Heymsfield, S. B. & Wadden, T. A. Mechanisms, pathophysiology, and management of obesity. N. Engl. J. Med. 376, 254–266 (2017).
Booth, F. W., Roberts, C. K. & Laye, M. J. Lack of exercise is a major cause of chronic diseases. Compr. Physiol. 2, 1143–1211 (2012).
Tsai, A. G., Williamson, D. F. & Glick, H. A. Direct medical cost of overweight and obesity in the USA: a quantitative systematic review. Obes. Rev. 12, 50–61 (2011).
Yach, D., Stuckler, D. & Brownell, K. D. Epidemiologic and economic consequences of the global epidemics of obesity and diabetes. Nat. Med. 12, 62–66 (2006).
Gautron, L., Elmquist, J. K. & Williams, K. W. Neural control of energy balance: translating circuits to therapies. Cell 161, 133–145 (2015).
Clemmensen, C. et al. Gut-brain cross-talk in metabolic control. Cell 168, 758–774 (2017).
Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).
Ahima, R. S. et al. Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252 (1996).
Kojima, M. et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656–660 (1999).
Tschop, M., Smiley, D. L. & Heiman, M. L. Ghrelin induces adiposity in rodents. Nature 407, 908–913 (2000).
Mojsov, S., Weir, G. C. & Habener, J. F. Insulinotropin: glucagon-like peptide I (7–37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J. Clin. Invest. 79, 616–619 (1987).
Holst, J. J., Orskov, C., Nielsen, O. V. & Schwartz, T. W. Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut. FEBS Lett. 211, 169–174 (1987).
Kreymann, B., Williams, G., Ghatei, M. A. & Bloom, S. R. Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet 2, 1300–1304 (1987).
Turton, M. D. et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379, 69–72 (1996).
Tang-Christensen, M. et al. Central administration of GLP-1-(7–36) amide inhibits food and water intake in rats. Am. J. Physiol. 271, R848–R856 (1996).
Flint, A., Raben, A., Astrup, A. & Holst, J. J. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J. Clin. Invest. 101, 515–520 (1998).
Pi-Sunyer, X. et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N. Engl. J. Med. 373, 11–22 (2015).
le Roux, C. W. et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet 389, 1399–1409 (2017).
Marso, S. P. et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 375, 311–322 (2016).
O’Neil, P. M. et al. Neuropsychiatric safety with liraglutide 3.0 mg for weight management: results from randomized controlled phase 2 and 3a trials. Diabetes Obes. Metab. 19, 1529–1536 (2017).
Zinman, B. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373, 2117–2128 (2015).
Mazidi, M., Rezaie, P., Gao, H. K. & Kengne, A. P. Effect of sodium-glucose cotransport-2 inhibitors on blood pressure in people with type 2 diabetes mellitus: a systematic review and meta-analysis of 43 randomized control trials with 22 528 patients. J. Am. Heart Assoc. 6, e004007 (2017).
Ludvik, B. et al. Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 6, 370–381 (2018).
Frias, J. P. et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 4, 1004–1016 (2016).
Madsbad, S., Dirksen, C. & Holst, J. J. Mechanisms of changes in glucose metabolism and bodyweight after bariatric surgery. Lancet Diabetes Endocrinol. 2, 152–164 (2014).
Beamish, A. J., Olbers, T., Kelly, A. S. & Inge, T. H. Cardiovascular effects of bariatric surgery. Nat. Rev. Cardiol. 13, 730–743 (2016).
Seeley, R. J., Chambers, A. P. & Sandoval, D. A. The role of gut adaptation in the potent effects of multiple bariatric surgeries on obesity and diabetes. Cell Metab. 21, 369–378 (2015).
Yanovski, S. Z. & Yanovski, J. A. Toward precision approaches for the prevention and treatment of obesity. JAMA 319, 223–224 (2018).
Van Gaal, L. & Scheen, A. Weight management in type 2 diabetes: current and emerging approaches to treatment. Diabetes Care 38, 1161–1172 (2015).
