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Metabolic Characterization of a Mouse Deficient in All Known Leptin Receptor Isoforms

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Abstract

We have characterized a newly generated mouse model of obesity, a mouse strain deficient in all five previously described leptin receptor isoforms. These transgenic mice, named the db 333/db 333 mice, were identified from an ENU mutagenesis screen and carry a point mutation in the seventh exon of the db gene encoding the leptin receptor, resulting in a premature stop codon (Y333Stop) and gene product that lacks STAT signaling domains. db 333/db 333 mice have a morbidly obese phenotype, with body weights diverging from wild type as early as 4 weeks of age (P < 0.05). To determine the contribution of the short isoforms of the leptin receptor in this metabolic phenotype, we performed an extensive metabolic characterization of the db 333/db 333 mouse in relation to the well-characterized db/db mouse lacking only the long form of the leptin receptor. db 333/db 333 mice have similar endocrine and metabolic parameters as previously described in other leptin receptor transgenic mice including db/db mice that lack only the long isoform of the leptin receptor. However, db 333/db 333 mice show a subtle trend toward higher body weight and insulin levels, lower oxygen, carbon dioxide production, respiratory exchange ratio (RER), and temperature than db/db mice suggesting the short isoforms may play an additional role in energy homeostasis.

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References

  • Ahima RS, Prabakaran D et al (1996) Role of leptin in the neuroendocrine response to fasting. Nature 382(6588):250–252

    Article  CAS  PubMed  Google Scholar 

  • Ahima RS, Dushay J et al (1997) Leptin accelerates the onset of puberty in normal female mice. J Clin Invest 99(3):391–395

    Article  CAS  PubMed  Google Scholar 

  • Aubert R, Herzog J et al (1985) Description of a new model of genetic obesity: the dbPas mouse. J Nutr 115(3):327–333

    CAS  PubMed  Google Scholar 

  • Bates SH, Myers MG Jr (2003) The role of leptin receptor signaling in feeding and neuroendocrine function. Trends Endocrinol Metab 14(10):447–452

    Article  CAS  PubMed  Google Scholar 

  • Bates SH, Dundon TA et al (2004) LRb-STAT3 signaling is required for the neuroendocrine regulation of energy expenditure by leptin. Diabetes 53(12):3067–3073

    Article  CAS  PubMed  Google Scholar 

  • Brown SD, Peters J (1996) Combining mutagenesis and genomics in the mouse—closing the phenotype gap. Trends Genet 12(11):433–435

    Article  CAS  PubMed  Google Scholar 

  • Campfield LA, Smith FJ et al (1995) Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269(5223):546–549

    Article  CAS  PubMed  Google Scholar 

  • Chehab FF, Lim ME et al (1996) Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet 12(3):318–320

    Article  CAS  PubMed  Google Scholar 

  • Chen H, Charlat O et al (1996) Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84(3):491–495

    Article  CAS  PubMed  Google Scholar 

  • Chua SC Jr (1997) Monogenic models of obesity. Behav Genet 27(4):277–284

    Article  PubMed  Google Scholar 

  • Chua SC Jr, Chung WK et al (1996) Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 271(5251):994–996

    Article  CAS  PubMed  Google Scholar 

  • Chua SC Jr, Koutras IK et al (1997) Fine structure of the murine leptin receptor gene: splice site suppression is required to form two alternatively spliced transcripts. Genomics 45(2):264–270

    Article  CAS  PubMed  Google Scholar 

  • Elmquist JK, Maratos-Flier E et al (1998) Unraveling the central nervous system pathways underlying responses to leptin. Nat Neurosci 1(6):445–450

    Article  CAS  PubMed  Google Scholar 

  • Emilsson V, Liu YL et al (1997) Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion. Diabetes 46(2):313–316

    Article  CAS  PubMed  Google Scholar 

  • Farooqi S, O’Rahilly S (2006) Genetics of obesity in humans. Endocr Rev 27(7):710–718

    CAS  PubMed  Google Scholar 

  • Farooqi IS, Matarese G et al (2002) Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 110(8):1093–1103

    CAS  PubMed  Google Scholar 

  • Fei H, Okano HJ et al (1997) Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc Natl Acad Sci USA 94(13):7001–7005

    Article  CAS  PubMed  Google Scholar 

  • Frederich RC, Hamann A et al (1995) Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med 1(12):1311–1314

