Down-regulation of orexin gene expression by severe obesity in the rats: studies in Zucker fatty and Zucker diabetic fatty rats and effects of rosiglitazone

• Published in: Brain research. Molecular brain research. Vol. 77; no. 1; pp. 131 - 137
• Main Authors: Cai, Xue J., Lister, Carolyn A., Buckingham, Robin E., Pickavance, Lucy, Wilding, John, Arch, Jonathan R.S., Wilson, Shelagh, Williams, Gareth
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 14-04-2000; Elsevier
• Subjects: Animals; Biological and medical sciences; Blood Glucose - metabolism; Diabetes Mellitus - blood; Diabetes Mellitus - genetics; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene Expression Regulation - drug effects; Hyperglycemia - genetics; hypocretins; Hypoglycemic Agents - pharmacology; Hypothalamus - metabolism; Insulin - blood; Intracellular Signaling Peptides and Proteins; Leptin - blood; Medical sciences; Neuropeptides; Obesity; Obesity - genetics; Orexins; Orexins/hypocretins; Protein Precursors - genetics; Rats; Rats, Zucker; RNA, Messenger - genetics; Rosiglitazone; Thiazoles - pharmacology; thiazolidinedione; Thiazolidinediones; Thinness; Transcription, Genetic - drug effects; Zucker diabetic fatty rats; Zucker fatty rats; Obesity; Zucker diabetic fatty rats; thiazolidinedione; Zucker fatty rats; Neural basis of behaviour; Orexins/hypocretins; Endocrinopathy; Rat; Diabetes mellitus; Rodentia; Central nervous system; Hypothalamus; Gene expression; Neuropeptide; Feeding; Vertebrata; Mammalia; Animal; Brain (vertebrata)
• ISSN: 0169-328X; 1872-6941
• DOI: 10.1016/S0169-328X(00)00041-3

Orexins (hypocretins) are lateral hypothalamic neuropeptides implicated in regulating feeding and the sleep–wake cycle. To study their possible relevance to obesity and diabetes, we measured hypothalamic prepro-orexin mRNA levels in obese, normoglycemic Zucker fatty (
fa/fa) and in hyperglycemic, non-obese Zucker diabetic fatty (ZDF) rats. Hypothalamic prepro-orexin mRNA concentrations in Zucker fatty rats were 31% lower than those in lean controls (0.69±0.06 vs. 1.00±0.10 arbitrary units,
P<0.05), but did not differ between ZDF diabetic rats and non-diabetic controls. Treatment of ZDF diabetic rats with rosiglitazone (1 or 3 mg/kg body weight daily for 13 weeks) normalized plasma glucose and significantly reduced plasma insulin, while leptin levels were 67% higher than in untreated ZDF rats (20.2±0.5 vs. 12.1±2.5,
P<0.001). Rosiglitazone treatment markedly enhanced weight gain compared with untreated ZDF rats (final weight 732±13 g vs. 409±13 g,
P<0.001) even though they were restricted to the same food intake. Rosiglitazone-treated ZDF rats had significantly lower hypothalamic prepro-orexin mRNA levels (0.68±0.07 arbitrary units) than both non-diabetic lean controls (1.00±0.10,
P=0.02) and untreated diabetics (1.03±0.14,
P=0.03). Our data suggest that prepro-orexin gene expression may be suppressed by substantial weight gain. Obesity-related signals that might mediate this effect have not been identified, but plasma leptin, insulin and glucose are not obviously involved.