Wilson-Perez, H. E. et al. Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagon-like peptide 1 receptor deficiency. Diabetes 62, 2380–2385 (2013).
Zander, M., Madsbad, S., Madsen, J. L. & Holst, J. J. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 359, 824–830 (2002).
Vilsboll, 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 344, d7771 (2012).
Bettge, K., Kahle, M., Abd El Aziz, M. S., Meier, J. J. & Nauck, M. A. Occurrence of nausea, vomiting and diarrhoea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: a systematic analysis of published clinical trials. Diabetes Obes. Metab. 19, 336–347 (2017).
Gutzwiller, J. P., Degen, L., Matzinger, D., Prestin, S. & Beglinger, C. Interaction between GLP-1 and CCK-33 in inhibiting food intake and appetite in men. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287, R562–R567 (2004).
Neary, N. M. et al. Peptide YY3-36 and glucagon-like peptide-17-36 inhibit food intake additively. Endocrinology 146, 5120–5127 (2005).
Tan, T. M. et al. Coadministration of glucagon-like peptide-1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia. Diabetes 62, 1131–1138 (2013).
Madsen, K. B. et al. Acute effects of continuous infusions of glucagon-like peptide (GLP)-1, GLP-2 and the combination (GLP-1+GLP-2) on intestinal absorption in short bowel syndrome (SBS) patients. A placebo-controlled study. Regul. Pept. 184, 30–39 (2013).
Finan, B. et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci. Transl Med. 5, 209ra151 (2013).
Suarez-Pinzon, W. L. et al. Combination therapy with glucagon-like peptide-1 and gastrin restores normoglycemia in diabetic NOD mice. Diabetes 57, 3281–3288 (2008).
Grunddal, K. V. et al. Neurotensin is coexpressed, coreleased, and acts together with GLP-1 and PYY in enteroendocrine control of metabolism. Endocrinology 157, 176–194 (2016).
[No authors listed.] Abstracts of the 47th annual meeting of the European Association for the Study of Diabetes. September 16, 2011. Lisbon, Portugal. Diabetologia 54, S1–S543 (2011).
Clemmensen, C. et al. Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice. EMBO Mol. Med. 7, 288–298 (2015).
Balena, R., Hensley, I. E., Miller, S. & Barnett, A. H. Combination therapy with GLP-1 receptor agonists and basal insulin: a systematic review of the literature. Diabetes Obes. Metab. 15, 485–502 (2013).
Muller, T. D., Finan, B., Clemmensen, C., DiMarchi, R. D. & Tschop, M. H. The new biology and pharmacology of glucagon. Physiol. Rev. 97, 721–766 (2017).
Sharma, A. X. et al. Glucagon receptor antagonism improves glucose metabolism and cardiac function by promoting AMP-mediated protein kinase in diabetic mice. Cell Rep. 22, 1760–1773 (2018).
Pettus, J. et al. Effect of a glucagon receptor antibody (REMD-477) in type 1 diabetes: a randomized controlled trial. Diabetes Obes. Metab. 20, 1302–1305 (2018).
Guzman, C. B. et al. Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes. Diabetes Obes. Metab. 19, 1521–1528 (2017).
Kazda, C. M. et al. Treatment with the glucagon receptor antagonist LY2409021 increases ambulatory blood pressure in patients with type 2 diabetes. Diabetes Obes. Metab. 19, 1071–1077 (2017).
Kazda, C. M. et al. Evaluation of efficacy and safety of the glucagon receptor antagonist LY2409021 in patients with type 2 diabetes: 12- and 24-week phase 2 studies. Diabetes Care 39, 1241–1249 (2016).
Hjorth, 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. 269, 30121–30124 (1994).
Day, J. W. et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat. Chem. Biol. 5, 749–757 (2009).
Pocai, A. et al. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 58, 2258–2266 (2009).
Evers, A. et al. Design of novel exendin-based dual glucagon-like peptide 1 (GLP-1)/glucagon receptor agonists. J. Med. Chem. 60, 4293–4303 (2017).
Henderson, S. J. 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. 18, 1176–1190 (2016).
