Disruption of hypothalamic leptin signaling in mice leads to early-onset obesity, but physiological adaptations in mature animals stabilize adiposity levels

Journal of Clinical Investigation

Volumn 120, Issue 8, 2010, Pages 2931-2941

  Ring, Laurence E ^a,b   Zeltser, Lori M ^b  

^a Och Spine at New York Presbyterian Hospitals   (United States)

^b NewYork Presbyterian Hospital   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CRE RECOMBINASE; LEPTIN; LEPTIN RECEPTOR;

ALLELE; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BODY FAT; BRAIN REGION; BRAIN STEM; COLD TOLERANCE; CONTROLLED STUDY; ENERGY EXPENDITURE; FEMALE; GROWTH REGULATION; HYPERPHAGIA; HYPOTHALAMUS; INSULIN RESISTANCE; MALE; MESENCEPHALON; MOUSE; NERVE CELL; NONHUMAN; OBESITY; ONSET AGE; PATHOPHYSIOLOGY; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; WEIGHT GAIN;

ADAPTATION, PHYSIOLOGICAL; ADIPOSITY; ANIMALS; BODY COMPOSITION; EATING; ENERGY METABOLISM; FEMALE; GLUCOSE; GROWTH; HYPOTHALAMUS; INSULIN RESISTANCE; LEPTIN; MALE; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; NUCLEAR PROTEINS; OBESITY; RECEPTORS, LEPTIN; SIGNAL TRANSDUCTION; STAT3 TRANSCRIPTION FACTOR; TRANSCRIPTION FACTORS;

EID: 77955296183     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI41985     Document Type: Article

References (70)

1. Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA. 2010;303(3):235-241.
2. Popkin BM. Recent dynamics suggest selected countries catching up to US obesity. Am J Clin Nutr. 2010;91(1):284S-288S.
3. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505): 425-432. (Pubitemid 24365442)
4. Maffei M, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med. 1995;1(11):1155-1161.
5. Tartaglia LA, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995;83(7):1263-1271.
6. Chen H, et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell. 1996;84(3):491-495.
7. Coleman DL. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia. 1978;14(3):141-148.
8. Halaas JL, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995;269(5223):543-546.
9. Pelleymounter MA, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 1995;269(5223):540-543.
10. Chua SC Jr, et al. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science. 1996;271(5251):994-996.
11. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science. 1995;269(5223):546-549.
12. Seeley RJ, et al. Intraventricular leptin reduces food intake and body weight of lean rats but not obese Zucker rats. Horm Metab Res. 1996;28(12):664-668.
13. Cohen P, et al. Selective deletion of leptin receptor in neurons leads to obesity. J Clin Invest. 2001;108(8):1113-1121. (Pubitemid 32995369)
14. de Luca C, et al. Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. J Clin Invest. 2005;115(12):3484-3493.
15. Elmquist JK, Bjørbaek C, Ahima RS, Flier JS, Saper CB. Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol. 1998;395(4):535-547. (Pubitemid 28226097)
16. Leshan RL, Björnholm M, Münzberg H, Myers MG Jr. Leptin receptor signaling and action in the central nervous system. Obesity (Silver Spring). 2006;14(suppl 5):208S-212S.
17. Hetherington AW, Ranson SW. Hypothalamic lesions and adiposity in the rat. Anat Rec. 1940;78(2):149-172.
18. Anand BK, Brobeck JR. Localization of a feeding center in the hypothalamus of the rat. Proc Soc Exp Biol Med. 1951;77(2):323-324.
19. Debons AF, Krimsky I, Maayan ML, Fani K, Jemenez FA. Gold thioglucose obesity syndrome. Fed Proc. 1977;36(2):143-147.
20. Lorden JF, Caudle A. Behavioral and endocrinological effects of single injections of monosodium glutamate in the mouse. Neurobehav Toxicol Teratol. 1986;8(5):509-519. (Pubitemid 17221700)
21. Morton GJ, et al. Arcuate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of Koletsky (fa(k)/fa(k)) rats. Endocrinology. 2003;144(5):2016-2024.
22. Coppari R, et al. The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity. Cell Metab. 2005;1(1):63-72.
23. Balthasar N, et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron. 2004;42(6): 983-991. (Pubitemid 38798236)
24. Dhillon H, et al. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron. 2006;49(2):191-203. (Pubitemid 43089637)
25. van de Wall E, et al. Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion. Endocrinology. 2008;149(4):1773-1785.
26. Grill HJ. Distributed neural control of energy balance: contributions from hindbrain and hypothalamus. Obesity (Silver Spring). 2006;14(suppl 5):216S-221S.
27. Hayes MR, et al. Endogenous leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation. Cell Metab. 2010;11(1):77-83.
28. Yadav VK, et al. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell. 2009;138(5):976-989.
29. Fulton S, et al. Leptin regulation of the mesoaccumbens dopamine pathway. Neuron. 2006;51(6):811-822. (Pubitemid 44374918)
30. Hommel JD, et al. Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron. 2006;51(6):801-810.
31. Leinninger GM, et al. Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding. Cell Metab. 2009;10(2):89-98.
32. Xu Q, Tam M, Anderson SA. Fate mapping Nkx2.1-lineage cells in the mouse telencephalon. J Comp Neurol. 2008;506(1):16-29. (Pubitemid 350293488)
33. McMinn JE, et al. An allelic series for the leptin receptor gene generated by CRE and FLP recombinase. Mamm Genome. 2004;15(9):677-685.
34. Bray GA, York DA. Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. Physiol Rev. 1979;59(3):719-809.
35. Mizuno K, Gonzalez FJ, Kimura S. Thyroid-specific enhancer-binding protein (T/EBP): cDNA cloning, functional characterization, and structural identity with thyroid transcription factor TTF-1. Mol Cell Biol. 1991;11(10):4927-4933. (Pubitemid 21895253)
36. Sussel L, Marin O, Kimura S, Rubenstein JL. Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum. Development. 1999;126(15):3359-3370. (Pubitemid 29396776)
37. Soriano P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet. 1999;21(1):70-71. (Pubitemid 29036285)
38. Smith JT, Acohido BV, Clifton DK, Steiner RA. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. J Neuroendocrinol. 2006;18(4):298-303.
39. Vaisse C, Halaas JL, Horvath CM, Darnell JE Jr, Stoffel M, Friedman JM. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat Genet. 1996;14(1):95-97. (Pubitemid 26301554)
