Transgenic complementation of leptin-receptor deficiency - I. Rescue of the obesity/diabetes phenotype of LEPR-null mice expressing a LEPR-B transgene

被引:110
作者
Kowalski, TJ
Liu, SM
Leibel, RL
Chua, SC
机构
[1] Columbia Univ Coll Phys & Surg, Dept Pediat, Div Mol Genet, New York, NY 10032 USA
[2] Columbia Univ Coll Phys & Surg, Naomi Berrie Diabet Ctr, New York, NY 10032 USA
关键词
D O I
10.2337/diabetes.50.2.425
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Mice homozygous for the Lepr(db3J) (db(3J)) mutation are null for all known isoforms of the leptin receptor (LEPR). These animals are obese, hyperphagic, cold intolerant, insulin resistant, and infertile. Mice homozygous for the Lepr(db) (db) mutation (lacking the B isoform only) have the same phenotype as db(3J) animals. To better understand the function(s) of the LEPR isoforms in vivo, we generated db(3J)/db(3J) and db/db mice bearing a transgene (neuron-specific enolase [NSE]Rb) expressing the B isoform of LEPR, the isoform capable of activating the signal transducer and activator of transcription (STAT) pathway, under the control of the neuron-specific enolase enhancer/promoter. The NSE-Rb transgene was expressed in the brain, with low levels of expression in adrenals, testis, and white adipose tissue. LEPR-B transgene expression in NSE-Rb db(3J)/db(3J) mice partially corrected the increased fat mass, hyperphagia, and glucose intolerance while restoring fertility in males and rescuing the cold intolerance in both sexes. The body weights of NSE-Rb transgenic mice that possessed the full complement of short LEPR isoforms (NSE-Rb db/db mice) were similar to those of NSE-Rb db(3J)/db(3J) mice, suggesting that the short LEPR isoforms play little role in body weight regulation. Based on quantitative analysis of hypothalamic neuropeptide gene expression in the transgenic animals, we infer full restoration of leptin sensitivity to proopiomelanocortin (POMC) neurons, partial correction of leptin sensitivity in agouti gene-related protein (AGRP)/neuropeptide Y (NPY) neurons, and a lack of effect on leptin sensitivity of melanin concentrating hormone neurons. Thus, hypothalamic POMC and AGRP/NPY neurons are primary candidates as the mediators of the effects of the NSE-Rb transgene on energy homeostasis, ingestive behavior, the neuroendocrine system, and glucose metabolism.
引用
收藏
页码:425 / 435
页数:11
相关论文
共 63 条
[1]   Role of leptin in the neuroendocrine response to fasting [J].
Ahima, RS ;
Prabakaran, D ;
Mantzoros, C ;
Qu, DQ ;
Lowell, B ;
MaratosFlier, E ;
Flier, JS .
NATURE, 1996, 382 (6588) :250-252
[2]   COMPARISON OF 3 ACTIN-CODING SEQUENCES IN THE MOUSE - EVOLUTIONARY RELATIONSHIPS BETWEEN THE ACTIN GENES OF WARM-BLOODED VERTEBRATES [J].
ALONSO, S ;
MINTY, A ;
BOURLET, Y ;
BUCKINGHAM, M .
JOURNAL OF MOLECULAR EVOLUTION, 1986, 23 (01) :11-22
[3]  
[Anonymous], 1994, MANIPULATING MOUSE E
[4]   DESCRIPTION OF A NEW MODEL OF GENETIC OBESITY - THE DBPAS MOUSE [J].
AUBERT, R ;
HERZOG, J ;
CAMUS, MC ;
GUENET, JL ;
LEMONNIER, D .
JOURNAL OF NUTRITION, 1985, 115 (03) :327-333
[5]   MOLECULAR MAPPING OF THE MOUSE DB MUTATION [J].
BAHARY, N ;
LEIBEL, RL ;
JOSEPH, L ;
FRIEDMAN, JM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (21) :8642-8646
[6]   Passage of leptin across the blood-testis barrier [J].
Banks, WA ;
McLay, RN ;
Kastin, AJ ;
Sarmiento, U ;
Scully, S .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 1999, 276 (06) :E1099-E1104
[7]   Leptin sensitive neurons in the hypothalamus [J].
Baskin, DG ;
Hahn, TM ;
Schwartz, MW .
HORMONE AND METABOLIC RESEARCH, 1999, 31 (05) :345-350
[8]   INTRONS INCREASE TRANSCRIPTIONAL EFFICIENCY IN TRANSGENIC MICE [J].
BRINSTER, RL ;
ALLEN, JM ;
BEHRINGER, RR ;
GELINAS, RE ;
PALMITER, RD .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1988, 85 (03) :836-840
[9]   Hypothalamic cocaine- and amphetamine-regulated transcript (CART) neurons: histochemical relationship to thyrotropin-releasing hormone, melanin-concentrating hormone, orexin/hypocretin and neuropeptide Y [J].
Broberger, C .
BRAIN RESEARCH, 1999, 848 (1-2) :101-113
[10]   The neuropeptide Y agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice [J].
Broberger, C ;
Johansen, J ;
Johansson, C ;
Schalling, M ;
Hökfelt, T .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (25) :15043-15048