Evers, A. et al. Dual glucagon-like peptide 1 (GLP-1)/glucagon receptor agonists specifically optimized for multidose formulations. J. Med. Chem. 61, 5580–5593 (2018).
Sanchez-Garrido, M. A. et al. GLP-1/glucagon receptor co-agonism for treatment of obesity. Diabetologia 60, 1851–1861 (2017).
Ambery, P. et al. MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study. Lancet 391, 2607–2618 (2018).
Finan, B. et al. Reappraisal of GIP pharmacology for metabolic diseases. Trends Mol. Med. 22, 359–376 (2016).
Miyawaki, K. et al. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat. Med. 8, 738–742 (2002).
McClean, P. L. et al. GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet. Am. J. Physiol. Endocrinol. Metab. 293, E1746–E1755 (2007).
Campbell, J. E. et al. TCF1 links GIPR signaling to the control of beta cell function and survival. Nat. Med. 22, 84–90 (2016).
Sparre-Ulrich, A. H. et al. Species-specific action of (Pro3)GIP — a full agonist at human GIP receptors, but a partial agonist and competitive antagonist at rat and mouse GIP receptors. Br. J. Pharmacol. 173, 27–38 (2016).
Asmar, M. et al. Insulin plays a permissive role for the vasoactive effect of GIP regulating adipose tissue metabolism in humans. J. Clin. Endocrinol. Metab. 101, 3155–3162 (2016).
Asmar, M. et al. The gluco- and liporegulatory and vasodilatory effects of glucose-dependent insulinotropic polypeptide (GIP) are abolished by an antagonist of the human GIP receptor. Diabetes 66, 2363–2371 (2017).
Nauck, M. A. et al. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J. Clin. Invest. 91, 301–307 (1993).
Hojberg, P. V. et al. Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia 52, 199–207 (2009).
Norregaard, P. K. 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. 20, 60–68 (2018).
Frias, J. P. et al. The sustained effects of a dual GIP/GLP-1 receptor agonist, NNC0090-2746, in patients with type 2 diabetes. Cell Metab. 26, 343–352 (2017).
Schmitt, C., Portron, A., Jadidi, S., Sarkar, N. & DiMarchi, R. Pharmacodynamics, pharmacokinetics and safety of multiple ascending doses of the novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist RG7697 in people with type 2 diabetes mellitus. Diabetes Obes. Metab. 19, 1436–1445 (2017).
Coskun, T. et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol. Metab. https://doi.org/10.1016/j.molmet.2018.09.009 (2018).
Frias, J. P. et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet https://doi.org/10.1016/S0140-6736(18)32260-8 (2018).
Finan, B. et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat. Med. 21, 27–36 (2015).
Jall, S. et al. Monomeric GLP-1/GIP/glucagon triagonism corrects obesity, hepatosteatosis, and dyslipidemia in female mice. Mol. Metab. 6, 440–446 (2017).
Tschop, M. H. et al. Unimolecular polypharmacy for treatment of diabetes and obesity. Cell Metab. 24, 51–62 (2016).
Kochar, B. et al. Safety and efficacy of teduglutide (Gattex) in patients with Crohn’s disease and need for parenteral support due to short bowel syndrome-associated intestinal failure. J. Clin. Gastroenterol. 51, 508–511 (2017).
Cani, P. D. et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 58, 1091–1103 (2009).
Wismann, P. et al. Novel GLP-1/GLP-2 co-agonists display marked effects on gut volume and improves glycemic control in mice. Physiol. Behav. 192, 72–81 (2018).
Winer, D. A., Luck, H., Tsai, S. & Winer, S. The intestinal immune system in obesity and insulin resistance. Cell Metab. 23, 413–426 (2016).
Cheng, C. Y., Chu, J. Y. & Chow, B. K. Central and peripheral administration of secretin inhibits food intake in mice through the activation of the melanocortin system. Neuropsychopharmacology 36, 459–471 (2011).
