Agouti-related protein is a mediator of diabetic hyperphagia

Regul Pept. 2001 Apr 2;98(1-2):69-75. doi: 10.1016/s0167-0115(00)00230-5.

Abstract

To explore the role of agouti-related protein (AGRP) in diabetic hyperphagia changes in hypothalamic AGRP mRNA levels were examined in diabetic rats. Rats rendered diabetic by streptozotocin displayed marked hyperglycemia (blood glucose 456.0+/-8.4 mg/dl versus 71.8+/-1.9 mg/dl) and hyperphagia (36.9+/-1.0 g/day versus 22.0+/-0.4 g/day), that was associated with a 286.6+/-4.4% increase in hypothalamic AGRP mRNA and a 178.9+/-13.5% increase in hypothalamic NPY mRNA. Insulin treatment of diabetic rats partially corrected blood glucose (147.4+/-13.1 mg/dl) and ameliorated hyperphagia (26.6+/-2.0 g/day). Insulin replacement was also associated with a return of hypothalamic AGRP mRNA (111.7+/-8.3% of controls) and NPY mRNA (125.0+/-8.9% of controls) from the elevated levels that were observed in untreated diabetic rats. In contrast to insulin treated rats, sodium orthovanadate treated diabetic rats remained significantly hyperglycemic (361.5+/-12.5 mg/dl). However, despite their persistent hyperglycemia, orthovanadate treated diabetic rats were still observed to have a significant reduction of hypothalamic AGRP mRNA (138.7+/-11.4%) and NPY mRNA (129.9+/-9.8%). Simultaneous measurement of serum leptin revealed suppressed levels in both untreated diabetic (0.5+/-0.1 ng/ml) and sodium orthovanadate treated rats (0.5+/-0.1 ng/ml) compared to non-diabetic controls (2.1+/-0.1 ng/ml). These data indicate that AGRP is a mediator of diabetic hyperhpagia and suggest that insulin can directly influence hypothalamic AGRP and NPY mRNA expression.

Publication types

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

MeSH terms

  • Agouti-Related Protein
  • Animals
  • Blood Glucose / analysis
  • Body Weight / drug effects
  • Diabetes Mellitus, Experimental / complications*
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism
  • Drinking / drug effects
  • Eating / drug effects
  • Enzyme Inhibitors / pharmacology
  • Hyperphagia / metabolism*
  • Hypothalamus / metabolism
  • Insulin / blood
  • Insulin / pharmacology
  • Intercellular Signaling Peptides and Proteins
  • Leptin / blood
  • Male
  • Neuropeptide Y / drug effects
  • Neuropeptide Y / genetics
  • Neuropeptide Y / metabolism
  • Protein Tyrosine Phosphatases / antagonists & inhibitors
  • Proteins / genetics
  • Proteins / metabolism*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Vanadates / pharmacology

Substances

  • AGRP protein, rat
  • Agouti-Related Protein
  • Blood Glucose
  • Enzyme Inhibitors
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Leptin
  • Neuropeptide Y
  • Proteins
  • RNA, Messenger
  • Vanadates
  • Protein Tyrosine Phosphatases