40. Butler AA, Kozak LP. A recurring problem with the analysis of energy expenditure in genetic models expressing lean and obese phenotypes. Diabetes. 2010;59(2):323-329.
41. McMinn JE, et al. Neuronal deletion of Lepr elicits diabesity in mice without affecting cold tolerance or fertility. Am J Physiol Endocrinol Metab. 2005;289(3):E403-E411.
42. Bray GA. Endocrine disturbances and reduced sympathetic activity in the development of obesity. Infusionstherapie. 1990;17(3):124-130.
43. Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature. 2006;443(7109):289-295. (Pubitemid 44435142)
44. Bates SH, Myers MG. The role of leptin->STAT3 signaling in neuroendocrine function: an integrative perspective. J Mol Med. 2004;82(1):12-20.
45. Williams KW, Scott MM, Elmquist JK. From observation to experimentation: leptin action in the mediobasal hypothalamus. Am J Clin Nutr. 2009;89(3):985S-990S.
46. Luquet S, Perez FA, Hnasko TS, Palmiter RD. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science. 2005;310(5748):683-685. (Pubitemid 41528162)
47. Gropp E, et al. Agouti-related peptide-expressing neurons are mandatory for feeding. Nat Neurosci. 2005;8(10):1289-1291.
48. Bewick GA, et al. Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J. 2005;19(12):1680-1682.
49. Bates SH, et al. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature. 2003;421(6925):856-859.
50. Bjorbaek C, et al. Divergent roles of SHP-2 in ERK activation by leptin receptors. J Biol Chem. 2001;276(7):4747-4755. (Pubitemid 37371358)
51. Kloek C, Haq AK, Dunn SL, Lavery HJ, Banks AS, Myers MG Jr. Regulation of Jak kinases by intracellular leptin receptor sequences. J Biol Chem. 2002;277(44):41547-41555. (Pubitemid 35257458)
52. Wolff GL. Growth of inbred yellow (Aya) and non-yellow (Aa) mice in parabiosis. Genetics. 1963;48:1041-1058.
53. Huszar D, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 1997;88(1):131-141.
54. Belgardt BF, et al. PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response. Cell Metab. 2008;7(4):291-301.
55. Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG Jr, Schwartz MW. Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature. 2001;413(6858):794-795.
56. Bates SH, Myers MG Jr. The role of leptin receptor signaling in feeding and neuroendocrine function. Trends Endocrinol Metab. 2003;14(10):447-452.
57. Buettner C, Pocai A, Muse ED, Etgen AM, Myers MG Jr, Rossetti L. Critical role of STAT3 in leptin's metabolic actions. Cell Metab. 2006;4(1):49-60. (Pubitemid 43942253)
58. Rahmouni K, Sigmund CD, Haynes WG, Mark AL. Hypothalamic ERK mediates the anorectic and thermogenic sympathetic effects of leptin. Diabetes. 2009;58(3):536-542.
59. Skibicka KP, Grill HJ. Hindbrain leptin stimulation induces anorexia and hyperthermia mediated by hindbrain melanocortin receptors. Endocrinology. 2009;150(4):1705-1711.
60. Hayes MR, Skibicka KP, Bence KK, Grill HJ. Dorsal hindbrain 5?-adenosine monophosphate-activated protein kinase as an intracellular mediator of energy balance. Endocrinology. 2009;150(5):2175-2182.
61. Myers MG Jr, Münzberg H, Leinninger GM, Leshan RL. The geometry of leptin action in the brain: more complicated than a simple ARC. Cell Metab. 2009;9(2):117-123.
62. Bates SH, Dundon TA, Seifert M, Carlson M, Maratos-Flier E, Myers MG Jr. LRb-STAT3 signaling is required for the neuroendocrine regulation of energy expenditure by leptin. Diabetes. 2004;53(12):3067-3073. (Pubitemid 39564480)
63. Võikar V Kõks S, Vasar E, Rauvala H. Strain and gender differences in the behavior of mouse lines commonly used in transgenic studies. Physiol Behav. 2001;72(1-2):271-281. (Pubitemid 32184818)
64. Huo L, et al. Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metab. 2009;9(6):537-547.
65. Ahima RS, et al. Role of leptin in the neuroendocrine response to fasting. Nature. 1996;382(6588):250-252.
66. Morton GJ, Gelling RW, Niswender KD, Morrison CD, Rhodes CJ, Schwartz MW. Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab. 2005;2(6):411-420.
67. Chua S Jr, Liu SM, Li Q, Yang L, Thassanapaff VT, Fisher P. Differential beta cell responses to hyperglycaemia and insulin resistance in two novel congenic strains of diabetes (FVB- Lepr (db)) and obese (DBA- Lep (ob)) mice. Diabetologia. 2002;45(7):976-990. (Pubitemid 34762192)
68. Haluzik M, et al. Genetic background (C57BL/6J versus FVB/N) strongly influences the severity of diabetes and insulin resistance in ob/ob mice. Endocrinology. 2004;145(7):3258-3264. (Pubitemid 38829998)
69. Le Marchand-Brustel Y, Jeanrenaud B. Pre- and postweaning studies on development of obesity in mdb/ mdb mice. Am J Physiol. 1978;234(6):E568-E574. (Pubitemid 9125687)
70. Bates SH, Kulkarni RN, Seifert M, Myers MG Jr. Roles for leptin receptor/STAT3-dependent and -independent signals in the regulation of glucose homeostasis. Cell Metab. 2005;1(3):169-178. (Pubitemid 43960601)