Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med. 2003;349:941–8. https://doi.org/10.1056/NEJMoa030204.
Troke RC, Tan TM, Bloom SR. The future role of gut hormones in the treatment of obesity. Ther Adv Chronic Dis. 2014;5:4–14. https://doi.org/10.1177/2040622313506730.
van der Klaauw AA, et al. High protein intake stimulates postprandial GLP1 and PYY release. Obesity (Silver Spring). 2013;21:1602–7. https://doi.org/10.1002/oby.20154.
Meguid MM, Glade MJ, Middleton FA. Weight regain after Roux-en-Y: a significant 20% complication related to PYY. Nutrition. 2008;24:832–42. https://doi.org/10.1016/j.nut.2008.06.027.
Lluis F, Fujimura M, Gómez G, Salvá JA, Greeley GH Jr, Thompson JC. Cellular localization, half-life, and secretion of peptide YY. Rev Esp Fisiol. 1989;45:377–84.
Zac-Varghese S, De Silva A, Bloom SR. Translational studies on PYY as a novel target in obesity. Curr Opin Pharmacol. 2011;11:582–5. https://doi.org/10.1016/j.coph.2011.10.001.
•• Tchang BG, Shukla AP, Aronne LJ. Metreleptin and generalized lipodystrophy and evolving therapeutic perspectives. Expert Opin Biol Ther. 2015;15:1061–75. https://doi.org/10.1517/14712598.2015.1052789. This paper covers the physiology of leptin, pharmacological properties of recombinant metreleptin, and its efficacy in the treatment of generalized lipodystrophy.
Akinci G, Akinci B. Metreleptin treatment in patients with non-HIV associated lipodystrophy. Recent patents on endocrine, metabolic & immune drug discovery. 2015;9:74–8.
Chan JL, et al. Clinical effects of long-term metreleptin treatment in patients with lipodystrophy. Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2011;17:922–32. https://doi.org/10.4158/ep11229.or.
• Brown RJ, et al. Effects of metreleptin in pediatric patients with lipodystrophy. J Clin Endocrinol Metab. 2017;102:1511–9. https://doi.org/10.1210/jc.2016-3628. Metreleptin also has important implications in children with lipodsytrophy and low levels of leptin, leading to improved metabolic abnormalities.
Meehan CA, Cochran E, Kassai A, Brown RJ, Gorden P. Metreleptin for injection to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy. Expert Rev Clin Pharmacol. 2016;9:59–68. https://doi.org/10.1586/17512433.2016.1096772.
Chou K, Perry CM. Metreleptin: first global approval. Drugs. 2013;73:989–97. https://doi.org/10.1007/s40265-013-0074-7.
Chan JL, Koda J, Heilig JS, Cochran EK, Gorden P, Oral EA, et al. Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy. Clin Endocrinol. 2016;85:137–49. https://doi.org/10.1111/cen.12980.
Myalept [package insert]. Amylin Pharmaceuticals https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125390s000lbl.pdf Acccessed September 5, 2017 (2014).
Lutz TA. Pancreatic amylin as a centrally acting satiating hormone. Curr Drug Targets. 2005;6:181–9.
Singh-Franco D, Perez A, Harrington C. The effect of pramlintide acetate on glycemic control and weight in patients with type 2 diabetes mellitus and in obese patients without diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2011;13:169–80. https://doi.org/10.1111/j.1463-1326.2010.01337.x.
Chan JL, Roth JD, Weyer C. It takes two to tango: combined amylin/leptin agonism as a potential approach to obesity drug development. J Investig Med: Off Publ Am Fed Clin Res. 2009;57:777–83. https://doi.org/10.2310/JIM.0b013e3181b91911.
Ravussin E, et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity (Silver Spring, Md.). 2009;17:1736–43. https://doi.org/10.1038/oby.2009.184.
Chun E, Han CK, Yoon JH, Sim TB, Kim YK, Lee KY. Novel inhibitors targeted to methionine aminopeptidase 2 (MetAP2) strongly inhibit the growth of cancers in xenografted nude model. Int J Cancer. 2005;114:124–30. https://doi.org/10.1002/ijc.20687.
Kim EJ, Shin WH. General pharmacology of CKD-732, a new anticancer agent: effects on central nervous, cardiovascular, and respiratory system. Biol Pharm Bull. 2005;28:217–23.
