Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell‐permeable activator of AMP‐activated protein kinase

Sullivan, John T.; Brocklehurst, Katy J.; Marley, Anna; Carey, Frank; Carling, David; Beri, Raj K.

doi:10.1016/0014-5793(94)01006-4

Cited by 454 publications

(365 citation statements)

References 25 publications

Supporting

Mentioning

336

Contrasting

Unclassified

Order By: Relevance

“…Activation of AMPK by AICAR has been shown to inhibit lipolysis and lipogenesis in vitro in adipocytes [8,24,25] and in vivo in both lean and insulin-resistant obese rat models [5]. This study is the first to demonstrate that i.v.…”

Section: Discussionmentioning

confidence: 66%

“…It acts as a cellular energy sensor, and is activated by metabolic stress, such as hypoxia, and muscle contraction [1]. AMPK controls both fatty acid and carbohydrate metabolism [2][3][4][5][6] by increasing skeletal muscle glucose [2,4,6,7] and fatty acid [2,3] uptake and/or oxidation, suppression of hepatic glucose output [4] and inhibition of adipose tissue lipolysis [5,8]. Importantly, AMPK regulates these processes in an insulin-independent manner.…”

Section: Introductionmentioning

confidence: 99%

“…AMPK is activated by 5-aminoimidazole-4-carboxamide riboside (AICAR) in skeletal muscle [2][3][4], adipocytes [8] and hepatocytes [17]. Although this agent has been widely used to study the metabolic effects of AMPK activation in rodents [2-4, 8, 17], studies investigating the effect of AICAR on AMPK-regulated substrate metabolism in human tissue are scarce [13,14,18].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients

et al. 2008

View full text Add to dashboard Cite

Aims/hypothesis The 5′-AMP-activated protein kinase (AMPK) pathway is intact in type 2 diabetic patients and is seen as a target for diabetes treatment. In this study, we aimed to assess the impact of the AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR) on both glucose and fatty acid metabolism in vivo in type 2 diabetic patients.Methods Stable isotope methodology and blood and muscle biopsy sampling were applied to assess blood glucose and fatty acid kinetics following continuous i.v. infusion of AICAR (0.75 mg kg −1 min −1 ) and/or NaCl (0.9%) in ten male type 2 diabetic patients (age 64±2 years; BMI 28±1 kg/m 2 ). Results Plasma glucose rate of appearance (R a ) was reduced following AICAR administration, while plasma glucose rate of disappearance (R d ) was similar in the AICAR and control test. Consequently, blood glucose disposal (R d expressed as a percentage of R a ) was increased following AICAR infusion (p<0.001). Accordingly, a greater decline in plasma glucose concentration was observed following AICAR infusion (p<0.001). Plasma NEFA R a and R d were both significantly reduced in response to AICAR infusion, and were accompanied by a significant decline in plasma NEFA concentration. Although AMPK phosphorylation in skeletal muscle was not increased, we observed a significant increase in acetyl-CoA carboxylase phosphorylation (p<0.001). Conclusions/interpretation The i.v. administration of AICAR reduces hepatic glucose output, thereby lowering blood glucose concentrations in vivo in type 2 diabetic patients. Furthermore, AICAR administration stimulates hepatic fatty acid oxidation and/or inhibits whole body lipolysis, thereby reducing plasma NEFA concentration.

show abstract

Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Circulating amounts of NEFA and triglyceride were increased in diabetic mice following 7-days of AICAR treatment. Because AI-CAR treatment inhibits lipogenesis through increased phosphorylation of acetyl-CoA carboxylase [37], these deleterious effects of AICAR on the blood lipid profile are not surprising. Increased plasma NEFA is probably due to increased lipolysis in adipocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Increased plasma NEFA is probably due to increased lipolysis in adipocytes. Short-term (60 min) AICAR exposure in isolated adipocytes inhibits isoprenaline-stimulated lipolysis, without any significant direct effect [10,37]. Activation of AMPK by AICAR is known to phosphorylate and inhibit acetyl CoA carboxylase, leading to a decrease in malonyl CoA and an increase in fatty acid oxidation [38,39].…”

Section: Discussionmentioning

confidence: 99%

5-Aminoimidazole-4-carboxamide ribonucleoside treatment improves glucose homeostasis in insulin-resistant diabetic (ob/ob) mice

