Leptin increases hepatic insulin sensitivity and protein tyrosine phosphatase 1B expression

Mol Endocrinol. 2004 Jun;18(6):1333-45. doi: 10.1210/me.2002-0193. Epub 2004 Feb 19.


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 d of leptin treatment improved fasting but not postprandial 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, overexpression 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 counterregulate insulin action and to maintain insulin signaling in proper balance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Blood Glucose / metabolism
  • Body Weight
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Glucose / metabolism
  • Glucose Tolerance Test
  • Hepatocytes / metabolism
  • Humans
  • Immunoblotting
  • Insulin / metabolism*
  • Insulin Secretion
  • Leptin / metabolism*
  • Liver / metabolism*
  • Mice
  • Mice, Obese
  • Muscle, Skeletal / metabolism
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases / metabolism*
  • Receptor, Insulin / metabolism
  • Receptors, Cell Surface / metabolism
  • Receptors, Leptin
  • Signal Transduction
  • Time Factors
  • Transfection
  • Up-Regulation


  • Blood Glucose
  • Insulin
  • Leptin
  • Receptors, Cell Surface
  • Receptors, Leptin
  • leptin receptor, human
  • leptin receptor, mouse
  • Receptor, Insulin
  • PTPN1 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases
  • Ptpn1 protein, mouse
  • Glucose