Howland RH. Aspergillus, angiogenesis, and obesity: the story behind beloranib. J Psychosoc Nurs Ment Health Serv. 2015;53:13–6. https://doi.org/10.3928/02793695-20150219-01.
Hughes TE, et al. Ascending dose-controlled trial of beloranib, a novel obesity treatment for safety, tolerability, and weight loss in obese women. Obesity (Silver Spring). 2013;21:1782–8. https://doi.org/10.1002/oby.20356.
Kim DD, Krishnarajah J, Lillioja S, de Looze F, Marjason J, Proietto J, et al. Efficacy and safety of beloranib for weight loss in obese adults: a randomized controlled trial. Diabetes Obes Metab. 2015;17:566–72. https://doi.org/10.1111/dom.12457.
Elfers CT, Roth CL. Robust reductions of excess weight and hyperphagia by beloranib in rat models of genetic and hypothalamic obesity. Endocrinology. 2017;158:41–55. https://doi.org/10.1210/en.2016-1665.
The Boston Globe: Zafgen drug halted after second patient dies. https://www.bostonglobe.com/business/2015/12/03/fda-orders-zafgen-halt-clinical-trial-for-obesity-drug/PwGxnqvLoIYpXZN59hPT6M/story.html Accessed September 27, 2017 (2015).
Yamada Y, Kato T, Ogino H, Ashina S, Kato K. Cetilistat (ATL-962), a novel pancreatic lipase inhibitor, ameliorates body weight gain and improves lipid profiles in rats. Horm Metab Res. 2008;40:539–43. https://doi.org/10.1055/s-2008-1076699.
Kopelman P, Bryson A, Hickling R, Rissanen A, Rossner S, Toubro S, et al. Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients. Int J Obes. 2007;31:494–9. https://doi.org/10.1038/sj.ijo.0803446.
Kopelman P, et al. Weight loss, HbA1c reduction, and tolerability of cetilistat in a randomized, placebo-controlled phase 2 trial in obese diabetics: comparison with orlistat (Xenical). Obesity (Silver Spring). 2010;18:108–15. https://doi.org/10.1038/oby.2009.155.
Hansen HH, Jensen MM, Overgaard A, Weikop P, Mikkelsen JD. Tesofensine induces appetite suppression and weight loss with reversal of low forebrain dopamine levels in the diet-induced obese rat. Pharmacol Biochem Behav. 2013;110:265–71. https://doi.org/10.1016/j.pbb.2013.07.018.
Astrup A, Madsbad S, Breum L, Jensen TJ, Kroustrup JP, Larsen TM. Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1906–13. https://doi.org/10.1016/S0140-6736(08)61525-1.
Doggrell SS. Tesofensine—a novel potent weight loss medicine. Evaluation of: Astrup A, Breum L, Jensen TJ, Kroustrup JP, Larsen TM. Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet 2008;372:1906-13. Expert Opin Investig Drugs. 2009;18:1043–6. https://doi.org/10.1517/13543780902967632.
Giralt M, Gavalda-Navarro A, Villarroya F. Fibroblast growth factor-21, energy balance and obesity. Mol Cell Endocrinol. 2015;418(Pt 1):66–73. https://doi.org/10.1016/j.mce.2015.09.018.
Fisher FM, Maratos-Flier E. Understanding the physiology of FGF21. Annu Rev Physiol. 2016;78:223–41. https://doi.org/10.1146/annurev-physiol-021115-105339.
Badman MK, Koester A, Flier JS, Kharitonenkov A, Maratos-Flier E. Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis. Endocrinology. 2009;150:4931–40. https://doi.org/10.1210/en.2009-0532.
Domouzoglou EM, Maratos-Flier E. Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis. Am J Clin Nutr. 2011;93:901s–905. https://doi.org/10.3945/ajcn.110.001941.
Cuevas-Ramos D & Aguilar-Salinas CA Modulation of energy balance by fibroblast growth factor 21. Horm Mol Biol Clin Inv 2016, 30, doi:https://doi.org/10.1515/hmbci-2016-0023.
Gomez-Samano MA, et al. Fibroblast growth factor 21 and its novel association with oxidative stress. Redox Biol. 2017;11:335–41. https://doi.org/10.1016/j.redox.2016.12.024.
