The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity - and thus also leptin levels - in the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.

Department of Adipose Tissue Biology Institute of Physiology CAS Prague the Czech Republic

Department of Molecular Biosciences The Wenner Gren Institute Stockholm University Stockholm Sweden

Global Drug Discovery Novo Nordisk A S Måløv Denmark

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Barnes AJ, Bloom SR, Goerge K, Alberti GM, Smythe P, Alford FP, Chisholm DJ. Ketoacidosis in pancreatectomized man. N Engl J Med 296: 1250–1253, 1977. doi:10.1056/NEJM197706022962202. PubMed DOI

Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, Kaul MG, Tromsdorf UI, Weller H, Waurisch C, Eychmüller A, Gordts PL, Rinninger F, Bruegelmann K, Freund B, Nielsen P, Merkel M, Heeren J. Brown adipose tissue activity controls triglyceride clearance. Nat Med 17: 200–205, 2011. doi:10.1038/nm.2297. PubMed DOI

Brand CL, Rolin B, Jørgensen PN, Svendsen I, Kristensen JS, Holst JJ. Immunoneutralization of endogenous glucagon with monoclonal glucagon antibody normalizes hyperglycaemia in moderately streptozotocin-diabetic rats. Diabetologia 37: 985–993, 1994. doi:10.1007/BF00400461. PubMed DOI

Chong AY, Lupsa BC, Cochran EK, Gorden P. Efficacy of leptin therapy in the different forms of human lipodystrophy. Diabetologia 53: 27–35, 2010. doi:10.1007/s00125-009-1502-9. PubMed DOI

Damond N, Thorel F, Moyers JS, Charron MJ, Vuguin PM, Powers AC, Herrera PL. Blockade of glucagon signaling prevents or reverses diabetes onset only if residual β-cells persist. eLife 5: e13828, 2016. doi:10.7554/eLife.13828. PubMed DOI PMC

de Jong JM, Larsson O, Cannon B, Nedergaard J. A stringent validation of mouse adipose tissue identity markers. Am J Physiol Endocrinol Metab 308: E1085–E1105, 2015. doi:10.1152/ajpendo.00023.2015. PubMed DOI

Deeds MC, Anderson JM, Armstrong AS, Gastineau DA, Hiddinga HJ, Jahangir A, Eberhardt NL, Kudva YC. Single dose streptozotocin-induced diabetes: considerations for study design in islet transplantation models. Lab Anim 45: 131–140, 2011. doi:10.1258/la.2010.010090. PubMed DOI PMC

Denroche HC, Huynh FK, Kieffer TJ. The role of leptin in glucose homeostasis. J Diabetes Investig 3: 115–129, 2012. doi:10.1111/j.2040-1124.2012.00203.x. PubMed DOI PMC

Denroche HC, Kwon MM, Glavas MM, Tudurí E, Philippe M, Quong WL, Kieffer TJ. The role of autonomic efferents and uncoupling protein 1 in the glucose-lowering effect of leptin therapy. Mol Metab 5: 716–724, 2016. doi:10.1016/j.molmet.2016.06.009. PubMed DOI PMC

Denroche HC, Kwon MM, Quong WL, Neumann UH, Kulpa JE, Karunakaran S, Clee SM, Brownsey RW, Covey SD, Kieffer TJ. Leptin induces fasting hypoglycaemia in a mouse model of diabetes through the depletion of glycerol. Diabetologia 58: 1100–1108, 2015. doi:10.1007/s00125-015-3529-4. PubMed DOI

Engin A. Diet-induced obesity and the mechanism of leptin resistance. Adv Exp Med Biol 960: 381–397, 2017. doi:10.1007/978-3-319-48382-5_16. PubMed DOI

Fischer AW, Cannon B, Nedergaard J. Optimal housing temperatures for mice to mimic the thermal environment of humans: an experimental study. Mol Metab 7: 161–170, 2018. doi:10.1016/j.molmet.2017.10.009. PubMed DOI PMC

Fischer AW, Hoefig CS, Abreu-Vieira G, de Jong JMA, Petrovic N, Mittag J, Cannon B, Nedergaard J. Leptin raises defended body temperature without activating thermogenesis. Cell Reports 14: 1621–1631, 2016. doi:10.1016/j.celrep.2016.01.041. PubMed DOI

Fischer AW, Shabalina IG, Mattsson CL, Abreu-Vieira G, Cannon B, Nedergaard J, Petrovic N. UCP1 inhibition in Cidea-overexpressing mice is physiologically counteracted by brown adipose tissue hyperrecruitment. Am J Physiol Endocrinol Metab 312: E72–E87, 2017. doi:10.1152/ajpendo.00284.2016. PubMed DOI

Ganeshan K, Chawla A. Warming the mouse to model human diseases. Nat Rev Endocrinol 13: 458–465, 2017. doi:10.1038/nrendo.2017.48. PubMed DOI PMC

