title: In uncontrolled diabetes, thyroid hormone and sympathetic activators induce thermogenesis without increasing glucose uptake in brown adipose tissue.
abstract: Recent advances in human brown adipose tissue (BAT) imaging technology have renewed interest in the identification of BAT activators for the treatment of obesity and diabetes. In uncontrolled diabetes (uDM), activation of BAT is implicated in glucose lowering mediated by intracerebroventricular (icv) administration of leptin, which normalizes blood glucose levels in streptozotocin (STZ)-induced diabetic rats. The potent effect of icv leptin to increase BAT glucose uptake in STZ-diabetes is accompanied by the return of reduced plasma thyroxine (T4) levels and BAT uncoupling protein-1 (Ucp1) mRNA levels to nondiabetic controls. We therefore sought to determine whether activation of thyroid hormone receptors is sufficient in and of itself to lower blood glucose levels in STZ-diabetes and whether this effect involves activation of BAT. We found that, although systemic administration of the thyroid hormone (TR)β-selective agonist GC-1 increases energy expenditure and induces further weight loss in STZ-diabetic rats, it neither increased BAT glucose uptake nor attenuated diabetic hyperglycemia. Even when GC-1 was administered in combination with a β(3)-adrenergic receptor agonist to mimic sympathetic nervous system activation, glucose uptake was not increased in STZ-diabetic rats, nor was blood glucose lowered, yet this intervention potently activated BAT. Similar results were observed in animals treated with active thyroid hormone (T3) instead of GC-1. Taken together, our data suggest that neither returning normal plasma thyroid hormone levels nor BAT activation has any impact on diabetic hyperglycemia, and that in BAT, increases of Ucp1 gene expression and glucose uptake are readily dissociated from one another in this setting.
authors: Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, WA, USA.
authors: Miles E
authors: ME
authors: Matsen
authors: Joshua P
authors: JP
authors: Thaler
authors: Brent E
authors: BE
authors: Wisse
authors: Stephan J
authors: SJ
authors: Guyenet
authors: Thomas H
authors: TH
authors: Meek
authors: Kayoko
authors: K
authors: Ogimoto
authors: Alex
authors: A
authors: Cubelo
authors: Jonathan D
authors: JD
authors: Fischer
authors: Karl J
authors: KJ
authors: Kaiyala
authors: Michael W
authors: MW
authors: Schwartz
authors: Gregory J
authors: GJ
authors: Morton
mesh_terms: D000085:Acetates / Q000494:pharmacology; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism*; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D001823:Body Composition / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D004435:Eating / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006943:Hyperglycemia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D024101:Mitochondrial Proteins / Q000187:drug effects / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D013311:Streptozocin; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*; D022722:Thermogenesis / Q000187:drug effects / Q000502:physiology*; D037042:Thyroid Hormone Receptors beta / Q000819:agonists / Q000378:metabolism*; D014284:Triiodothyronine / Q000494:pharmacology; D000071256:Uncoupling Protein 1
chemical_list: D000085:Acetates; D058667:Adrenergic beta-3 Receptor Agonists; C413355:GC 1 compound; D007473:Ion Channels; D024101:Mitochondrial Proteins; D010636:Phenols; D022702:Receptors, Adrenergic, beta-3; D037042:Thyroid Hormone Receptors beta; C000604371:UCP1 protein, human; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; D014284:Triiodothyronine; D013311:Streptozocin; D005947:Glucose
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