Increased glucose metabolism and insulin sensitivity in transgenic skinny mice overexpressing leptin

被引:170
作者
Ogawa, Y
Masuzaki, H
Hosoda, K
Aizawa-Abe, M
Suga, J
Suda, M
Ebihara, K
Iwai, H
Matsuoka, N
Satoh, N
Odaka, H
Kasuga, H
Fujisawa, Y
Inoue, G
Nishimura, H
Yoshimasa, Y
Nakao, K
机构
[1] Kyoto Univ, Grad Sch Med, Dept Med & Clin Sci, Sakyo Ku, Kyoto 6068507, Japan
[2] Takeda Chem Ind Ltd, Div Pharmaceut Res, Osaka 532, Japan
关键词
D O I
10.2337/diabetes.48.9.1822
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Excess of body fat, or obesity, is a major health problem and confers a higher risk of cardiovascular and metabolic disorders such as diabetes, hypertension, and coronary heart disease. Leptin is an adipocyte-derived satiety factor that plays an important role in the regulation of energy homeostasis, and its synthesis and secretion are markedly increased in obese subjects. To explore the metabolic consequences of an increased amount of leptin on a long-term basis in vivo, we generated transgenic skinny mice with elevated plasma leptin concentrations comparable to those in obese subjects. Overexpression of leptin in the liver has resulted in complete disappearance of white and brown adipose tissue for a long period of time in mice. Transgenic skinny mice exhibit increased glucose metabolism accompanied by the activation of insulin signaling in the skeletal muscle and liver. They also show small-sized livers with a marked decrease in glycogen and lipid storage. The phenotypes are in striking contrast to those of recently reported animal models of lipoatrophic diabetes and patients with lipoatrophic diabetes with reduced amount of leptin. The present study provides evidence that leptin is an adipocyte-derived antidiabetic hormone in vivo and suggests its pathophysiologic and therapeutic implications in diabetes.
引用
收藏
页码:1822 / 1829
页数:8
相关论文
共 44 条
[1]   CELLULAR AND MOLECULAR ASPECTS OF ADIPOSE-TISSUE DEVELOPMENT [J].
AILHAUD, G ;
GRIMALDI, P ;
NEGREL, R .
ANNUAL REVIEW OF NUTRITION, 1992, 12 :207-233
[2]   Leptin enhances glycogen storage in hepatocytes by inhibition of phosphorylase and exerts an additive effect with insulin [J].
Aiston, S ;
Agius, L .
DIABETES, 1999, 48 (01) :15-20
[3]   Independent and additive effects of central POMC and leptin pathways on murine obesity [J].
Boston, BA ;
Blaydon, KM ;
Varnerin, J ;
Cone, RD .
SCIENCE, 1997, 278 (5343) :1641-1644
[4]   Genetics of human obesity: research directions [J].
Bray, G ;
Bouchard, C .
FASEB JOURNAL, 1997, 11 (12) :937-945
[5]   Troglitazone action is independent of adipose tissue [J].
Burant, CF ;
Sreenan, S ;
Hirano, KI ;
Tai, TAC ;
Lohmiller, J ;
Lukens, J ;
Davidson, NO ;
Ross, S ;
Graves, RA .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (11) :2900-2908
[6]   RECOMBINANT MOUSE OB PROTEIN - EVIDENCE FOR A PERIPHERAL SIGNAL LINKING ADIPOSITY AND CENTRAL NEURAL NETWORKS [J].
CAMPFIELD, LA ;
SMITH, FJ ;
GUISEZ, Y ;
DEVOS, R ;
BURN, P .
SCIENCE, 1995, 269 (5223) :546-549
[7]   Decreased cerebrospinal-fluid/serum leptin ratio in obesity: A possible mechanism for leptin resistance [J].
Caro, JF ;
Kolaczynski, JW ;
Nyce, MR ;
Ohannesian, JP ;
Opentanova, I ;
Goldman, WH ;
Lynn, RB ;
Zhang, PL ;
Sinha, MK ;
Considine, RV .
LANCET, 1996, 348 (9021) :159-161
[8]   Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy [J].
Chen, GX ;
Koyama, K ;
Yuan, X ;
Lee, Y ;
Zhou, YT ;
ODoherty, R ;
Newgard, CB ;
Unger, RH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (25) :14795-14799
[9]   Serum immunoreactive leptin concentrations in normal-weight and obese humans [J].
Considine, RV ;
Sinha, MK ;
Heiman, ML ;
Kriauciunas, A ;
Stephens, TW ;
Nyce, MR ;
Ohannesian, JP ;
Marco, CC ;
McKee, LJ ;
Bauer, TL ;
Caro, JF .
NEW ENGLAND JOURNAL OF MEDICINE, 1996, 334 (05) :292-295
[10]   Chronic central leptin infusion enhances insulin-stimulated glucose metabolism and favors the expression of uncoupling proteins [J].
Cusin, I ;
Zakrzewska, KE ;
Boss, O ;
Muzzin, P ;
Giacobino, JP ;
Ricquier, D ;
Jeanrenaud, B ;
Rohner-Jeanrenaud, F .
DIABETES, 1998, 47 (07) :1014-1019