German JP, Thaler JP, Wisse BE, Oh-I S, Sarruf DA, Matsen ME, Fischer JD, Taborsky GJ Jr, Schwartz MW, Morton GJ. Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia. Endocrinology 152: 394–404, 2011. doi:10.1210/en.2010-0890. PubMed DOI PMC

German JP, Wisse BE, Thaler JP, Oh-I S, Sarruf DA, Ogimoto K, Kaiyala KJ, Fischer JD, Matsen ME, Taborsky GJ Jr, Schwartz MW, Morton GJ. Leptin deficiency causes insulin resistance induced by uncontrolled diabetes. Diabetes 59: 1626–1634, 2010. doi:10.2337/db09-1918. PubMed DOI PMC

Golozoubova V, Cannon B, Nedergaard J. UCP1 is essential for adaptive adrenergic nonshivering thermogenesis. Am J Physiol Endocrinol Metab 291: E350–E357, 2006. doi:10.1152/ajpendo.00387.2005. PubMed DOI

Hankir MK, Kranz M, Keipert S, Weiner J, Andreasen SG, Kern M, Patt M, Klöting N, Heiker JT, Brust P, Hesse S, Jastroch M, Fenske WK. Dissociation between brown adipose tissue 18F-FDG uptake and thermogenesis in uncoupling protein 1-deficient mice. J Nucl Med 58: 1100–1103, 2017. doi:10.2967/jnumed.116.186460. PubMed DOI

Hebert SL, Nair KS. Protein and energy metabolism in type 1 diabetes. Clin Nutr 29: 13–17, 2010. doi:10.1016/j.clnu.2009.09.001. PubMed DOI PMC

Hedbacker K, Birsoy K, Wysocki RW, Asilmaz E, Ahima RS, Farooqi IS, Friedman JM. Antidiabetic effects of IGFBP2, a leptin-regulated gene. Cell Metab 11: 11–22, 2010. doi:10.1016/j.cmet.2009.11.007. PubMed DOI

Heyman E, Berthon P, Youssef H, Delamarche A, Briard D, Gamelin FX, Delamarche P, de Kerdanet M. Metabolic dysfunction in late-puberty adolescent girls with type 1 diabetes: relationship to physical activity and dietary intakes. Diabetes Metab 38: 337–342, 2012. doi:10.1016/j.diabet.2012.03.001. PubMed DOI

Hsu WC, Okeke E, Cheung S, Keenan H, Tsui T, Cheng K, King GL. A cross-sectional characterization of insulin resistance by phenotype and insulin clamp in East Asian Americans with type 1 and type 2 diabetes. PLoS One 6: e28311, 2011. doi:10.1371/journal.pone.0028311. PubMed DOI PMC

Huml M, Kobr J, Siala K, Varvařovská J, Pomahačová R, Karlíková M, Sýkora J. Gut peptide hormones and pediatric type 1 diabetes mellitus. Physiol Res 60: 647–658, 2011. PubMed

Kim J, Okamoto H, Huang Z, Anguiano G, Chen S, Liu Q, Cavino K, Xin Y, Na E, Hamid R, Lee J, Zambrowicz B, Unger R, Murphy AJ, Xu Y, Yancopoulos GD, Li WH, Gromada J. Amino acid transporter Slc38a5 controls glucagon receptor inhibition-induced pancreatic alpha cell hyperplasia in mice. Cell Metab 25: 1348–1361.e8, 2017. doi:10.1016/j.cmet.2017.05.006. PubMed DOI PMC

Knight ZA, Hannan KS, Greenberg ML, Friedman JM. Hyperleptinemia is required for the development of leptin resistance. PLoS One 5: e11376, 2010. doi:10.1371/journal.pone.0011376. PubMed DOI PMC

Kodra JT, Conde-Frieboes KW, Paulsson JF, Raun K. Leptin Derivatives. US Patent 2014/0018290 A1. January 16, 2014.

Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, Kern PA, Friedman JM. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1: 1155–1161, 1995. doi:10.1038/nm1195-1155. PubMed DOI

Meek TH, Dorfman MD, Matsen ME, Fischer JD, Cubelo A, Kumar MR, Taborsky GJ Jr, Morton GJ. Evidence that in uncontrolled diabetes, hyperglucagonemia is required for ketosis but not for increased hepatic glucose production or hyperglycemia. Diabetes 64: 2376–2387, 2015. doi:10.2337/db14-1562. PubMed DOI PMC

Mittendorfer B, Horowitz JF, DePaoli AM, McCamish MA, Patterson BW, Klein S. Recombinant human leptin treatment does not improve insulin action in obese subjects with type 2 diabetes. Diabetes 60: 1474–1477, 2011. doi:10.2337/db10-1302. PubMed DOI PMC

Mizuno A, Murakami T, Otani S, Kuwajima M, Shima K. Leptin affects pancreatic endocrine functions through the sympathetic nervous system. Endocrinology 139: 3863–3870, 1998. doi:10.1210/endo.139.9.6201. PubMed DOI

