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Unimolecular Polypharmacy for Treatment of Diabetes and Obesity

2016; Cell Press; Volume: 24; Issue: 1 Linguagem: Inglês

10.1016/j.cmet.2016.06.021

1932-7420

Matthias H. Tschöp, Brian Finan, Christoffer Clemmensen, Vasily M. Gelfanov, Diego Pérez–Tilve, Timo D. Müller, Richard D. DiMarchi,

Diet and metabolism studies

Many complex diseases have historically proven to be defiant to the best mono-therapeutic approaches. Several examples of combination therapies have largely overcome such challenges, notably for the treatment of severe hypertension and tuberculosis. Obesity and its consequences, such as type 2 diabetes, have proven to be equally resistant to therapeutic approaches based on single medicines. Proper management of type 2 diabetes often requires adjunctive medications, and the recent registration of a few compound mixtures has set the precedent for combinatorial treatment of obesity. On the other hand, double or triple therapeutic combinations are more difficult to advance to regulatory approval than single molecules. More recently, several classes of novel unimolecular combination therapeutics have emerged with superior efficacy than currently prescribed options and pose the potential to reverse obesity and type 2 diabetes. Here, we summarize the discovery, pre-clinical validation, and first clinical test of such peptide hormone poly-agonist drug candidates. Many complex diseases have historically proven to be defiant to the best mono-therapeutic approaches. Several examples of combination therapies have largely overcome such challenges, notably for the treatment of severe hypertension and tuberculosis. Obesity and its consequences, such as type 2 diabetes, have proven to be equally resistant to therapeutic approaches based on single medicines. Proper management of type 2 diabetes often requires adjunctive medications, and the recent registration of a few compound mixtures has set the precedent for combinatorial treatment of obesity. On the other hand, double or triple therapeutic combinations are more difficult to advance to regulatory approval than single molecules. More recently, several classes of novel unimolecular combination therapeutics have emerged with superior efficacy than currently prescribed options and pose the potential to reverse obesity and type 2 diabetes. Here, we summarize the discovery, pre-clinical validation, and first clinical test of such peptide hormone poly-agonist drug candidates. According to the International Diabetes Federation (IDF), global diabetes prevalence is nearly 10% among adults, with deaths attributable to diabetes anticipated to rise by >50% over the next decade. Type 2 diabetes (T2D) accounts for more than 90% of the disease (Guariguata et al., 2014Guariguata L. Whiting D.R. Hambleton I. Beagley J. Linnenkamp U. Shaw J.E. Global estimates of diabetes prevalence for 2013 and projections for 2035.Diabetes Res. Clin. Pract. 2014; 103: 137-149Abstract Full Text Full Text PDF PubMed Scopus (3067) Google Scholar). Although not everybody with excess body weight develops T2D, and not everyone suffering from T2D is overweight, the increased T2D prevalence is predominantly enhanced by excess body weight, with two billion adults and forty million children currently overweight or obese, according to estimates from the World Health Organization (WHO). As disease incidence steadily grew throughout the last three decades, research efforts to effectively address it intensified. This period is characterized by unprecedented advances in the understanding of the cellular processes, molecular targets, and neuroendocrine signals controlling metabolism. Nonetheless, initial drug candidates for obesity have limited efficacy and/or cause unacceptable adverse effects (Adan, 2013Adan R.A. Mechanisms underlying current and future anti-obesity drugs.Trends Neurosci. 2013; 36: 133-140Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, Rodgers et al., 2012Rodgers R.J. Tschöp M.H. Wilding J.P. Anti-obesity drugs: past, present and future.Dis. Model. Mech. 2012; 5: 621-626Crossref PubMed Scopus (305) Google Scholar, Scheen and Van Gaal, 2014Scheen A.J. Van Gaal L.F. Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes.Lancet Diabetes Endocrinol. 