Hansen, C. F. et al. Hypertrophy dependent doubling of L-cells in Roux-en-Y gastric bypass operated rats. PLOS ONE 8, e65696 (2013).
van Witteloostuijn, S. B. et al. GUB06-046, a novel secretin/glucagon-like peptide 1 co-agonist, decreases food intake, improves glycemic control, and preserves beta cell mass in diabetic mice. J. Pept. Sci. 23, 845–854 (2017).
Chance, W. T., Balasubramaniam, A., Zhang, F. S., Wimalawansa, S. J. & Fischer, J. E. Anorexia following the intrahypothalamic administration of amylin. Brain Res. 539, 352–354 (1991).
Chesnut, C. H. 3rd et al. Salmon calcitonin: a review of current and future therapeutic indications. Osteoporos. Int. 19, 479–491 (2008).
Andreassen, K. V. et al. A novel oral dual amylin and calcitonin receptor agonist (KBP-042) exerts antiobesity and antidiabetic effects in rats. Am. J. Physiol. Endocrinol. Metab. 307, E24–E33 (2014).
Hjuler, S. T., Andreassen, K. V., Gydesen, S., Karsdal, M. A. & Henriksen, K. KBP-042 improves bodyweight and glucose homeostasis with indices of increased insulin sensitivity irrespective of route of administration. Eur. J. Pharmacol. 762, 229–238 (2015).
Gydesen, S. et al. 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. 310, E821–E827 (2016).
Hjuler, S. T. et al. The dual amylin- and calcitonin-receptor agonist KBP-042 increases insulin sensitivity and induces weight loss in rats with obesity. Obesity 24, 1712–1722 (2016).
Gydesen, S. et al. A novel dual amylin and calcitonin receptor agonist, KBP-089, induces weight loss through a reduction in fat, but not lean mass, while improving food preference. Br. J. Pharmacol. 174, 591–602 (2017).
Rooman, I., Lardon, J. & Bouwens, L. Gastrin stimulates beta-cell neogenesis and increases islet mass from transdifferentiated but not from normal exocrine pancreas tissue. Diabetes 51, 686–690 (2002).
Morisset, J., Julien, S. & Laine, J. Localization of cholecystokinin receptor subtypes in the endocine pancreas. J. Histochem. Cytochem. 51, 1501–1513 (2003).
Fosgerau, K. et al. The novel GLP-1-gastrin dual agonist, ZP3022, increases beta-cell mass and prevents diabetes in db/db mice. Diabetes Obes. Metab. 15, 62–71 (2013).
Dalboge, L. S. et al. The novel GLP-1-gastrin dual agonist ZP3022 improves glucose homeostasis and increases beta-cell mass without affecting islet number in db/db mice. J. Pharmacol. Exp. Ther. 350, 353–360 (2014).
Skarbaliene, J. et al. The anti-diabetic effects of GLP-1-gastrin dual agonist ZP3022 in ZDF rats. Peptides 69, 47–55 (2015).
Trevaskis, J. L. et al. Improved glucose control and reduced body weight in rodents with dual mechanism of action peptide hybrids. PLOS ONE 8, e78154 (2013).
Hjuler, S. T., Gydesen, S., Andreassen, K. V., Karsdal, M. A. & 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. 362, 24–30 (2017).
Gydesen, S. et al. Optimization of tolerability and efficacy of the novel dual amylin and calcitonin receptor agonist KBP-089 through dose escalation and combination with a GLP-1 analog. Am. J. Physiol. Endocrinol. Metab. 313, E598–E607 (2017).
Dugger, S. A., Platt, A. & Goldstein, D. B. Drug development in the era of precision medicine. Nat. Rev. Drug Discov. 17, 183–196 (2018).
Gao, Q. et al. Anorectic estrogen mimics leptin’s effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Nat. Med. 13, 89–94 (2007).
Martinez de Morentin, P. B. et al. Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK. Cell Metab. 20, 41–53 (2014).
Zhou, Z. et al. Estrogen receptor alpha protects pancreatic beta-cells from apoptosis by preserving mitochondrial function and suppressing endoplasmic reticulum stress. J. Biol. Chem. 293, 4735–4751 (2018).
