Effect of metformin on nitric oxide synthase in genetically obese (ob/ob) mice

Kumar, Vijaya B.; Bernardo, Adonis E.; Vyas, Kamlesh; Franko, Mark; Farr, Susan A.; Lakshmanan, Lakshmi; Buddhiraju, Chakradhar; Morley, John E.

doi:10.1016/s0024-3205(01)01359-5

Cited by 26 publications

(10 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The importance of lifestyle modifications in this study similarly reflected prior findings in Finland and China [47,48]. Metformin, which decreases insulin resistance and produces anorexia and weight loss, possibly through its effects on nitric oxide synthase [49,50], was not useful in delaying the onset of diabetes in persons over 60 years of age [51].…”

Section: Why Is Metabolic Syndrome In the Geriatric Population Importsupporting

confidence: 74%

Metabolic syndrome and the older male population

Mazza

Morley

2007

The Aging Male

Self Cite

View full text Add to dashboard Cite

Section: Why Is Metabolic Syndrome In the Geriatric Population Importsupporting

confidence: 74%

Metabolic syndrome and the older male population

Mazza

Morley

2007

The Aging Male

Self Cite

View full text Add to dashboard Cite

“…This is somewhat unexpected considering the orexigenic action of ghrelin [17,18,19,20] and the well-documented inhibitory effect of metformin on food intake [3,4,5,6,7,8,9]. Our data, however, resolve this discrepancy by demonstrating that metformin could actually block the action of ghrelin in the hypothalamus, thus presumably counteracting the stimulatory effect on circulating ghrelin levels.…”

Section: Discussionmentioning

confidence: 43%

“…The observed effect was associated with the inhibition of ghrelin-triggered activation of hypothalamic AMPK, as well as with the restoration of mTOR activity. These data suggest that the previously well-documented anorexigenic effect of metformin [3,4,5,6,7,8,9] could, at least partly, be mediated at the hypothalamic level through interference with ghrelin-induced orexigenic AMPK signalling.…”

Section: Discussionmentioning

confidence: 51%

“…Metformin has also been suggested to reduce weight in diabetic and non-diabetic patients, in contrast to sulphonylureas, thiazolidinediones and insulin, which all induce weight gain [2]. The positive effect of metformin on weight control has been associated with reduced food intake both in humans and experimental animals [3,4,5,6,7,8,9], but the mechanisms responsible for the metformin-mediated reduction of food consumption have not been fully clarified. Consistent with the ability of orally administered metformin to readily cross the blood-brain barrier [10], some recent data suggest that its anorexigenic effect might result from a direct action on the hypothalamic centres regulating satiety and feeding [11,12,13].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Intracerebroventricular Administration of Metformin Inhibits Ghrelin-Induced Hypothalamic AMP-Kinase Signalling and Food Intake

Stevanović¹,

Janjetović

Misirkić

et al. 2012

Neuroendocrinology

View full text Add to dashboard Cite

Background/Aims: The antihyperglycaemic drug metformin reduces food consumption through mechanisms that are not fully elucidated. The present study investigated the effects of intracerebroventricular administration of metformin on food intake and hypothalamic appetite-regulating signalling pathways induced by the orexigenic peptide ghrelin. Methods: Rats were injected intracerebroventricularly with ghrelin (5 µg), metformin (50, 100 or 200 µg), 5-amino-imidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR, 25 µg) and L-leucine (1 µg) in different combinations. Food intake was monitored during the next 4 h. Hypothalamic activation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), regulatory-associated protein of mTOR (Raptor), mammalian target of rapamycin (mTOR) and p70 S6 kinase 1 (S6K) after 1 h of treatment was analysed by immunoblotting. Results: Metformin suppressed the increase in food consumption induced by intracerebroventricular ghrelin in a dose-dependent manner. Ghrelin increased phosphorylation of hypothalamic AMPK and its targets ACC and Raptor, which was associated with the reduced phosphorylation of mTOR. The mTOR substrate, S6K, was activated by intracerebroventricular ghrelin despite the inhibition of mTOR. Metformin treatment blocked ghrelin-induced activation of hypothalamic AMPK/ACC/Raptor and restored mTOR activity without affecting S6K phosphorylation. Metformin also reduced food consumption induced by the AMPK activator AICAR while the ghrelin-triggered food intake was inhibited by the mTOR activator L-leucine. Conclusion: Metformin could reduce food intake by preventing ghrelin-induced AMPK signalling and mTOR inhibition in the hypotalamus.

show abstract

“…The levels of the two oxidative products of NO metabolism, nitrites, and nitrates were found to be higher in ob/ob livers than in lean littermates, confirming NOS induction in ob/ob livers. 32,33 In contrast, nitrosothiols, a combination of NO with thiol (SH) groups, 34 are significantly reduced in livers from ob/ob animals despite the increased production of NO. Indeed, the formation of nitrosothiols does not depend only on the availability of NO, but also on the degree of oxidative stress affecting the steady-state concentration of SH radicals, as exemplified by the increase in nitrosothiol concentration in fibroblasts treated with SOD.…”

Section: Discussionmentioning

confidence: 99%

Pivotal role of superoxide anion and beneficial effect of antioxidant molecules in murine steatohepatitis

et al. 2004

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease, frequently associated with obesity, can lead to nonalcoholic steatohepatitis (NASH) and cirrhosis. The pathophysiology of NASH is poorly understood, and no effective treatment is available. In view of a potential deleterious role for reactive oxygen species (ROS), we investigated the origin of ROS overproduction in NASH. Mitochondrial production of ROS and its alterations in the presence of antioxidant molecules were studied in livers from ob/ob mice that bear a mutation of the leptin gene and develop experimental NASH. N-acetyl-cysteine and the superoxide dismutase (SOD) mimics ambroxol, manganese [III] tetrakis (5,10,15,20 benzoic acid) (MnTBAP), and copper [II] diisopropyl salicylate (CuDIPS) were used to target different checkpoints of the oxidative cascade to determine the pathways involved in ROS production. Liver mitochondria from ob/ob mice generated more O 2°؊ than those of lean littermates (P < .01). Ex vivo, all three SOD mimics decreased O 2°؊ generation (P < .001) and totally inhibited lipid peroxidation (P < .001) versus untreated ob/ob mice. Those modifications were associated with in vivo improvements: MnTBAP and CuDIPS reduced weight (P < .02) and limited the extension of histological liver steatosis by 30% and 52%, respectively, versus untreated ob/ob mice. In conclusion, these data demonstrate deleterious effects of superoxide anions in NASH and point at the potential interest of nonpeptidyl mimics of SOD in the treatment of NASH in

show abstract

Effect of metformin on nitric oxide synthase in genetically obese (ob/ob) mice

Cited by 26 publications

References 0 publications

Metabolic syndrome and the older male population

Metabolic syndrome and the older male population

Intracerebroventricular Administration of Metformin Inhibits Ghrelin-Induced Hypothalamic AMP-Kinase Signalling and Food Intake

Pivotal role of superoxide anion and beneficial effect of antioxidant molecules in murine steatohepatitis

Contact Info

Product

Resources

About