2014; 2: 911-922Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). We propose that synergistic integration of multiple hormones of differentiated mechanisms to single molecules may conquer the endogenous systems that defend increased body weight and have limited the effectiveness in agents employing a single mechanism of action. Energy balance is central to survival and as such it is intricately regulated. In a relative sense, the long-standing strategy to drive weight loss has been conceptually simple and constituted by increased caloric use (energy expenditure) or reduced caloric consumption (energy restriction). More than a century ago, thyroid extracts were recognized for their weight-lowering properties by increasing caloric burn. Indeed, the first generation of weight-loss medications of the 1950s and 1960s, which included sympathomimetics, amphetamines, and chemical uncouplers, lowered body weight by increasing metabolic rate. However, sustained use of such agents resulted in severe adverse cardiovascular effects that terminated their use. In contrast, agents targeting reduction in food intake, including serotonergics, dopaminergics, and endocannabinoid antagonists have largely been safer, but of relatively lesser efficacy when compared to the aforementioned thermogenic drugs. However, these anorectic agents are not without their own limitations, including prominent cardiovascular effects and psychiatric symptoms resulting from action within the CNS. More recently, research in the fields of metabolism and neuroscience has revealed a complex entwinement of satiety and thermogenic signaling cues that are reciprocally coordinated between peripheral tissues and metabolic control centers in the CNS. These molecular findings have paved the way for drug discovery in the modern era. The identification of the adipose tissue-derived hormone leptin 20 years ago, and its unprecedented effectiveness to induce satiety and increase energy expenditure (Farooqi et al., 1999Farooqi I.S. Jebb S.A. Langmack G. Lawrence E. Cheetham C.H. Prentice A.M. Hughes I.A. McCamish M.A. O’Rahilly S. Effects of recombinant leptin therapy in a child with congenital leptin deficiency.N. Engl. J. Med. 1999; 341: 879-884Crossref PubMed Scopus (1533) Google Scholar, Halaas et al., 1995Halaas J.L. Gajiwala K.S. Maffei M. Cohen S.L. Chait B.T. Rabinowitz D. Lallone R.L. Burley S.K. Friedman J.M. 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Nonetheless, the discovery of leptin profoundly transformed modern obesity research and promoted interest for circulating signals that, similar to leptin, simultaneously target brain circuits governing feeding and cellular processes that control energy metabolism in peripheral tissues (Bates et al., 2003Bates S.H. Stearns W.H. Dundon T.A. Schubert M. Tso A.W. Wang Y. Banks A.S. Lavery H.J. Haq A.K. Maratos-Flier E. et al.STAT3 signalling is required for leptin regulation of energy balance but not reproduction.Nature. 2003; 421: 856-859Crossref PubMed Scopus (824) Google Scholar, Elias et al., 1999Elias C.F. Aschkenasi C. Lee C. Kelly J. Ahima R.S. Bjorbaek C. Flier J.S. Saper C.B. Elmquist J.K. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area.Neuron. 1999; 23: 775-786Abstract Full Text Full Text PDF PubMed Scopus (771) Google Scholar, Schwartz et al., 1997Schwartz M.W. Seeley R.J. Woods S.C. Weigle D.S. Campfield L.A. Burn P. Baskin D.G. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus.Diabetes. 1997; 46: 2119-2123Crossref PubMed Google Scholar, Tschöp et al., 2000Tschöp M. Smiley D.L. Heiman M.L. Ghrelin induces adiposity in rodents.Nature. 2000; 407: 908-913Crossref PubMed Scopus (3383) Google Scholar). Genome-wide searches for associations between obesity and single-gene mutations confirmed a central role for the brain, as most known “obesity genes” appear to be expressed or function predominantly in the CNS (Locke et al., 2015Locke A.E. Kahali B. Berndt S.I. Justice A.E. Pers T.H. Day F.R. Powell C. Vedantam S. Buchkovich M.L. Yang J. et al.LifeLines Cohort StudyADIPOGen ConsortiumAGEN-BMI Working GroupCARDIOGRAMplusC4D ConsortiumCKDGen ConsortiumGLGCICBPMAGIC InvestigatorsMuTHER ConsortiumMIGen ConsortiumPAGE ConsortiumReproGen ConsortiumGENIE ConsortiumInternational Endogene ConsortiumGenetic studies of body mass index yield new insights for obesity biology.Nature. 