Metformin inhibits catecholamine‐stimulated lipolysis in obese, hyperinsulinemic, hypertensive subjects in subcutaneous adipose tissue: an <i>in situ</i> microdialysis study

Flechtner-Mors, Marion; Ditschuneit, H.; Jenkinson, Christopher P.; Alt, Andreas; Adler, Guido

doi:10.1046/j.1464-5491.1999.00189.x

Cited by 26 publications

(28 citation statements)

References 37 publications

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“…An in situ microdialysis study indicated that pre-perfusion of metformin inhibited the release of glycerol in vivo in abdominal adipose tissue of obese and hyperinsulinemic subjects after administration of catecholamine (Flechtner-Mors et al 1999). However, this study did not investigate the cellular basis by which metformin lowered glycerol release from adrenaline-stimulated adipose tissue.…”

Section: Discussionmentioning

confidence: 86%

Metformin reduces lipolysis in primary rat adipocytes stimulated by tumor necrosis factor-α or isoproterenol

Ren

He²,

Jiang³

et al. 2006

Journal of Molecular Endocrinology

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In patients with type 2 non-insulin-dependent diabetes mellitus (NIDDM), the biguanide, metformin, exerts its antihyperglycemic effect by improving insulin sensitivity, which is associated with decreased level of circulating free fatty acids (FFA). The flux of FFA and glycerol from adipose tissue to the blood stream primarily depends on the lipolysis of triacylglycerols in the adipocytes. Adipocyte lipolysis is physiologically stimulated by catecholamine hormones. Tumor necrosis factor-a (TNF-a), a cytokine largely expressed in adipose tissue, stimulates chronic lipolysis, which may be associated with increased systemic FFA and insulin resistance in obesity and NIDDM. In this study, we examined the role of metformin in inhibiting lipolytic action upon various lipolytic stimulations in primary rat adipocytes. Treatment with metformin attenuated TNF-a-mediated lipolysis by suppressing phosphorylation of extracellular signal-related kinase 1/2 and reversing the downregulation of perilipin protein in TNF-a-stimulated adipocytes. The acute lipolytic response to adrenergic stimulation of isoproterenol was also restricted by metformin. A high concentration of glucose in the adipocyte culture promoted the basal rate of glycerol release and significantly enhanced the lipolytic action stimulated by either TNF-a or isoproterenol. Metformin not only inhibits the basal lipolysis simulated by high glucose, but also suppresses the high glucose-enhanced lipolysis response to TNF-a or isoproterenol. The antilipolytic action in adipocytes could be the mechanism by which cellular action by metformin reduces systemic FFA concentration and thus improves insulin sensitivity in obese patients and the hyperglycemic conditions of NIDDM.

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Section: Discussionmentioning

confidence: 86%

Metformin reduces lipolysis in primary rat adipocytes stimulated by tumor necrosis factor-α or isoproterenol

Ren

He²,

Jiang³

et al. 2006

Journal of Molecular Endocrinology

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show abstract

“…In addition, the patients received different forms of oral glucose-lowering pharmacotherapy, including metformin. Metformin can inhibit human lipolysis both in vivo and in in vitro adipocyte cultures [47,48]. However, the anti-lipolytic effect of metformin is observed only upon stimulated lipolysis, and should not affect the presently investigated spontaneous rate.…”

Section: Discussionmentioning

confidence: 99%

Increased fat cell size: a major phenotype of subcutaneous white adipose tissue in non-obese individuals with type 2 diabetes

et al. 2015

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Aims/hypothesis We aimed to elucidate the impact of fat cell size and inflammatory status of adipose tissue on the development of type 2 diabetes in non-obese individuals. Methods We characterised subcutaneous abdominal adipose tissue by examining stromal cell populations by 13 colour flow cytometry, measuring expression of adipogenesis genes in the progenitor cell fraction and determining lipolysis and adipose secretion of inflammatory proteins in 14 non-obese men with type 2 diabetes and 13 healthy controls matched for age, sex, body weight and total fat mass. Results Individuals with diabetes had larger fat cells than the healthy controls but stromal cell population frequencies, adipose lipolysis and secretion of inflammatory proteins did not differ between the two groups. However, in the entire cohort fat cell size correlated positively with the ratio of M1/M2 macrophages, TNF-α secretion, lipolysis and insulin resistance. Expression of genes encoding regulators of adipogenesis and adipose morphology (BMP4, CEBPα [also known as CEBPA], PPARγ [also known as PPARG] and EBF1) correlated negatively with fat cell size. Conclusions/interpretation We show that a major phenotype of white adipose tissue in non-obese individuals with type 2 diabetes is adipocyte hypertrophy, which may be mediated by an impaired adipogenic capacity in progenitor cells. Consequently, this could have an impact on adipose tissue inflammation, release of fatty acids, ectopic fat deposition and insulin sensitivity.

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“…These blots are representative of two independent experiments results showing an anti-lipolytic effect of both metformin and the related biguanide phenformin in rodent adipocytes [8,40], attributed for the latter drug to an activation of AMPK. Moreover, in humans, a perfusion of metformin in microdialysis experiments has an anti-lipolytic effect [22,41].…”

Section: Discussionmentioning

confidence: 99%

“…The biguanide metformin decreases the high hepatic glucose output observed in type 2 diabetes, whereas thiazolidinediones such as pioglitazone or rosiglitazone increase muscle glucose uptake in response to insulin and are called insulin sensitisers. Metformin and thiazolidinediones have been reported to decrease the plasma concentrations of non-esterified fatty acids in type 2 diabetic patients [17][18][19][20][21] and the lipolytic rate in obese humans [22][23][24]. In rodent adipocytes, biguanides and thiazolidinediones are able to activate AMPK, and biguanides are able to reduce lipolysis [8,25,26].…”

Section: Introductionmentioning

confidence: 99%

Biguanides and thiazolidinediones inhibit stimulated lipolysis in human adipocytes through activation of AMP-activated protein kinase

et al. 2009

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Aims/hypothesis In rodent adipocytes, activated AMPactivated 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. AMPactivated 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 AMPactivated protein kinase and inhibited lipolysis by 30-40%, at least in part by inhibiting hormone-sensitive lipase translocation to the lipid droplet. Inhibition of AMPactivated 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/interpretation 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, β-agonistor 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.

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Metformin inhibits catecholamine‐stimulated lipolysis in obese, hyperinsulinemic, hypertensive subjects in subcutaneous adipose tissue: an in situ microdialysis study

Cited by 26 publications

References 37 publications

Metformin reduces lipolysis in primary rat adipocytes stimulated by tumor necrosis factor-α or isoproterenol

Metformin reduces lipolysis in primary rat adipocytes stimulated by tumor necrosis factor-α or isoproterenol

Increased fat cell size: a major phenotype of subcutaneous white adipose tissue in non-obese individuals with type 2 diabetes

Biguanides and thiazolidinediones inhibit stimulated lipolysis in human adipocytes through activation of AMP-activated protein kinase

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