    Article  CAS  PubMed  Google Scholar 

  • Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395(6704):763–770

    Article  CAS  PubMed  Google Scholar 

  • Ge H, Huang L et al (2002) Generation of soluble leptin receptor by ectodomain shedding of membrane-spanning receptors in vitro and in vivo. J Biol Chem 277(48):45898–45903

    Article  CAS  PubMed  Google Scholar 

  • Ghilardi N, Ziegler S et al (1996) Defective STAT signaling by the leptin receptor in diabetic mice. Proc Natl Acad Sci USA 93(13):6231–6235

    Article  CAS  PubMed  Google Scholar 

  • Golden PL, Maccagnan TJ et al (1997) Human blood-brain barrier leptin receptor. Binding and endocytosis in isolated human brain microvessels. J Clin Invest 99(1):14–18

    Article  CAS  PubMed  Google Scholar 

  • Halaas JL, Gajiwala KS et al (1995) Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269(5223):543–546

    Article  CAS  PubMed  Google Scholar 

  • Harris RB, Mitchell TD et al (2001) Metabolic responses to leptin in obese db/db mice are strain dependent. Am J Physiol Regul Integr Comp Physiol 281(1):R115–R132

    CAS  PubMed  Google Scholar 

  • Heiman ML, Ahima RS et al (1997) Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress. Endocrinology 138(9):3859–3863

    Article  CAS  PubMed  Google Scholar 

  • Hosoi T, Okuma Y et al (2002) Leptin regulates interleukin-1beta expression in the brain via the STAT3-independent mechanisms. Brain Res 949(1–2):139–146

    Article  CAS  PubMed  Google Scholar 

  • Hummel KP, Dickie MM et al (1966) Diabetes, a new mutation in the mouse. Science 153(740):1127–1128

    Article  CAS  PubMed  Google Scholar 

  • Hwa JJ, Ghibaudi L et al (1996) Intracerebroventricular injection of leptin increases thermogenesis and mobilizes fat metabolism in ob/ob mice. Horm Metab Res 28(12):659–663

    Article  CAS  PubMed  Google Scholar 

  • Ingalls AM, Dickie MM et al (1950) Obese, a new mutation in the house mouse. J Hered 41(12):317–318

    CAS  PubMed  Google Scholar 

  • Juge-Aubry CE, Somm E et al (2003) Adipose tissue is a major source of interleukin-1 receptor antagonist: upregulation in obesity and inflammation. Diabetes 52(5):1104–1110

    Article  CAS  PubMed  Google Scholar 

  • Kowalski TJ, Liu SM et al (2001) Transgenic complementation of leptin-receptor deficiency. I. Rescue of the obesity/diabetes phenotype of LEPR-null mice expressing a LEPR-B transgene. Diabetes 50(2):425–435

    Article  CAS  PubMed  Google Scholar 

  • Lee GH, Proenca R et al (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379(6566):632–635

    Article  CAS  PubMed  Google Scholar 

  • Lee G, Li C et al (1997) Leptin receptor mutations in 129 db3 J/db3 J mice and NIH facp/facp rats. Mamm Genome 8(6):445–447

    Article  CAS  PubMed  Google Scholar 

  • Leiter EH, Coleman DL et al (1980) A new mutation (db3 J) at the diabetes locus in strain 129/J mice. I. Physiological and histological characterization. Diabetologia 19(1):58–65

    Article  CAS  PubMed  Google Scholar 

  • Levin N, Nelson C et al (1996) Decreased food intake does not completely account for adiposity reduction after ob protein infusion. Proc Natl Acad Sci USA 93(4):1726–1730

    Article  CAS  PubMed  Google Scholar 

  • Li C, Ioffe E et al (1998) Absence of soluble leptin receptor in plasma from dbPas/dbPas and other db/db mice. J Biol Chem 273(16):10078–10082

    Article  CAS  PubMed  Google Scholar 

  • Loffreda S, Yang SQ et al (1998) Leptin regulates proinflammatory immune responses. FASEB J 12(1):57–65

    CAS  PubMed  Google Scholar 

  • Lollmann B, Gruninger S et al (1997) Detection and quantification of the leptin receptor splice variants Ob-Ra, b, and, e in different mouse tissues. Biochem Biophys Res Commun 238(2):648–652

    Article  CAS  PubMed  Google Scholar 

  • Lord GM, Matarese G et al (1998) Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394(6696):897–901

    Article  CAS  PubMed  Google Scholar 

  • Ludvik B, Kautzky-Willer A et al (1997) Amylin: history and overview. Diabet Med 14(Suppl 2):S9–S13

