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.
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.
Cai
X J
XJ
Diabetes and Endocrinology Research Group, Department of Medicine, University of Liverpool, Liverpool, UK. xjcai@liv.ac.uk
Lister
C A
CA
Buckingham
R E
RE
Pickavance
L
L
Wilding
J
J
Arch
J R
JR
Wilson
S
S
Williams
G
G
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D006943:Hyperglycemia / Q000235:genetics; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007031:Hypothalamus / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin / Q000097:blood; D009479:Neuropeptides; D009765:Obesity / Q000235:genetics*; D000068797:Orexins; D011498:Protein Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011924:Rats, Zucker; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D013851:Thinness; D014158:Transcription, Genetic / Q000187:drug effects
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D009479:Neuropeptides; D000068797:Orexins; D011498:Protein Precursors; D012333:RNA, Messenger; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone