Agouti-related protein is a mediator of diabetic hyperphagia.
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.
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Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. igantz@umich.edu
Yang
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Li
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Zeng
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Gantz
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D054369:Agouti-Related Protein; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006963:Hyperphagia / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin / Q000097:blood; D008297:Male; D009478:Neuropeptide Y / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014638:Vanadates / Q000494:pharmacology
C515197:AGRP protein, rat; D054369:Agouti-Related Protein; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D009478:Neuropeptide Y; D011506:Proteins; D012333:RNA, Messenger; D014638:Vanadates; D017027:Protein Tyrosine Phosphatases