Leptin transgene expression in the hypothalamus enforces euglycemia in diabetic, insulin-deficient nonobese Akita mice and leptin-deficient obese ob/ob mice

Peptides. 2006 Sep;27(9):2332-42. doi: 10.1016/j.peptides.2006.03.006. Epub 2006 Apr 18.


We have tested the hypothesis that sustained leptin action in the hypothalamus alone can engender and maintain euglycemia in wild type mice and in two monogenic diabetic models, the insulin-deficient nonobese Akita mice and the hyperinsulinemic leptin-deficient obese, ob/ob mice. A single intracerebroventricular injection of recombinant adeno-associated virus vector encoding leptin (rAAV-lep) enhanced leptin transgene expression in the hypothalamus without any evidence of leptin leakage to the peripheral circulation, and promptly reinstated euglycemia that persisted along with severe insulinopenia in all three genotypes through the 7-week period of observation. A comparative evaluation of known etiologic factors of hyperglycemia showed that this long-term benefit on glucose homeostasis was not due to diminished energy consumption, weight and adiposity, but was conferred by at least two mechanisms operating simultaneously, enhanced glucose metabolism to meet the demand for the rAAV-lep induced increased non-shivering thermogenesis mediated by brown adipose tissue and insulin hypersensitivity. These findings endorse the hypothesis that increased leptin action locally in the hypothalamus can impose euglycemia independent of pancreatic insulin, and central leptin reinforcement may serve as a newer adjunct therapy to treat type 1 and type 2 diabetes.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Blood Glucose / analysis*
  • Body Weight / genetics
  • Body Weight / physiology
  • Diabetes Mellitus / blood
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / metabolism*
  • Eating / genetics
  • Eating / physiology
  • Genetic Vectors / administration & dosage
  • Glucose Clamp Technique
  • Glucose Tolerance Test
  • Hypothalamus / cytology
  • Hypothalamus / metabolism*
  • Insulin / blood*
  • Insulin / genetics
  • Ion Channels / genetics
  • Ion Channels / metabolism
  • Leptin / genetics*
  • Leptin / metabolism
  • Male
  • Mice
  • Mice, Obese
  • Mice, Transgenic
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Time Factors
  • Transgenes
  • Uncoupling Protein 1


  • Blood Glucose
  • Insulin
  • Ion Channels
  • Leptin
  • Mitochondrial Proteins
  • Uncoupling Protein 1