Disruption of Hepatic Leptin Signaling Protects Mice From Age- and Diet-Related Glucose Intolerance

被引:66
作者
Huynh, Frank K. [1 ]
Levi, Jasna [1 ]
Denroche, Heather C. [1 ]
Gray, Sarah L. [1 ]
Voshol, Peter J. [2 ]
Neumann, Ursula H. [1 ]
Speck, Madeleine [1 ]
Chua, Streamson C. [3 ,4 ]
Covey, Scott D. [1 ,5 ]
Kieffer, Timothy J. [1 ,6 ]
机构
[1] Univ British Columbia, Inst Life Sci, Dept Cellular & Physiol Sci, Vancouver, BC V5Z 1M9, Canada
[2] Univ Cambridge, Inst Metab Sci, Metab Res Labs, Cambridge, England
[3] Albert Einstein Coll Med, Dept Med, New York, NY USA
[4] Albert Einstein Coll Med, Dept Neurosci, New York, NY USA
[5] Univ British Columbia, Inst Life Sci, Dept Biochem & Mol Biol, Vancouver, BC V5Z 1M9, Canada
[6] Univ British Columbia, Dept Surg, Vancouver, BC V5Z 1M9, Canada
基金
加拿大自然科学与工程研究理事会; 加拿大健康研究院;
关键词
PANCREATIC BETA-CELL; INSULIN SENSITIVITY; BODY-WEIGHT; OBESE GENE; KEY SITE; RECEPTOR; RESISTANCE; NEURONS; CRE; HYPERINSULINEMIA;
D O I
10.2337/db10-0074
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
OBJECTIVE The liver plays a critical role in integrating and controlling glucose metabolism. Thus, it is important that the liver receive and react to signals from other tissues regarding the nutrient status of the body. Leptin, which is produced and secreted from adipose tissue, is a hormone that relays information regarding the status of adipose depots to other parts of the body. Leptin has a profound influence on glucose metabolism, so we sought to determine if leptin may exert this effect in part through the liver. RESEARCH DESIGN AND METHODS To explore this possibility, we created mice that have disrupted hepatic leptin signaling using a Cre-lox approach and then investigated aspects of glucose metabolism in these animals. RESULTS The loss of hepatic leptin signaling did not alter body weight, body composition, or blood glucose levels in the mild fasting or random-fed state. However, mice with ablated hepatic leptin signaling had increased lipid accumulation in the liver. Further, as male mice aged or were fed a high-fat diet, the loss of hepatic leptin signaling protected the mice from glucose intolerance. Moreover, the mice displayed increased liver insulin sensitivity and a trend toward enhanced glucose-stimulated plasma insulin levels. Consistent with increased insulin sensitivity, mice with ablated hepatic leptin signaling had increased insulin-stimulated phosphorylation of Akt in the liver. CONCLUSIONS These data reveal that unlike a complete deficiency of leptin action, which results in impaired glucose homeostasis, disruption of leptin action in the liver alone increases hepatic insulin sensitivity and protects against age- and diet-related glucose intolerance. Thus, leptin appears to act as a negative regulator of insulin action in the liver. Diabetes 59:3032-3040, 2010
引用
收藏
页码:3032 / 3040
页数:9
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