2015; 518: 197-206Crossref PubMed Scopus (2645) Google Scholar). However, translation of these novel findings into effective therapies for obesity and T2D has proven difficult. Adverse effects often accompany metabolic benefits (Christensen et al., 2007Christensen R. Kristensen P.K. Bartels E.M. Bliddal H. Astrup A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials.Lancet. 2007; 370: 1706-1713Abstract Full Text Full Text PDF PubMed Scopus (870) Google Scholar, Ettinger et al., 2003Ettinger M.P. Littlejohn T.W. Schwartz S.L. Weiss S.R. McIlwain H.H. Heymsfield S.B. Bray G.A. Roberts W.G. Heyman E.R. 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Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials.BMJ. 2012; 344: d7771Crossref PubMed Scopus (651) Google Scholar). The few drugs that have been approved for the treatment of T2D offer a meaningful but limited impact on adiposity. These include inhibitors of sodium-glucose co-transporter 2 (SGLT2) (Barnett, 2013Barnett A.H. Impact of sodium glucose cotransporter 2 inhibitors on weight in patients with type 2 diabetes mellitus.Postgrad. Med. 2013; 125: 92-100Crossref PubMed Scopus (36) Google Scholar) and analogs of the incretin hormone glucagon-like peptide 1 (GLP-1) (Vilsbøll et al., 2012Vilsbøll T. Christensen M. Junker A.E. Knop F.K. Gluud L.L. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials.BMJ. 2012; 344: d7771Crossref PubMed Scopus (651) Google Scholar). Additionally, a few small-molecule drugs have recently gained approval for weight management, including selective serotonin receptor agonists (lorcaserin) and unique combinations of a sympathomimetic with an anticonvulsant (phentermine/topiramate), as well as an opioid antagonist with an antidepressant (naltrexone/bupropion). However, mean body weight reduction remains well below 10% compared to placebo-treated controls with all of these therapies, although a high dose of the GLP-1 analog liraglutide is starting to push prior limits in responsive patients (Pi-Sunyer et al., 2015Pi-Sunyer X. Astrup A. Fujioka K. Greenway F. Halpern A. Krempf M. Lau D.C. le Roux C.W. Violante Ortiz R. Jensen C.B. Wilding J.P. SCALE Obesity and Prediabetes NN8022-1839 Study GroupA randomized, controlled trial of 3.0 mg of liraglutide in weight management.N. Engl. J. Med. 2015; 373: 11-22Crossref PubMed Scopus (1049) Google Scholar). Although the goal of translating novel molecular discoveries in metabolic control to useful medicines is far from being attained, there is empirical evidence that effective targets do exist. The effectiveness of specific surgical procedures inducing weight loss and improved glycemic control in morbidly obese patients is inspirational. Procedures such as Roux-en-Y gastric bypass or vertical sleeve gastrectomy not only sizably reduce fat mass, but also resolve insulin resistance and T2D in most patients. Interestingly, improvements in glucose metabolism precede significant weight loss (Stefater et al., 2012Stefater M.A. Wilson-Pérez H.E. Chambers A.P. Sandoval D.A. Seeley R.J. All bariatric surgeries are not created equal: insights from mechanistic comparisons.Endocr. Rev. 2012; 33: 595-622Crossref PubMed Scopus (220) Google Scholar). These observations, along with mechanistic insights gained from bariatric surgery in animal models of obesity and insulin resistance, suggest that re-programming of neuroendocrine signals rather than changes in mechanical function of the gut (i.e., adjusted stomach size and/or impaired calorie absorption per se) are predominantly responsible for the substantial improvements in caloric, glucose, and lipid metabolism (Adams et al., 2012Adams T.D. Davidson L.E. Litwin S.E. Kolotkin R.L. LaMonte M.J. Pendleton R.C. Strong M.B. Vinik R. Wanner N.A. Hopkins P.N. et al.Health benefits of gastric bypass surgery after 6 years.JAMA. 2012; 308: 1122-1131Crossref PubMed Scopus (461) Google Scholar, Buchwald et al., 2009Buchwald H. Estok R. Fahrbach K. Banel D. Jensen M.D. Pories W.J. Bantle J.P. Sledge I. Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis.Am. J. 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Importance of small bowel peptides for the improved glucose metabolism 20 years after jejunoileal bypass for obesity.Obes. Surg. 1998; 8: 253-260Crossref PubMed Scopus (109) Google Scholar), peptide YY (PYY) (Chan et al., 2006Chan J.L. Mun E.C. Stoyneva V. Mantzoros C.S. Goldfine A.B. Peptide YY levels are elevated after gastric bypass surgery.Obesity (Silver Spring). 