Ribas, V. et al. Skeletal muscle action of estrogen receptor alpha is critical for the maintenance of mitochondrial function and metabolic homeostasis in females. Sci. Transl Med. 8, 334ra54 (2016).
Finan, B. et al. Targeted estrogen delivery reverses the metabolic syndrome. Nat. Med. 18, 1847–1856 (2012).
Cao, X. et al. Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice. J. Clin. Invest. 124, 4351–4362 (2014).
Vogel, H. et al. GLP-1 and estrogen conjugate acts in the supramammillary nucleus to reduce food-reward and body weight. Neuropharmacology 110, 396–406 (2016).
Tiano, J. P., Tate, C. R., Yang, B. S., DiMarchi, R. & Mauvais-Jarvis, F. Effect of targeted estrogen delivery using glucagon-like peptide-1 on insulin secretion, insulin sensitivity and glucose homeostasis. Sci. Rep. 5, 10211 (2015).
Schwenk, R. W. et al. GLP-1-oestrogen attenuates hyperphagia and protects from beta cell failure in diabetes-prone New Zealand obese (NZO) mice. Diabetologia 58, 604–614 (2015).
Donath, M. Y. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat. Rev. Drug Discov. 13, 465–476 (2014).
Quarta, C. et al. Molecular integration of incretin and glucocorticoid action reverses immunometabolic dysfunction and obesity. Cell Metab. 26, 620–632 (2017).
Martinez-Sanchez, N. et al. Hypothalamic AMPK-ER stress-JNK1 axis mediates the central actions of thyroid hormones on energy balance. Cell Metab. 26, 212–229 (2017).
Lin, J. Z. et al. Pharmacological activation of thyroid hormone receptors elicits a functional conversion of white to brown fat. Cell Rep. 13, 1528–1537 (2015).
Sinha, R. A., Singh, B. K. & Yen, P. M. Direct effects of thyroid hormones on hepatic lipid metabolism. Nat. Rev. Endocrinol. 14, 259–269 (2018).
Considine, R. V. et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N. Engl. J. Med. 334, 292–295 (1996).
Heymsfield, S. B. et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282, 1568–1575 (1999).
Kissileff, H. R. et al. Leptin reverses declines in satiation in weight-reduced obese humans. Am. J. Clin. Nutr. 95, 309–317 (2012).
Rosenbaum, M. et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J. Clin. Invest. 115, 3579–3586 (2005).
Rosenbaum, M., Murphy, E. M., Heymsfield, S. B., Matthews, D. E. & Leibel, R. L. Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones. J. Clin. Endocrinol. Metab. 87, 2391–2394 (2002).
Quarta, C., Sanchez-Garrido, M. A., Tschop, M. H. & Clemmensen, C. Renaissance of leptin for obesity therapy. Diabetologia 59, 920–927 (2016).
Fruehwald-Schultes, B. et al. Short-term treatment with metformin decreases serum leptin concentration without affecting body weight and body fat content in normal-weight healthy men. Metabolism 51, 531–536 (2002).
Kim, Y. W. et al. Metformin restores leptin sensitivity in high-fat-fed obese rats with leptin resistance. Diabetes 55, 716–724 (2006).
Klein, J. et al. Metformin inhibits leptin secretion via a mitogen-activated protein kinase signalling pathway in brown adipocytes. J. Endocrinol. 183, 299–307 (2004).
Aubert, G., Mansuy, V., Voirol, M. J., Pellerin, L. & Pralong, F. P. The anorexigenic effects of metformin involve increases in hypothalamic leptin receptor expression. Metabolism 60, 327–334 (2011).
Roth, J. D. et al. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc. Natl Acad. Sci. USA 105, 7257–7262 (2008).
Ravussin, E. et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity 17, 1736–1743 (2009).
Mietlicki-Baase, E. G., Olivos, D. R., Jeffrey, B. A. & Hayes, M. R. Cooperative interaction between leptin and amylin signaling in the ventral tegmental area for the control of food intake. Am. J. Physiol. Endocrinol. Metab. 308, E1116–E1122 (2015).