et al. 2002

View full text Add to dashboard Cite

Type II (non-insulin-dependent) diabetes mellitus is one of the major causes of disability and death, these being due to the complications accompanying the disease, [1]. Today, the therapeutic tools commonly utilised to treat Type II diabetes mellitus include diet, exercise, anti-diabetic drugs and insulin treatment. These therapies have been successful in keeping metabolic control within an acceptable range. However, the management of Type II diabetes mellitus has failed with respect to the prevention of the disease Diabetologia (2002) AbstractAims/hypothesis. The 5'AMP-activated protein kinase is an important mediator of muscle contractioninduced glucose transport and a target for pharmacological treatment of Type II (non-insulin-dependent) diabetes mellitus. The 5'AMP-activated protein kinase can be activated by 5-aminoimidazole-4-carboxamide ribonucleoside. We hypothesised that 5-aminoimidazole-4-carboxamide ribonucleoside treatment could restore glucose homeostasis in ob/ob mice. Methods. Lean and ob/ob mice were given 5-aminoimidazole-4-carboxamide ribonucleoside (1 mg´g body wt ±1´d ay ±1 s.c) or 0.9 % NaCl (vehicle) for 1±7 days. Results. Short-term 5-aminoimidazole-4-carboxamide ribonucleoside treatment normalised glucose concentrations in ob/ob mice within 1 h, with effects persisting over 4 h. After 1 week of daily injections, 5-aminoimidazole-4-carboxamide ribonucleoside treatment corrected hyperglycaemia, improved glucose tolerance, and increased GLUT4 and hexokinase II protein expression in skeletal muscle, but had deleterious effects on plasma non-esterified fatty acids and triglycerides. Treatment with 5-aminoimidazole-4-carboxamide ribonucleoside increased liver glycogen in fasted and fed ob/ob mice and muscle glycogen in fasted, but not fed ob/ob and lean mice. Defects in insulin-stimulated phosphatidylinositol 3-kinase and glucose transport in skeletal muscle from ob/ob mice were not corrected by 5-aminoimidazole-4-carboxamide ribonucleoside treatment. While ex vivo insulin-stimulated glucose transport was reduced in isolated muscle from ob/ob mice, the 5-aminoimidazole-4-carboxamide ribonucleoside stimulated response was normal. Conclusion/interpretation. The 5-aminoimidazole-4-carboxamide ribonucleoside mediated improvements in glucose homeostasis in ob/ob mice can be explained by effects in skeletal muscle and liver. Due to the apparently deleterious effects of 5-aminoimidazole-4-carboxamide ribonucleoside on the blood lipid profile, strategies to develop tissue-specific and pathway-specific activators of 5'AMP-activated protein kinase should be considered in order to improve glucose homeostasis. [Diabetologia (2002) 45: 56±65] Keywords Glucose transport, glycogen, lipids, insulin signalling, glucose tolerance, obesity, GLUT4, hexokinase II, glycogen synthase, myocyte enhancer factor 2. Corresponding author: J. R. Zierath, Department of Physiology and Pharmacology, Integrative Physiology Karolinska Institutet, von Eulers väg 4, II, Stockholm, Sweden, e-mail: Juleen. Zierath@fyfa.ki.se...

show abstract

Involvement of purine nucleotide synthetic pathways in gonadotropin-induced meiotic maturation in mouse cumulus cell-enclosed oocytes

Downs

1997

Mol. Reprod. Dev.

View full text Add to dashboard Cite

This study was carried out to test the hypothesis that purine nucleotide‐generating pathways are required for ligand‐stimulated oocyte maturation in meiotically arrested cumulus cell‐enclosed oocytes. Oo‐cytes from hormonally primed, immature mice were cultured overnight in Eagle's minimum essential medium containing dibutyryl cyclic AMP (dbcAMP) (to maintain meiotic arrest), plus either mycophenolic acid or alanosine (inhibitors of guanyl and adenyl nucleotide production, respectively). Follicle‐stimulating hormone (FSH) was added either at the outset of culture or after a 3‐hr preincubation period. Under either of these conditions, the inhibitors suppressed FSH induction of germinal vesicle breakdown (GVB). In addition, the potency of FSH as an inducer of GVB was reduced following the 3‐hr preincubation period, but this could be prevented if nucleotide precursors such as hypoxanthine, guanosine, or adenosine were included during the first 3 hr. Furthermore, preincubation had little effect on FSH induction of GVB when hypoxanthine was used to maintain meiotic arrest for the entire culture period. The phosphodiesterase inhibitor, 3‐isobutyl‐l‐methylxanthine, could not mimic this protective effect of hypoxanthine. Azaserine and aminopterin, inhibitors of purine de novo synthesis, blocked hormone‐triggered maturation in dbcAMP‐arrested oocytes, but had little effect on hypoxanthine‐arrested oocytes. The effect of azaserine on dbcAMP‐treated oocytes could be reversed by the inclusion of AICA riboside, a compound that can be taken up by cells and phosphorylated to form AICAR, which can enter the purine de novo pathway at a point distal to the sites of azaserine inhibition. FSH was stimulatory to purine de novo synthesis, while azaserine, aminopterin, hypoxanthine, and AICA riboside all suppressed de novo synthesis in the presence or absence of FSH, with dbcAMP having no effect. HPLC analysis of 14C‐hypoxanthine metabolism in oocyte‐cumulus cell complexes revealed that changes in the pattern of purine metabolism did not mediate the meiosis‐inducing effect of FSH. These data support the conclusion that purine nucleotide‐generating pathways are vital participants in the mechanism(s) regulating hormone‐induced meiotic maturation, and that either the de novo or salvage pathway can fulfill this nucleotide requirement. Mol Reprod Dev 46:155–167, 1997. © 1997 Wiley‐Liss, Inc.

show abstract

Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell‐permeable activator of AMP‐activated protein kinase

Cited by 454 publications

References 25 publications

Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients

Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients

5-Aminoimidazole-4-carboxamide ribonucleoside treatment improves glucose homeostasis in insulin-resistant diabetic (ob/ob) mice

Involvement of purine nucleotide synthetic pathways in gonadotropin-induced meiotic maturation in mouse cumulus cell-enclosed oocytes

Contact Info

Product

Resources

About