2006; 14: 194-198Crossref PubMed Scopus (88) Google Scholar), bile acids (Patti et al., 2009Patti M.E. Houten S.M. Bianco A.C. Bernier R. Larsen P.R. Holst J.J. Badman M.K. Maratos-Flier E. Mun E.C. Pihlajamaki J. et al.Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism.Obesity (Silver Spring). 2009; 17: 1671-1677Crossref PubMed Scopus (441) Google Scholar, Ryan et al., 2014Ryan K.K. Tremaroli V. Clemmensen C. Kovatcheva-Datchary P. Myronovych A. Karns R. Wilson-Pérez H.E. Sandoval D.A. Kohli R. Bäckhed F. Seeley R.J. FXR is a molecular target for the effects of vertical sleeve gastrectomy.Nature. 2014; 509: 183-188Crossref PubMed Scopus (684) Google Scholar), glucagon (Jørgensen et al., 2013Jørgensen N.B. Dirksen C. Bojsen-Møller K.N. Jacobsen S.H. Worm D. Hansen D.L. Kristiansen V.B. Naver L. Madsbad S. Holst J.J. Exaggerated glucagon-like peptide 1 response is important for improved β-cell function and glucose tolerance after Roux-en-Y gastric bypass in patients with type 2 diabetes.Diabetes. 2013; 62: 3044-3052Crossref PubMed Scopus (221) Google Scholar), ghrelin (Cummings et al., 2002Cummings D.E. Weigle D.S. Frayo R.S. Breen P.A. Ma M.K. Dellinger E.P. Purnell J.Q. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery.N. Engl. J. Med. 2002; 346: 1623-1630Crossref PubMed Scopus (1977) Google Scholar), and fibroblast growth factors (FGFs) (Jansen et al., 2011Jansen P.L. van Werven J. Aarts E. Berends F. Janssen I. Stoker J. Schaap F.G. Alterations of hormonally active fibroblast growth factors after Roux-en-Y gastric bypass surgery.Dig. Dis. 2011; 29: 48-51Crossref PubMed Scopus (110) Google Scholar), among many others. Proof for these adjusted endocrine responses, either in support or opposition to their singular, combined, causal, or consequential involvement in metabolic benefits of weight loss surgeries, remains the subject of ongoing investigations. Despite the metabolic complexity in body weight management, modern obesity research has made steady progress. Both behavioral and cellular processes relevant for body weight homeostasis and systemic metabolism appear to be continuously co-regulated by finite brain control centers, including specific neural circuits in the hypothalamus. Moreover, it now appears that the brain is just as involved in the pathogenesis of obesity and T2D as traditional target organs such as the pancreas, skeletal muscle, liver, and adipose tissue. History has taught us that direct pharmacological intervention of CNS neurotransmission is difficult to limit to just those brain circuits controlling body weight and metabolism, and therefore they are susceptible to severe adverse effects (Dietrich and Horvath, 2012Dietrich M.O. Horvath T.L. Limitations in anti-obesity drug development: the critical role of hunger-promoting neurons.Nat. Rev. Drug Discov. 2012; 11: 675-691Crossref PubMed Scopus (146) Google Scholar). Nevertheless, it seems plausible that a sustained readjustment of CNS control centers to normalize body weight and glucose metabolism of obese and diabetic patients might be safely achieved. Gastric bypass surgery may be precedent setting by instating a different neuroendocrine multi-signal code. Using “mother nature’s tool kit” of afferent hormones, pharmacological mimicry of this integrated and adjusted enteroendocrine response may offer an effective and relatively safe approach to modulate brain circuits controlling body weight and systemic metabolism through relays to relevant peripheral tissues. The overarching questions are how many of these hormonal activities must be manipulated simultaneously, and whether these patterns vary across multiple forms of human obesity. Ideally, the integration of multiple actions into single drugs lessens the regulatory challenge and minimizes the number of mixtures that might ultimately be required, while producing coordinated actions in target tissues that provoke synergistic effects. Nonetheless, physical combinations of two independent mono-agonists do present some advantages, most notably the flexibility in adjusting activity ratios. The seminal obstacle in the development of effective