Turek, V. F. et al. Mechanisms of amylin/leptin synergy in rodent models. Endocrinology 151, 143–152 (2010).
Trevaskis, J. L. et al. Amylin/leptin synergy is absent in extreme obesity and not restored by calorie restriction-induced weight loss in rats. Obes. Sci. Pract. 2, 385–391 (2016).
Muller, T. D. et al. Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21. J. Pept. Sci. 18, 383–393 (2012).
Clemmensen, C. et al. GLP-1/glucagon coagonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet. Diabetes 63, 1422–1427 (2014).
Chinookoswong, N., Wang, J. L. & Shi, Z. Q. Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat. Diabetes 48, 1487–1492 (1999).
Fujikawa, T., Chuang, J. C., Sakata, I., Ramadori, G. & Coppari, R. Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc. Natl Acad. Sci. USA 107, 17391–17396 (2010).
German, J. P. et al. Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia. Endocrinology 152, 394–404 (2011).
Hidaka, S. et al. Chronic central leptin infusion restores hyperglycemia independent of food intake and insulin level in streptozotocin-induced diabetic rats. FASEB J. 16, 509–518 (2002).
Wang, M. Y. et al. Leptin therapy in insulin-deficient type I diabetes. Proc. Natl Acad. Sci. USA 107, 4813–4819 (2010).
Cummings, B. P. et al. Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats. Proc. Natl Acad. Sci. USA 108, 14670–14675 (2011).
Moon, H. S. et al. Efficacy of metreleptin in obese patients with type 2 diabetes: cellular and molecular pathways underlying leptin tolerance. Diabetes 60, 1647–1656 (2011).
German, J. P. et al. Leptin deficiency causes insulin resistance induced by uncontrolled diabetes. Diabetes 59, 1626–1634 (2010).
Moon, H. S. et al. Identification and saturable nature of signaling pathways induced by metreleptin in humans: comparative evaluation of in vivo, ex vivo, and in vitro administration. Diabetes 64, 828–839 (2015).
Vasandani, C., Clark, G. O., Adams-Huet, B., Quittner, C. & Garg, A. Efficacy and safety of metreleptin therapy in patients with type 1 diabetes: a pilot study. Diabetes Care 40, 694–697 (2017).
Yu, X., Park, B. H., Wang, M. Y., Wang, Z. V. & Unger, R. H. Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc. Natl Acad. Sci. USA 105, 14070–14075 (2008).
Perry, R. J. et al. Leptin reverses diabetes by suppression of the hypothalamic-pituitary-adrenal axis. Nat. Med. 20, 759–763 (2014).
Morton, G. J., Meek, T. H., Matsen, M. E. & Schwartz, M. W. Evidence against hypothalamic-pituitary-adrenal axis suppression in the antidiabetic action of leptin. J. Clin. Invest. 125, 4587–4591 (2015).
Ajluni, N. et al. Efficacy of metreleptin therapy in the treatment of fatty liver disease associated with partial lipodystrophy [abstract]. Endocr. Rev. 38, OR09-4 (2017).
Degirolamo, C., Sabba, C. & Moschetta, A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat. Rev. Drug Discov. 15, 51–69 (2016).
Kharitonenkov, A. & DiMarchi, R. FGF21 revolutions: recent advances illuminating FGF21 biology and medicinal properties. Trends Endocrinol. Metab. 26, 608–617 (2015).
Gaich, G. et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 18, 333–340 (2013).
Talukdar, S. et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 23, 427–440 (2016).
Owen, B. M. et al. FGF21 contributes to neuroendocrine control of female reproduction. Nat. Med. 19, 1153–1156 (2013).
Wei, W. et al. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor gamma. Proc. Natl Acad. Sci. USA 109, 3143–3148 (2012).
Lan, T. et al. FGF19, FGF21, and an FGFR1/beta-Klotho-activating antibody act on the nervous system to regulate body weight and glycemia. Cell Metab. 26, 709–718 (2017).