Fisher FM, et al. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes. 2010;59:2781–9. https://doi.org/10.2337/db10-0193.
Altabas V, Zjacic-Rotkvic V. Anti-ghrelin antibodies in appetite suppression: recent advances in obesity pharmacotherapy. Immunotargets Ther. 2015;4:123–30. https://doi.org/10.2147/ITT.S60398.
Colon-Gonzalez F, Kim GW, Lin JE, Valentino MA, Waldman SA. Obesity pharmacotherapy: what is next? Mol Asp Med. 2013;34:71–83. https://doi.org/10.1016/j.mam.2012.10.005.
Takagi K, Legrand R, Asakawa A, Amitani H, François M, Tennoune N, et al. Anti-ghrelin immunoglobulins modulate ghrelin stability and its orexigenic effect in obese mice and humans. Nat Commun. 2013;4:2685. https://doi.org/10.1038/ncomms3685.
Monteiro MP. Obesity vaccines. Hum Vaccin Immunother. 2014;10:887–95.
Haffer KN. Effects of novel vaccines on weight loss in diet-induced-obese (DIO) mice. J Anim Sci Biotechnol. 2012;3:21. https://doi.org/10.1186/2049-1891-3-21.
Yamada T, Hara K, Kadowaki T. Association of adenovirus 36 infection with obesity and metabolic markers in humans: a meta-analysis of observational studies. PLoS One. 2012;7:e42031. https://doi.org/10.1371/journal.pone.0042031.
• Na HN, Kim H, Nam JH. Prophylactic and therapeutic vaccines for obesity. Clin Exp Vaccine Res. 2014;3:37–41. https://doi.org/10.7774/cevr.2014.3.1.37. This review describes the ongoing development of therapeutic vaccines for the prevention of obesity, and the possibility of using inactivated adenovirus-36 as a vaccine and anti-obesity agent.
Na HN, Nam JH. Proof-of-concept for a virus-induced obesity vaccine; vaccination against the obesity agent adenovirus 36. Int J Obes. 2014;38:1470–4. https://doi.org/10.1038/ijo.2014.41.
Hill JO. Understanding and addressing the epidemic of obesity: an energy balance perspective. Endocr Rev. 2006;27:750–61. https://doi.org/10.1210/er.2006-0032.
Cone RD. Studies on the physiological functions of the melanocortin system. Endocr Rev. 2006;27:736–49. https://doi.org/10.1210/er.2006-0034.
Cone RD. Anatomy and regulation of the central melanocortin system. Nat Neurosci. 2005;8:571–8. https://doi.org/10.1038/nn1455.
Rossi M, Kim MS, Morgan DGA, Small CJ, Edwards CMB, Sunter D, et al. A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Endocrinology. 1998;139:4428–31. https://doi.org/10.1210/endo.139.10.6332.
Tolle V, Low MJ. In vivo evidence for inverse agonism of Agouti-related peptide in the central nervous system of proopiomelanocortin-deficient mice. Diabetes. 2008;57:86–94. https://doi.org/10.2337/db07-0733.
Kumar KG, Sutton GM, Dong JZ, Roubert P, Plas P, Halem HA, et al. Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R- and MC4R-deficient C57BL/6J mice. Peptides. 2009;30:1892–900. https://doi.org/10.1016/j.peptides.2009.07.012.
• Anderson EJ, et al. 60 YEARS OF POMC: regulation of feeding and energy homeostasis by alpha-MSH. J Mol Endocrinol. 2016;56:T157–74. https://doi.org/10.1530/JME-16-0014. This review discusses the history of POMC mRNA and melanocortin peptides as well as the latest work attempting to unravel feeding and regulation in the CNS by alpha-MSH.
Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. The cloning of a family of genes that encode the melanocortin receptors. Science. 1992;257:1248–51.
Krakoff J, Ma L, Kobes S, Knowler WC, Hanson RL, Bogardus C, et al. Lower metabolic rate in individuals heterozygous for either a frameshift or a functional missense MC4R variant. Diabetes. 2008;57:3267–72. https://doi.org/10.2337/db08-0577.
Girardet C, Butler AA. Neural melanocortin receptors in obesity and related metabolic disorders. Biochim Biophys Acta. 2014;1842:482–94. https://doi.org/10.1016/j.bbadis.2013.05.004.
