title: Loss of the anorexic response to systemic 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside administration despite reducing hypothalamic AMP-activated protein kinase phosphorylation in insulin-deficient rats.
abstract: This study tested whether chronic systemic administration of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) could attenuate hyperphagia, reduce lean and fat mass losses, and improve whole-body energy homeostasis in insulin-deficient rats. Male Wistar rats were first rendered diabetic through streptozotocin (STZ) administration and then intraperitoneally injected with AICAR for 7 consecutive days. Food and water intake, ambulatory activity, and energy expenditure were assessed at the end of the AICAR-treatment period. Blood was collected for circulating leptin measurement and the hypothalami were extracted for the determination of suppressor of cytokine signaling 3 (SOCS3) content, as well as the content and phosphorylation of AMP-kinase (AMPK), acetyl-CoA carboxylase (ACC), and the signal transducer and activator of transcription 3 (STAT3). Rats were thoroughly dissected for adiposity and lean body mass (LBM) determinations. In non-diabetic rats, despite reducing adiposity, AICAR increased (∼1.7-fold) circulating leptin and reduced hypothalamic SOCS3 content and food intake by 67% and 25%, respectively. The anorexic effect of AICAR was lost in diabetic rats, even though hypothalamic AMPK and ACC phosphorylation markedly decreased in these animals. Importantly, hypothalamic SOCS3 and STAT3 levels remained elevated and reduced, respectively, after treatment of insulin-deficient rats with AICAR. Diabetic rats were lethargic and displayed marked losses of fat and LBM. AICAR treatment increased ambulatory activity and whole-body energy expenditure while also attenuating diabetes-induced fat and LBM losses. In conclusion, AICAR did not reverse hyperphagia, but it promoted anti-catabolic effects on skeletal muscle and fat, enhanced spontaneous physical activity, and improved the ability of rats to cope with the diabetes-induced dysfunctional alterations in glucose metabolism and whole-body energy homeostasis.
authors: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, SP, Brazil.
authors: Kaio F
authors: KF
authors: Vitzel
authors: George
authors: G
authors: Bikopoulos
authors: Steven
authors: S
authors: Hung
authors: Rui
authors: R
authors: Curi
authors: Rolando B
authors: RB
authors: Ceddia
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001067:Appetite Depressants / Q000008:administration & dosage / Q000494:pharmacology; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003920:Diabetes Mellitus / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004326:Drinking / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D007328:Insulin / Q000097:blood / Q000172:deficiency*; D020738:Leptin / Q000097:blood / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012263:Ribonucleosides / Q000008:administration & dosage* / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
chemical_list: D001067:Appetite Depressants; D007328:Insulin; D020738:Leptin; D012263:Ribonucleosides; D050796:STAT3 Transcription Factor; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase
references: Nature. 2004 Apr 1;428(6982):569-74
references: 15058305
references: Physiol Res. 2001;50(6):537-46
references: 11829314
references: Diabetes. 2010 Apr;59(4):894-906
references: 20068134
references: Diabetes. 2002 Mar;51(3):567-73
references: 11872652
references: Nat Med. 2004 Jul;10(7):739-43
references: 15208705
references: Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):251-62
references: 22436748
references: J Appl Physiol (1985). 1999 Nov;87(5):1990-5
references: 10562646
references: Am J Physiol. 1997 Dec;273(6):E1107-12
references: 9435525
references: J Biol Chem. 2005 Dec 2;280(48):39681-3
references: 16219771
references: Cell Metab. 2010 Jun 9;11(6):554-65
references: 20519126
references: Neurochem Int. 1989;15(4):485-91
references: 20504523
references: Diabetes. 2011 Mar;60(3):766-74
references: 21282366
references: Neurosci Lett. 2011 Jul 25;499(3):194-8
references: 21658429
references: J Lipid Res. 2011 Sep;52(9):1702-11
references: 21737753
references: Cell Signal. 2011 Dec;23(12):1896-906
references: 21821120
references: Diabetes. 2005 Apr;54(4):928-34
references: 15793229
references: Am J Physiol Cell Physiol. 2012 Sep 1;303(5):C475-85
references: 22700795
references: Curr Probl Pediatr Adolesc Health Care. 2012 Nov-Dec;42(10):269-91
references: 23046732
references: Neuroendocrinology. 2012;96(1):24-31
references: 22343549
references: PLoS One. 2013 Apr 19;8(4):e62190
references: 23620811
references: Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12624-9
references: 14532332
references: Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17358-63
references: 17956983
references: Diabetes. 2002 Jul;51(7):2199-206
references: 12086950
references: J Appl Physiol (1985). 2000 Jun;88(6):2219-26
references: 10846039
references: Nat Med. 2004 Jul;10(7):734-8
references: 15220914
references: Endocrinology. 2010 Jul;151(7):3460-9
references: 20410193
references: J Biol Chem. 2006 Oct 27;281(43):32207-16
references: 16943194
references: Am J Physiol. 1997 Aug;273(2 Pt 2):R725-30
references: 9277561
references: Cell Metab. 2006 Aug;4(2):123-32
references: 16890540
references: Trends Endocrinol Metab. 2009 Nov;20(9):460-8
references: 19800813
references: Future Med Chem. 2013 Mar;5(4):411-30
references: 23495689
references: J Neurosci. 2012 Nov 28;32(48):17097-107
references: 23197703
references: Metabolism. 2013 Feb;62(2):171-8
references: 22898253
references: Am J Physiol. 1980 Dec;239(6):E454-60
references: 6449876
references: J Histochem Cytochem. 1973 Jan;21(1):51-5
references: 4348494
references: Physiol Rev. 2013 Jan;93(1):137-88
references: 23303908