| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on May 23, 2002
Accepted on February 11, 2004
Departments of Medicine and Physiology, University of Alberta, Edmonton, AB, Canada, T6G 2S2, Veterans Administration Medical Center, University of Tennessee, Memphis, Tennessee, TN, 38103, Division of Endocrinology, Diabetes and Hypertension, School of Medicine, University of California Los Angeles, 900 Veteran Ave, Warren Hall 24-130, Los Angeles, CA 90095and Department of Medicine, Louisiana State University School of Medicine, New Orleans, LA, 70112
* To whom correspondence should be addressed. E-mail: tim.kieffer{at}ubc.ca.
Leptin has been shown to improve insulin sensitivity and glucose metabolism in obese diabetic ob/ob mice, yet the mechanisms remain poorly defined. We found that 2 days of leptin treatment improved fasting but not post-prandial glucose homeostasis, suggesting enhanced hepatic insulin sensitivity. Consistent with this hypothesis, leptin improved in vivo insulin receptor (IR) activation in liver, but not in skeletal muscle or fat. To explore the cellular mechanism by which leptin up-regulates hepatic IR activation, we examined the expression of the protein tyrosine phosphatase PTP1B, recently implicated as an important negative regulator of insulin signaling. Unexpectedly, liver PTP1B protein abundance was increased by leptin to levels similar to lean controls, whereas levels in muscle and fat remained unchanged. The ability of leptin to augment liver IR activation and PTP1B expression was also observed in vitro in human hepatoma cells (HepG2). However, over-expression of PTP1B in HepG2 cells led to diminished insulin-induced IR phosphorylation supporting the role of PTP1B as a negative regulator of IR activation in hepatocytes. Collectively, our results suggest that leptin acutely improves hepatic insulin sensitivity in vivo with concomitant increases in PTP1B expression possibly serving to counter-regulate insulin action and to maintain insulin signaling in proper balance.
This article has been cited by other articles:
 |
|
 |
|
  J. M. Zabolotny, Y.-B. Kim, L. A. Welsh, E. E. Kershaw, B. G. Neel, and B. B. Kahn Protein-tyrosine Phosphatase 1B Expression Is Induced by Inflammation in Vivo J. Biol. Chem., May 23, 2008; 283(21): 14230 - 14241. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Alonso, R. Fernandez, M. Moreno, P. Ordonez, F. Diaz, and C. Gonzalez Leptin and Its Receptor Are Controlled by 17{beta}-Estradiol in Peripheral Tissues of Ovariectomized Rats Experimental Biology and Medicine, April 1, 2007; 232(4): 542 - 549. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Morrison, C. L. White, Z. Wang, S.-Y. Lee, D. S. Lawrence, W. T. Cefalu, Z.-Y. Zhang, and T. W. Gettys Increased Hypothalamic Protein Tyrosine Phosphatase 1B Contributes to Leptin Resistance with Age Endocrinology, January 1, 2007; 148(1): 433 - 440. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Girard The Inhibitory Effects of Insulin on Hepatic Glucose Production Are Both Direct and Indirect Diabetes, December 1, 2006; 55(Supplement_2): S65 - S69. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N T Lam, S D Covey, J T Lewis, S Oosman, T Webber, E C Hsu, A T Cheung, and T J Kieffer Leptin resistance following over-expression of protein tyrosine phosphatase 1B in liver J. Mol. Endocrinol., February 1, 2006; 36(1): 163 - 174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Li, G. Baquiran, F. Gu, M. L. Tremblay, A. Fazel, J. J. M. Bergeron, and B. I. Posner Insulin Receptor Kinase-Associated Phosphotyrosine Phosphatases in Hepatic Endosomes: Assessing the Role of Phosphotyrosine Phosphatase-1B Endocrinology, February 1, 2006; 147(2): 912 - 918. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. Thule, A. G. Campbell, D. J. Kleinhenz, D. E. Olson, J. J. Boutwell, R. L. Sutliff, and C. M. Hart Hepatic insulin gene therapy prevents deterioration of vascular function and improves adipocytokine profile in STZ-diabetic rats Am J Physiol Endocrinol Metab, January 1, 2006; 290(1): E114 - E122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Watson, S. Hahm, T. M. Mizuno, J. Windsor, C. Montgomery, P. E. Scherer, C. V. Mobbs, and S. R. J. Salton VGF Ablation Blocks the Development of Hyperinsulinemia and Hyperglycemia in Several Mouse Models of Obesity Endocrinology, December 1, 2005; 146(12): 5151 - 5163. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Moore, K. Kimura, H. Shibata, T. Honjoh, M. Saito, C. A. Everett, M. S. Smith, and A. D. Cherrington Portal 5-hydroxytryptophan infusion enhances glucose disposal in conscious dogs Am J Physiol Endocrinol Metab, August 1, 2005; 289(2): E225 - E231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. G. Haj, J. M. Zabolotny, Y.-B. Kim, B. B. Kahn, and B. G. Neel Liver-specific Protein-tyrosine Phosphatase 1B (PTP1B) Re-expression Alters Glucose Homeostasis of PTP1B-/-Mice J. Biol. Chem., April 15, 2005; 280(15): 15038 - 15046. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Moore, C. A. DiCostanzo, D. Dardevet, M. Lautz, B. Farmer, and A. D. Cherrington Interaction of a selective serotonin reuptake inhibitor with insulin in the control of hepatic glucose uptake in conscious dogs Am J Physiol Endocrinol Metab, March 1, 2005; 288(3): E556 - E563. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. X. Cawley, J. Zhou, J. M. Hill, D. Abebe, S. Romboz, T. Yanik, R. M. Rodriguiz, W. C. Wetsel, and Y. P. Loh The Carboxypeptidase E Knockout Mouse Exhibits Endocrinological and Behavioral Deficits Endocrinology, December 1, 2004; 145(12): 5807 - 5819. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Gutierrez-Juarez, S. Obici, and L. Rossetti Melanocortin-independent Effects of Leptin on Hepatic Glucose Fluxes J. Biol. Chem., November 26, 2004; 279(48): 49704 - 49715. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