Greenfield JR, Miller JW, Keogh JM, Henning E, Satterwhite JH, Cameron GS, et al. Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med. 2009;360:44–52. https://doi.org/10.1056/NEJMoa0803085.
Low MJ. Neuroendocrinology: new hormone treatment for obesity caused by POMC-deficiency. Nat Rev Endocrinol. 2016;12:627–8. https://doi.org/10.1038/nrendo.2016.156.
Kuhnen P, et al. Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N Engl J Med. 2016;375:240–6. https://doi.org/10.1056/NEJMoa1512693.
Rhythm Pharmaceuticals, Inc Product pipeline: peptide therapeutics for rare genetic deficiencies resulting in life-threatening metabolic disorders. http://www.rhythmtx.com/pipeline/product-pipeline/ Accessed August 28, 2017 (2017).
Double-blind, multi-center, randomized study to assess the efficacy and safety of velneperit (S-2367) and orlistat administered individually or combined with a reduced calorie diet (RCD) in obese subjects. https://clinicaltrials.gov/ct2/show/NCT01126970 Accessed September 13, 2017 (2011).
Wharton S, Serodio KJ. Next generation of weight management medications: implications for diabetes and CVD risk. Curr Cardiol Rep. 2015;17:35. https://doi.org/10.1007/s11886-015-0590-z.
Cluny NL, Vemuri VK, Chambers AP, Limebeer CL, Bedard H, Wood JT, et al. A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents. Br J Pharmacol. 2010;161:629–42. https://doi.org/10.1111/j.1476-5381.2010.00908.x.
Randall PA, Vemuri VK, Segovia KN, Torres EF, Hosmer S, Nunes EJ, et al. The novel cannabinoid CB1 antagonist AM6545 suppresses food intake and food-reinforced behavior. Pharmacol Biochem Behav. 2010;97:179–84. https://doi.org/10.1016/j.pbb.2010.07.021.
Kanoski SE, Hayes MR, Skibicka KP. GLP-1 and weight loss: unraveling the diverse neural circuitry. Am J Physiol Regul Integr Comp Physiol. 2016;310:R885–95. https://doi.org/10.1152/ajpregu.00520.2015.
Monami M, Nreu B, Scatena A, Cresci B, Andreozzi F, Sesti G, et al. Safety issues with glucagon-like peptide-1 receptor agonists (pancreatitis, pancreatic cancer and cholelithiasis): data from randomized controlled trials. Diabetes Obes Metab. 2017;19:1233–41. https://doi.org/10.1111/dom.12926.
Boess F, Bertinetti-Lapatki C, Zoffmann S, George C, Pfister T, Roth A, et al. Effect of GLP1R agonists taspoglutide and liraglutide on primary thyroid C-cells from rodent and man. J Mol Endocrinol. 2013;50:325–36. https://doi.org/10.1530/JME-12-0186.
Serge Jabbour, T. R. P., Julio Rosenstock, Marie-Louise Hartoft-Nielson, Oluf Kristian Hojbjerg Hansen, and Melanie Davies. Abract OR15-3 Robust dose-dependent glucose lowering and body weight (BW) reductions with the novel oral formulation of semaglutide in patients with early type 2 diabetes (T2D). Endocrine Society 2016 https://endo.confex.com/endo/2016endo/webprogram/Paper25706.html (April 2, 2016).
Fosgerau K, Hoffmann T. Peptide therapeutics: current status and future directions. Drug Discov Today. 2015;20:122–8. https://doi.org/10.1016/j.drudis.2014.10.003.
Seino Y, Fukushima M, Yabe D. GIP and GLP-1, the two incretin hormones: similarities and differences. J Diabetes Investig. 2010;1:8–23. https://doi.org/10.1111/j.2040-1124.2010.00022.x.
Christensen M, Vedtofte L, Holst JJ, Vilsboll T, Knop FK. Glucose-dependent insulinotropic polypeptide: a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans. Diabetes. 2011;60:3103–9. https://doi.org/10.2337/db11-0979.
Hansen MSS, Tencerova M, Frolich J, Kassem M, Frost M. Effects of gastric inhibitory polypeptide, glucagon-like peptide-1 and glucagon-like peptide-1 receptor agonists on bone cell metabolism. Basic Clin Pharmacol Toxicol. 2017;122:25–37. https://doi.org/10.1111/bcpt.12850.