Moon HS, Matarese G, Brennan AM, Chamberland JP, Liu X, Fiorenza CG, Mylvaganam GH, Abanni L, Carbone F, Williams CJ, De Paoli AM, Schneider BE, Mantzoros CS. Efficacy of metreleptin in obese patients with type 2 diabetes: cellular and molecular pathways underlying leptin tolerance. Diabetes 60: 1647–1656, 2011. doi:10.2337/db10-1791. PubMed DOI PMC

Morton GJ, Meek TH, Matsen ME, Schwartz MW. Evidence against hypothalamic-pituitary-adrenal axis suppression in the antidiabetic action of leptin. J Clin Invest 125: 4587–4591, 2015. doi:10.1172/JCI82723. PubMed DOI PMC

Neumann UH, Denroche HC, Mojibian M, Covey SD, Kieffer TJ. Insulin knockout mice have extended survival but volatile blood glucose levels on leptin therapy. Endocrinology 157: 1007–1012, 2016. doi:10.1210/en.2015-1890. PubMed DOI

Olsen JM, Csikasz RI, Dehvari N, Lu L, Sandström A, Öberg AI, Nedergaard J, Stone-Elander S, Bengtsson T. β3-adrenergically induced glucose uptake in brown adipose tissue is independent of UCP1 presence or activity: mediation through the mTOR pathway. Mol Metab 6: 611–619, 2017. doi:10.1016/j.molmet.2017.02.006. PubMed DOI PMC

Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A. Leptin-replacement therapy for lipodystrophy. N Engl J Med 346: 570–578, 2002. doi:10.1056/NEJMoa012437. PubMed DOI

Park JY, Chong AY, Cochran EK, Kleiner DE, Haller MJ, Schatz DA, Gorden P. Type 1 diabetes associated with acquired generalized lipodystrophy and insulin resistance: the effect of long-term leptin therapy. J Clin Endocrinol Metab 93: 26–31, 2008. doi:10.1210/jc.2007-1856. PubMed DOI PMC

Perry RJ, Zhang XM, Zhang D, Kumashiro N, Camporez JP, Cline GW, Rothman DL, Shulman GI. Leptin reverses diabetes by suppression of the hypothalamic-pituitary-adrenal axis. Nat Med 20: 759–763, 2014. doi:10.1038/nm.3579. PubMed DOI PMC

Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, Cline GW, DePaoli AM, Taylor SI, Gorden P, Shulman GI. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 109: 1345–1350, 2002. doi:10.1172/JCI0215001. PubMed DOI PMC

Rosell M, Kaforou M, Frontini A, Okolo A, Chan YW, Nikolopoulou E, Millership S, Fenech ME, MacIntyre D, Turner JO, Moore JD, Blackburn E, Gullick WJ, Cinti S, Montana G, Parker MG, Christian M. Brown and white adipose tissues: intrinsic differences in gene expression and response to cold exposure in mice. Am J Physiol Endocrinol Metab 306: E945–E964, 2014. doi:10.1152/ajpendo.00473.2013. PubMed DOI PMC

Schäffer L, Brand CL, Hansen BF, Ribel U, Shaw AC, Slaaby R, Sturis J. A novel high-affinity peptide antagonist to the insulin receptor. Biochem Biophys Res Commun 376: 380–383, 2008. doi:10.1016/j.bbrc.2008.08.151. PubMed DOI

Soliman AT, Omar M, Assem HM, Nasr IS, Rizk MM, El Matary W, El Alaily RK. Serum leptin concentrations in children with type 1 diabetes mellitus: relationship to body mass index, insulin dose, and glycemic control. Metabolism 51: 292–296, 2002. doi:10.1053/meta.2002.30502. PubMed DOI

Tsai M, Asakawa A, Amitani H, Inui A. Stimulation of leptin secretion by insulin. Indian J Endocrinol Metab 16, Suppl 3: S543–S548, 2012. doi:10.4103/2230-8210.105570. PubMed DOI PMC

Tudurí E, Marroquí L, Soriano S, Ropero AB, Batista TM, Piquer S, López-Boado MA, Carneiro EM, Gomis R, Nadal A, Quesada I. Inhibitory effects of leptin on pancreatic alpha-cell function. Diabetes 58: 1616–1624, 2009. doi:10.2337/db08-1787. PubMed DOI PMC

Vasandani C, Clark GO, 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. doi:10.2337/dc16-1553. PubMed DOI

Wang MY, Chen L, Clark GO, Lee Y, Stevens RD, Ilkayeva OR, Wenner BR, Bain JR, Charron MJ, Newgard CB, Unger RH. Leptin therapy in insulin-deficient type I diabetes. Proc Natl Acad Sci USA 107: 4813–4819, 2010. doi:10.1073/pnas.0909422107. PubMed DOI PMC

Yu X, Park BH, Wang MY, Wang ZV, Unger RH. Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc Natl Acad Sci USA 105: 14070–14075, 2008. doi:10.1073/pnas.0806993105. PubMed DOI PMC

A pyrexic effect of FGF21 independent of energy expenditure and UCP1