Kwon, M. M., O’Dwyer, S. M., Baker, R. K., Covey, S. D. & Kieffer, T. J. FGF21-mediated improvements in glucose clearance require uncoupling protein 1. Cell Rep. 13, 1521–1527 (2015).
Nedergaard, J., Bengtsson, T. & Cannon, B. Unexpected evidence for active brown adipose tissue in adult humans. Am. J. Physiol. Endocrinol. Metab. 293, E444–E452 (2007).
von Holstein-Rathlou, S. et al. FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver. Cell Metab. 23, 335–343 (2016).
Talukdar, S. et al. FGF21 regulates sweet and alcohol preference. Cell Metab. 23, 344–349 (2016).
Desai, B. N. et al. Fibroblast growth factor 21 (FGF21) is robustly induced by ethanol and has a protective role in ethanol associated liver injury. Mol. Metab. 6, 1395–1406 (2017).
Soberg, S. et al. FGF21, a liver hormone that inhibits alcohol intake in mice, increases in human circulation after acute alcohol ingestion and sustained binge drinking at Oktoberfest. Mol. Metab. 11, 96–103 (2018).
Lundsgaard, A. M. et al. Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates. Mol. Metab. 6, 22–29 (2017).
Soberg, S. et al. FGF21 is a sugar-induced hormone associated with sweet intake and preference in humans. Cell Metab. 25, 1045–1053 (2017).
Lee, S. et al. Structures of beta-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling. Nature 553, 501–505 (2018).
Adams, A. C. et al. Fundamentals of FGF19 and FGF21 action in vitro and in vivo. PLOS ONE 7, e38438 (2012).
Harrison, S. A. et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 391, 1174–1185 (2018).
Morton, G. J. et al. FGF19 action in the brain induces insulin-independent glucose lowering. J. Clin. Invest. 123, 4799–4808 (2013).
Ryan, K. K. et al. Fibroblast growth factor-19 action in the brain reduces food intake and body weight and improves glucose tolerance in male rats. Endocrinology 154, 9–15 (2013).
Benoit, B. et al. Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice. Nat. Med. 23, 990–996 (2017).
Zhou, M. et al. Mouse species-specific control of hepatocarcinogenesis and metabolism by FGF19/FGF15. J. Hepatol. 66, 1182–1192 (2017).
Zhou, M. et al. Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice. Hepatol. Commun. 1, 1024–1042 (2017).
Suh, J. M. et al. Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature 513, 436–439 (2014).
Scarlett, J. M. et al. Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents. Nat. Med. 22, 800–806 (2016).
Lynch, L. et al. iNKT cells induce FGF21 for thermogenesis and are required for maximal weight loss in GLP1 therapy. Cell Metab. 24, 510–519 (2016).
Hong, H. N. et al. YH25724, a novel long-acting GLP-1/FGF21 dual agonist provides potent and sustained glycaemic control, body weight loss and lipid profile improvement in animal models [abstract 111]. Diabetologia 59, S58 (2016).
Ryan, K. K., Woods, S. C. & Seeley, R. J. Central nervous system mechanisms linking the consumption of palatable high-fat diets to the defense of greater adiposity. Cell Metab. 15, 137–149 (2012).
Rosenbaum, M., Sy, M., Pavlovich, K., Leibel, R. L. & Hirsch, J. Leptin reverses weight loss-induced changes in regional neural activity responses to visual food stimuli. J. Clin. Invest. 118, 2583–2591 (2008).
Sims, E. A. et al. Endocrine and metabolic effects of experimental obesity in man. Recent Prog. Horm. Res. 29, 457–496 (1973).
Diaz, E. O., Prentice, A. M., Goldberg, G. R., Murgatroyd, P. R. & Coward, W. A. Metabolic response to experimental overfeeding in lean and overweight healthy volunteers. Am. J. Clin. Nutr. 56, 641–655 (1992).
Ravussin, Y., Leibel, R. L. & Ferrante, A. W. Jr. A missing link in body weight homeostasis: the catabolic signal of the overfed state. Cell Metab. 20, 565–572 (2014).