Elliott RM, Morgan LM, Tredger JA, Deacon S, Wright J, Marks V. Glucagon-like peptide-1 (7-36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h secretion patterns. J Endocrinol. 1993;138:159–66.
Yip RG, Boylan MO, Kieffer TJ, Wolfe MM. Functional GIP receptors are present on adipocytes. Endocrinology. 1998;139:4004–7. https://doi.org/10.1210/endo.139.9.6288.
Knapper JM, Puddicombe SM, Morgan LM, Fletcher JM. Investigations into the actions of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1(7-36)amide on lipoprotein lipase activity in explants of rat adipose tissue. J Nutr. 1995;125:183–8.
Paschetta E, Hvalryg M, Musso G. Glucose-dependent insulinotropic polypeptide: from pathophysiology to therapeutic opportunities in obesity-associated disorders. Obes Rev. 2011;12:813–28. https://doi.org/10.1111/j.1467-789X.2011.00897.x.
Miyawaki K, Yamada Y, Ban N, Ihara Y, Tsukiyama K, Zhou H, et al. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med. 2002;8:738–42. https://doi.org/10.1038/nm727.
Holst JJ. Gut hormones as pharmaceuticals. From enteroglucagon to GLP-1 and GLP-2. Regul Pept. 2000;93:45–51.
Jiang G, Zhang BB. Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab. 2003;284:E671–8. https://doi.org/10.1152/ajpendo.00492.2002.
Schulman JL, Carleton JL, Whitney G, Whitehorn JC. Effect of glucagon on food intake and body weight in man. J Appl Physiol. 1957;11:419–21.
Henderson SJ, Konkar A, Hornigold DC, Trevaskis JL, Jackson R, Fritsch Fredin M, et al. Robust anti-obesity and metabolic effects of a dual GLP-1/glucagon receptor peptide agonist in rodents and non-human primates. Diabetes Obes Metab. 2016;18:1176–90. https://doi.org/10.1111/dom.12735.
•• Farooqi IS, O'Rahilly S. 20 years of leptin: human disorders of leptin action. J Endocrinol. 2014;223:T63–70. https://doi.org/10.1530/joe-14-0480. The discovery of leptin has provided a robust framework to build our current understanding of energy regulation. This review describes how the identification of humans with mutations in leptin or leptin receptor has provided insight into leptin-responsive pathways controling eating behavior
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Gitanjali Srivastava has received compensation from Rhythm Pharmaceuticals for service on an advisory board.
Caroline Apovian has received research funding through grants from Orexigen, Aspire Bariatrics, GI Dynamics, MYOS, Takeda, Gelesis, Vela Foundation, Dr. Robert C. and Veronica Atkins Foundation, Coherence Lab, Energesis, Patient-Centered Outcomes Research Institute (PCORI), and the National Institutes of Health (NIH); has received compensation from Nutrisystem, Zafgen, Sanofi-Aventis, Orexigen, Novo Nordisk, GI Dynamics, Takeda, Scientific Intake, Gelesis, Merck, and Johnson & Johnson for service on advisory boards; and owns stock in Science-Smart LLC.
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GS reports personal fees from Rhythm Pharmaceuticals, outside the submitted work. Dr. Apovian reports personal fees from Nutrisystem, personal fees from Zafgen, personal fees from Sanofi-Aventis, grants and personal fees from Orexigen, personal fees from NovoNordisk, grants from Aspire Bariatrics, grants and personal fees from GI Dynamics, grants from Myos, grants and personal fees from Takeda, personal fees from Scientific Intake, grants and personal fees from Gelesis, other from Science-Smart LLC, personal fees from Merck, personal fees from Johnson & Johnson, grants from Vela Foundation, grants from Dr. Robert C. and Veronica Atkins Foundation, grants from Coherence Lab, grants from Energesis, grants from PCORI, and grants from NIH, outside the submitted work. However, the authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript.
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Srivastava, G., Apovian, C. Future Pharmacotherapy for Obesity: New Anti-obesity Drugs on the Horizon. Curr Obes Rep 7, 147–161 (2018). https://doi.org/10.1007/s13679-018-0300-4
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DOI: https://doi.org/10.1007/s13679-018-0300-4