Disruption of hepatic leptin signaling protects mice from age- and diet-related glucose intolerance

Frank K. Huynh, Jasna Levi, Heather C. Denroche, Sarah L. Gray, Peter J. Voshol, Ursula H. Neumann, Madeleine Speck, Streamson C. Chua, Jr., Scott D. Covey, Timothy J. Kieffer

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3032-3040
Number of pages9
JournalDiabetes
Volume59
Issue number12
DOIs
StatePublished - Dec 2010

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Glucose Intolerance
Leptin
Diet
Liver
Glucose
Insulin Resistance
Insulin
High Fat Diet
Body Composition
Human Body
Blood Glucose
Adipose Tissue
Fasting

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Huynh, F. K., Levi, J., Denroche, H. C., Gray, S. L., Voshol, P. J., Neumann, U. H., ... Kieffer, T. J. (2010). Disruption of hepatic leptin signaling protects mice from age- and diet-related glucose intolerance. Diabetes, 59(12), 3032-3040. https://doi.org/10.2337/db10-0074

Disruption of hepatic leptin signaling protects mice from age- and diet-related glucose intolerance. / Huynh, Frank K.; Levi, Jasna; Denroche, Heather C.; Gray, Sarah L.; Voshol, Peter J.; Neumann, Ursula H.; Speck, Madeleine; Chua, Jr., Streamson C.; Covey, Scott D.; Kieffer, Timothy J.

In: Diabetes, Vol. 59, No. 12, 12.2010, p. 3032-3040.

Research output: Contribution to journalArticle

Huynh, FK, Levi, J, Denroche, HC, Gray, SL, Voshol, PJ, Neumann, UH, Speck, M, Chua, Jr., SC, Covey, SD & Kieffer, TJ 2010, 'Disruption of hepatic leptin signaling protects mice from age- and diet-related glucose intolerance', Diabetes, vol. 59, no. 12, pp. 3032-3040. https://doi.org/10.2337/db10-0074
Huynh FK, Levi J, Denroche HC, Gray SL, Voshol PJ, Neumann UH et al. Disruption of hepatic leptin signaling protects mice from age- and diet-related glucose intolerance. Diabetes. 2010 Dec;59(12):3032-3040. https://doi.org/10.2337/db10-0074
Huynh, Frank K. ; Levi, Jasna ; Denroche, Heather C. ; Gray, Sarah L. ; Voshol, Peter J. ; Neumann, Ursula H. ; Speck, Madeleine ; Chua, Jr., Streamson C. ; Covey, Scott D. ; Kieffer, Timothy J. / Disruption of hepatic leptin signaling protects mice from age- and diet-related glucose intolerance. In: Diabetes. 2010 ; Vol. 59, No. 12. pp. 3032-3040.
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