O’Neil, P. M. et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet 392, 637–649 (2018).
Singh, S., Loke, Y. K. & Furberg, C. D. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 298, 1189–1195 (2007).
Kosiborod, M. et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors). Circulation 136, 249–259 (2017).
Marso, S. P. et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 375, 1834–1844 (2016).
Hernandez, A. F. et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet https://doi.org/10.1016/S0140-6736(18)32261-X (2018).
Buse, J. B. Liraglutide and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 375, 1798–1799 (2016).
Pfeffer, M. A. et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N. Engl. J. Med. 373, 2247–2257 (2015).
Holman, R. R. et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 377, 1228–1239 (2017).
Lim, S., Kim, K. M. & Nauck, M. A. Glucagon-like peptide-1 receptor agonists and cardiovascular events: class effects versus individual patterns. Trends Endocrinol. Metab. 29, 238–248 (2018).
Moller, C. L. et al. Glucose-dependent insulinotropic polypeptide is associated with lower low-density lipoprotein but unhealthy fat distribution, independent of insulin: the ADDITION-PRO study. J. Clin. Endocrinol. Metab. 101, 485–493 (2016).
Ussher, J. R. et al. Inactivation of the glucose-dependent insulinotropic polypeptide receptor improves outcomes following experimental myocardial infarction. Cell Metab. 27, 450–460 (2018).
Kahles, F. et al. The incretin hormone GIP is upregulated in patients with atherosclerosis and stabilizes plaques in ApoE−/− mice by blocking monocyte/macrophage activation. Mol. Metab. 14, 150–157 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03586830 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03486392 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03235050 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03244800 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02492763 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02973321 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03437720 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02119819 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03406377 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03308721 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02692781 (2018).
ZealandPharma. Zealand and Boehringer Ingelheim to change development program on novel dual-acting glucagon/GLP-1 receptor agonists to treat Type 2 diabetes and/or obesity with a new lead compound that will replace ZP2929. Zealand Pharma Company Release https://cws.huginonline.com/Z/136974/PR/201401/2026559_5.html (2014).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03175211 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03591718 (2018).
Eli Lilly and Company. Q2 2018 earnings. Lilly Investors https://investor.lilly.com/static-files/3556875d-ae48-4911-99ba-05647b225ed5 (2018).
Kamal, S. Spitfire Pharma’s SP-1373 outscored semaglutide and elafibranor in a biopsy-proven translational mouse model of non-alcoholic steatohepatitis (NASH). Velocity Pharmaceutical Development http://www.vpd.net/press_releases/VPD_1.4.2018.html (2018).
You, S. et al. Long-acting GLP-1 and glucagon receptor dual agonists for the treatment of type 2 diabetes. Diabetes 65, A274 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03311724 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03131687 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02205528 (2018).
Sanofi. Q2 2018 performance positions Sanofi for new growth phase. Hugin.info http://hugin.info/152918/R/2208107/858824.pdf (2018).
Knudsen, C. B. et al. An optimized novel GLP-1-GIP receptor dual agonist with potent effects on body weight and glucose control in mice has the potential for once-weekly administration in humans. Diabetes 64, A528 (2015).
SCOHIA PHARMA, Inc. SCO-094. SCOHIA PHARMA, Inc. Pipeline https://www.scohia.com/eng/sys/pipeline/sco-094 (2017).
Hansen, S. K. Carmot Therapeutics announces close of series B financing. Carmot Therapeutics http://carmot-therapeutics.us/2018/01/16/carmot-therapeutics-announces-close-of-series-b-financing (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03374241 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03661879 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03095807 (2017).
Sanofi. Sustaining innovation analyst day. Sanofi https://www.sanofi.com/media/Project/One-Sanofi-Web/sanofi-com/en/investors/docs/Sustaining_innovation_day_2017_presentation_appendices_Web.pdf (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03230786 (2018).
Eli Lilly and Company. Medicines in development — molecule and potential indication data as of July 17, 2018. Lilly Discovery https://www.lilly.com/discovery/pipeline (2018).