anti-obesity drugs is the fact that CNS control centers respond to decreased food intake by decreasing energy expenditure or, conversely, increasing appetite when confronted with elevated metabolism, as is the case with exercise. Therefore, combining a satiety-inducing hormone with a factor that promotes calorie burning into a single unimolecular entity should create a drug candidate of increased efficacy. This strategy seems more straightforward to assess in macromolecules, where size is not a limitation to achieving high potency and balanced pharmacology. Additionally, the action of large molecules is generally more restrictive than conventional small molecules, and subsequent drug metabolism is rarely a dose-limiting element to pharmacology. The starting point in our efforts to generate safe and potent poly-agonists for the treatment of obesity and T2D was GLP-1. The choice of GLP-1 was justified by a number of reasons. GLP-1 serves a role in the mediation of bariatric surgery benefits (Habegger et al., 2013aHabegger K.M. Kirchner H. Yi C.X. Heppner K.M. Sweeney D. Ottaway N. Holland J. Amburgy S. Raver C. Krishna R. et al.GLP-1R agonism enhances adjustable gastric banding in diet-induced obese rats.Diabetes. 2013; 62: 3261-3267Crossref PubMed Scopus (19) Google Scholar, Habegger et al., 2014Habegger K.M. Heppner K.M. Amburgy S.E. Ottaway N. Holland J. Raver C. Bartley E. Müller T.D. Pfluger P.T. Berger J. et al.GLP-1R responsiveness predicts individual gastric bypass efficacy on glucose tolerance in rats.Diabetes. 2014; 63: 505-513Crossref PubMed Scopus (37) Google Scholar, Salehi and D’Alessio, 2014Salehi M. D’Alessio D.A. Effects of glucagon like peptide-1 to mediate glycemic effects of weight loss surgery.Rev. Endocr. Metab. Disord. 2014; 15: 171-179Crossref PubMed Scopus (24) Google Scholar, Salehi et al., 2011Salehi M. Prigeon R.L. D’Alessio D.A. Gastric bypass surgery enhances glucagon-like peptide 1-stimulated postprandial insulin secretion in humans.Diabetes. 2011; 60: 2308-2314Crossref PubMed Scopus (250) Google Scholar). GLP-1 agonists target both the CNS and pancreas to promote satiety and insulin secretion, which has led to regulatory approval for several GLP-1-based therapies in the treatment of T2D. Currently prescribed GLP-1 mono-agonists provide a meaningful yet insufficient body weight loss in most obese patients, primarily through anorectic or satiation properties (Vilsbøll et al., 2012Vilsbøll T. Christensen M. Junker A.E. Knop F.K. Gluud L.L. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials.BMJ. 2012; 344: d7771Crossref PubMed Scopus (651) Google Scholar). Increasing the dose of most GLP-1 agonists enhances weight loss, as with high-dose liraglutide (Pi-Sunyer et al., 2015Pi-Sunyer X. Astrup A. Fujioka K. Greenway F. Halpern A. Krempf M. Lau D.C. le Roux C.W. Violante Ortiz R. Jensen C.B. Wilding J.P. SCALE Obesity and Prediabetes NN8022-1839 Study GroupA randomized, controlled trial of 3.0 mg of liraglutide in weight management.N. Engl. J. Med. 2015; 373: 11-22Crossref PubMed Scopus (1049) Google Scholar), but magnifies a dose-dependent increase in adverse gastrointestinal effects and acute tachycardia (Marino et al., 2014Marino A.B. Cole S.W. Nuzum D.S. Alternative dosing strategies for liraglutide in patients with type 2 diabetes mellitus.Am. J. Health Syst. Pharm. 2014; 71: 223-226Crossref PubMed Scopus (12) Google Scholar). Combining GLP-1 agonism with an independent thermogenic factor seems intuitively attractive to propel greater body weight loss. In addition, less reliance on GLP-1-mediated signaling to drive greater body weight loss can circumvent the adverse events that preclude the use of such mono-agonists at higher doses. In our search for a complementary component that promotes weight loss through biochemical and physiological mechanisms that are distinct from GLP-1, we were intrigued by reports from as early as the 1950s that detailed the chronic actions of the pancreatic hormone glucagon to increase lipolysis and thermogenesis (Davidson et al., 1957Davidson I.W. Salter J.M. Best C.H. Calorigenic action of glucagon.Nature. 