    Article  PubMed  Google Scholar 

  • Luheshi GN, Gardner JD et al (1999) Leptin actions on food intake and body temperature are mediated by IL-1. Proc Natl Acad Sci USA 96(12):7047–7052

    Article  CAS  PubMed  Google Scholar 

  • Luo N, Liu SM et al (2006) Allelic variation on chromosome 5 controls beta-cell mass expansion during hyperglycemia in leptin receptor-deficient diabetes mice. Endocrinology 147(5):2287–2295

    Article  CAS  PubMed  Google Scholar 

  • Meier CA, Bobbioni E et al (2002) IL-1 receptor antagonist serum levels are increased in human obesity: a possible link to the resistance to leptin? J Clin Endocrinol Metab 87(3):1184–1188

    Article  CAS  PubMed  Google Scholar 

  • Montague CT, Farooqi IS et al (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387(6636):903–908

    Article  CAS  PubMed  Google Scholar 

  • Myers MG Jr (2004) Leptin receptor signaling and the regulation of mammalian physiology. Recent Prog Horm Res 59:287–304

    Article  CAS  PubMed  Google Scholar 

  • Overton JM, Williams TD et al (2001) Cardiovascular and metabolic responses to fasting and thermoneutrality are conserved in obese Zucker rats. Am J Physiol Regul Integr Comp Physiol 280(4):R1007–R1015

    CAS  PubMed  Google Scholar 

  • Pelleymounter MA, Cullen MJ et al (1995) Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269(5223):540–543

    Article  CAS  PubMed  Google Scholar 

  • Satoh N, Ogawa Y et al (1998) Satiety effect and sympathetic activation of leptin are mediated by hypothalamic melanocortin system. Neurosci Lett 249(2–3):107–110

    Article  CAS  PubMed  Google Scholar 

  • Schwartz MW, Baskin DG et al (1996) Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes 45(4):531–535

    Article  CAS  PubMed  Google Scholar 

  • Somm E, Henrichot E et al (2005) Decreased fat mass in interleukin-1 receptor antagonist-deficient mice: impact on adipogenesis, food intake, and energy expenditure. Diabetes 54(12):3503–3509

    Article  CAS  PubMed  Google Scholar 

  • Somm E, Cettour-Rose P et al (2006) Interleukin-1 receptor antagonist is upregulated during diet-induced obesity and regulates insulin sensitivity in rodents. Diabetologia 49(2):387–393

    Article  CAS  PubMed  Google Scholar 

  • Spanswick D, Smith MA et al (1997) Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature 390(6659):521–525

    Article  CAS  PubMed  Google Scholar 

  • Tartaglia LA (1997) The leptin receptor. J Biol Chem 272(10):6093–6096

    CAS  PubMed  Google Scholar 

  • Trayhurn P, James WP (1978) Thermoregulation and non-shivering thermogenesis in the genetically obese (ob/ob) mouse. Pflugers Arch 373(2):189–193

    Article  CAS  PubMed  Google Scholar 

  • Unger RH, Zhou YT et al (1999) Regulation of fatty acid homeostasis in cells: novel role of leptin. Proc Natl Acad Sci USA 96(5):2327–2332

    Article  CAS  PubMed  Google Scholar 

  • Vaisse C, Halaas JL et al (1996) Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat Genet 14(1):95–97

    Article  CAS  PubMed  Google Scholar 

  • Wu-Peng XS, Chua SC Jr et al (1997) Phenotype of the obese Koletsky (f) rat due to Tyr763Stop mutation in the extracellular domain of the leptin receptor (Lepr): evidence for deficient plasma-to-CSF transport of leptin in both the Zucker and Koletsky obese rat. Diabetes 46(3):513–518

    Article  CAS  PubMed  Google Scholar 

  • Yu WH, Kimura M et al (1997) Role of leptin in hypothalamic-pituitary function. Proc Natl Acad Sci USA 94(3):1023–1028

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Proenca R et al (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505):425–432

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

These studies were supported by funds from The Harold L. Dorris Neurological Institute endowment and from grants from the Skaggs Institute of Chemical Biology.

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Correspondence to Olivia Osborn.

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Osborn, O., Sanchez-Alavez, M., Brownell, S.E. et al. Metabolic Characterization of a Mouse Deficient in All Known Leptin Receptor Isoforms. Cell Mol Neurobiol 30, 23–33 (2010). https://doi.org/10.1007/s10571-009-9427-x

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  • DOI: https://doi.org/10.1007/s10571-009-9427-x

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