Biguanides and thiazolidinediones inhibit stimulated lipolysis in human adipocytes through activation of AMP-activated protein kinase.
OBJECTIVE
In rodent adipocytes, activated AMP-activated protein kinase reduces the lipolytic rate. As the hypoglycaemic drugs metformin and thiazolidinediones activate this enzyme in rodents, we tested the hypothesis that in addition to their known actions they could have an anti-lipolytic effect in human adipocytes.


METHODS
Adipose tissue was obtained from individuals undergoing plastic surgery. Adipocytes were isolated and incubated with lipolytic agents (isoprenaline, atrial natriuretic peptide) and biguanides or thiazolidinediones. Lipolysis was quantified by the glycerol released in the medium. AMP-activated protein kinase activity and phosphorylation state were determined using standard procedures.


RESULTS
In human adipocytes, isoprenaline and atrial natriuretic peptide stimulated the lipolytic rate three- to fourfold. Biguanides and thiazolidinediones activated AMP-activated protein kinase and inhibited lipolysis by 30-40%, at least in part by inhibiting hormone-sensitive lipase translocation to the lipid droplet. Inhibition of AMP-activated protein kinase by compound C precluded this inhibitory effect on lipolysis. Stimulation of lipolysis also induced an activation of AMP-activated protein kinase concomitant with a drop in ATP concentration.


CONCLUSIONS
We show for the first time in human adipocytes that biguanides and thiazolidinediones activate AMP-activated protein kinase, thus counteracting lipolysis induced by lipolytic agents. In addition, beta-agonist- or ANP-stimulated lipolysis increases AMP-activated protein kinase activity. This is because of an increase in the AMP/ATP ratio, linked to activation of some of the released fatty acids into acyl-CoA. AMP-activated protein kinase activation could represent a physiological means of avoiding a deleterious drain of energy during lipolysis but could be used to restrain pharmacological release of fatty acids.
Bourron
O
O
Centre de Recherche des Cordeliers, INSERM, UMR-S 872, 15 rue de l'école de médecine, Paris F-75006, France.
Daval
M
M
Hainault
I
I
Hajduch
E
E
Servant
J M
JM
Gautier
J F
JF
Ferré
P
P
Foufelle
F
F
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000273:Adipose Tissue / Q000473:pathology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D019943:Amino Acid Substitution; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D050110:Bariatric Surgery; D001645:Biguanides / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D008066:Lipolysis / Q000187:drug effects*; D050177:Overweight / Q000378:metabolism / Q000601:surgery; D018579:Patient Selection; D012265:Ribonucleotides / Q000494:pharmacology; D012694:Serine / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology*; D013912:Threonine / Q000235:genetics
D000318:Adrenergic beta-Agonists; D001645:Biguanides; D012265:Ribonucleotides; D045162:Thiazolidinediones; D013912:Threonine; D000620:Aminoimidazole Carboxamide; D000249:Adenosine Monophosphate; D012694:Serine; D000255:Adenosine Triphosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase; C031143:AICA ribonucleotide