1957; 180: 1124Crossref PubMed Scopus (33) Google Scholar, Joel, 1966Joel C.D. Stimulation of metabolism of rat brown adipose tissue by addition of lipolytic hormones in vitro.J. Biol. Chem. 1966; 241: 814-821Abstract Full Text PDF PubMed Google Scholar, Kuroshima and Yahata, 1979Kuroshima A. Yahata T. Thermogenic responses of brown adipocytes to noradrenaline and glucagon in heat-acclimated and cold-acclimated rats.Jpn. J. Physiol. 1979; 29: 683-690Crossref PubMed Scopus (85) Google Scholar). However, integrating glucagon action into agents directed to patients with impaired glycemic control was a radical idea, as common belief held that glucagon was part of the problem promoting T2D (Müller et al., 1970Müller W.A. Faloona G.R. Aguilar-Parada E. Unger R.H. Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion.N. Engl. J. Med. 1970; 283: 109-115Crossref PubMed Scopus (476) Google Scholar). The logic was one of “fighting fire with fire” at a molecular level, and to do so, GLP-1 agonism was pursued as a means to buffer against the inherent diabetogenic risk of unopposed glucagon pharmacology, but also to provide supplemental efficacy by an independent weight-lowering mechanism. A series of single-molecule glucagon receptor (GcgR)/GLP-1 receptor (GLP-1R) dual agonists were generated using glucagon as a template sequence to which chemical modifications were introduced. Extensive structure-activity relationship (SAR) profiling, as well as knowledge gained from chimeric peptides used to map receptor recognition epitopes (Hjorth et al., 1994Hjorth S.A. Adelhorst K. Pedersen B.B. Kirk O. Schwartz T.W. Glucagon and glucagon-like peptide 1: selective receptor recognition via distinct peptide epitopes.J. Biol. Chem. 1994; 269: 30121-30124Abstract Full Text PDF PubMed Google Scholar), resulted in a hybrid peptide of mixed glucagon and GLP-1 sequence that was structurally supplemented to prevent proteolysis and delay metabolic clearance (Figure 1) (Day et al., 2009Day J.W. Ottaway N. Patterson J.T. Gelfanov V. Smiley D. Gidda J. Findeisen H. Bruemmer D. Drucker D.J. Chaudhary N. et al.A new glucagon and GLP-1 co-agonist eliminates obesity in rodents.Nat. Chem. Biol. 2009; 5: 749-757Crossref PubMed Scopus (437) Google Scholar). The resulting peptides were of comparable structure to glucagon and GLP-1, but of balanced agonism at each receptor and comparable inherent potency to native hormones. This mixed agonist sizably lowered body weight of diet-induced obese mice (Clemmensen et al., 2014Clemmensen C. Chabenne J. Finan B. Sullivan L. Fischer K. Küchler D. Sehrer L. Ograjsek T. Hofmann S.M. Schriever S.C. et al.GLP-1/glucagon coagonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet.Diabetes. 2014; 63: 1422-1427Crossref PubMed Scopus (104) Google Scholar, Day et al., 2009Day J.W. Ottaway N. Patterson J.T. Gelfanov V. Smiley D. Gidda J. Findeisen H. Bruemmer D. Drucker D.J. Chaudhary N. et al.A new glucagon and GLP-1 co-agonist eliminates obesity in rodents.Nat. Chem. Biol. 2009; 5: 749-757Crossref PubMed Scopus (437) Google Scholar, Day et al., 2012Day J.W. Gelfanov V. Smiley D. Carrington P.E. Eiermann G. Chicchi G. Erion M.D. Gidda J. Thornberry N.A. Tschöp M.H. et al.Optimization of co-agonism at GLP-1 and glucagon receptors to safely maximize weight reduction in DIO-rodents.Biopolymers. 2012; 98: 443-450Crossref PubMed Scopus (92) Google Scholar), and the magnitude of weight loss was dependent on the percentage of glucagon activity. The body weight loss is almost entirely due to decreased body fat mass, and there was no appearance of hyperglycemia until the GLP-1 activity was reduced to a level that was appreciably less than glucagon. In opposition to the prevailing logic, these GcgR/GLP-1R dual agonists safely improved glucose tolerance, hyperinsulinemia, hepatic steatosis, and body weight to a greater extent than possible with either mono-agonist in preclinical models of obesity and those with hyperglycemia. Genetic loss-of-function studies using GLP-1R knockout (GLP-1R−/−) mice proved that the superior performance of these dual GcgR/GLP-1R co-agonists was indeed dependent on mixed pharmacology and not simply a result of enhanced GLP-1 potency. Based on in vitro data, it had also been suggested that oxyntomodulin, another gut peptide involved in metabolic control (Dakin et al., 2001Dakin C.L. Gunn I. Small C.J. Edwards C.M. Hay D.L. Smith D.M. Ghatei M.A. Bloom S.R. Oxyntomodulin inhibits food intake in the rat.Endocrinology. 2001; 142: 4244-4250Crossref P