Possible involvement of AMP‐activated protein kinase in obesity resistance induced by respiratory uncoupling in white fat

Matejkova, O; Mustard, Kirsty J.; Sponarová, J; Flachs, Pavel; Rossmeisl, Martin; Mikšı́k, Ivan; Thomason-Hughes, Michaela; Hardie, D. Grahame; Kopecký, Jan

doi:10.1016/j.febslet.2004.06.002

Cited by 61 publications

(61 citation statements)

References 45 publications

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“…In fact, variations in the activity/expression of UCP2 in b-cells directly influence the ATP/ADP ratio and insulin secretion (Affourtit & Brand 2008). Furthermore, ectopic expression of UCP1 in white adipose tissue decreases the cellular energy content, activates AMPK and increases lipid oxidation (Matejkova et al 2004). We investigated the induction of lipolysis and found a marked increase in metformin-treated cells although it is only apparent after a 5-day exposure.…”

Section: Discussionmentioning

confidence: 99%

Metformin induces oxidative stress in white adipocytes and raises uncoupling protein 2 levels

Anedda

Rial²,

González-Barroso

2008

Journal of Endocrinology

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Metformin is a drug widely used to treat type 2 diabetes. It enhances insulin sensitivity by improving glucose utilization in tissues like liver or muscle. Metformin inhibits respiration, and the decrease in cellular energy activates the AMPactivated protein kinase that in turn switches on catabolic pathways. Moreover, metformin increases lipolysis and b-oxidation in white adipose tissue, thereby reducing the triglyceride stores. The uncoupling proteins (UCPs) are transporters that lower the efficiency of mitochondrial oxidative phosphorylation. UCP2 is thought to protect against oxidative stress although, alternatively, it could play an energy dissipation role. The aim of this work was to analyse the involvement of UCP2 on the effects of metformin in white adipocytes. We studied the effect of this drug in differentiating 3T3-L1 adipocytes and found that metformin causes oxidative stress since it increases the levels of reactive oxygen species (ROS) and lowers the aconitase activity. Variations in UCP2 protein levels parallel those of ROS. Metformin also increases lipolysis in these cells although only when the levels of ROS and UCP2 have decreased. Hence, UCP2 does not appear to be needed to facilitate fatty acid oxidation. Furthermore, treatment of C57BL/6 mice with metformin also augmented the levels of UCP2 in epididymal white adipose tissue. We conclude that metformin treatment leads to the overexpression of UCP2 in adipocytes to minimize the oxidative stress that is probably due to the inhibition of respiration caused by the drug.

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Section: Discussionmentioning

confidence: 99%

Metformin induces oxidative stress in white adipocytes and raises uncoupling protein 2 levels

Anedda

Rial²,

González-Barroso

2008

Journal of Endocrinology

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“…AMPK activation in adipocytes results in increased mitochondrial biogenesis and lipid catabolism [4,48]. Moreover, AMPK closely interacts with deacetylase sirtuin 1 (SIRT1), which controls metabolic processes in response to calorie restriction and exerts antiinflammatory effects in WAT [49].…”

Section: Discussionmentioning

confidence: 99%

“…When (post)prandial plasma levels of NEFA and triacylglycerol (TG) exceed the storage capacity of WAT [1], other tissues including the liver and muscle become overloaded with lipids, which results in insulin resistance, the key event in the pathophysiology of metabolic syndrome [2]. The important role of WAT in energy homeostasis is underscored by the findings that WAT is one of the key organs affected by calorie restriction, the most effective strategy to prolong a healthy life in several species [3], and by the fact that accumulation of body fat can be reduced through upregulation of lipid catabolism in WAT [4][5][6][7][8][9][10]. The metabolism and secretory functions of WAT are also modulated by longchain (LC) n-3 polyunsaturated fatty acids (PUFA), namely eicosapentaenoic acid (EPA; 20:5 n-3) and docosahexaenoic acid (DHA; 22:6 n-3), which exert numerous beneficial effects on health, including improvements in lipid metabolism and prevention of obesity and diabetes [11], while decreasing the rate of fatal coronary heart disease in diabetic patients who have had a myocardial infarction [12].…”

Section: Introductionmentioning

confidence: 99%

Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids

et al. 2011

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Aims/hypothesis Calorie restriction is an essential component in the treatment of obesity and associated diseases. Longchain n-3 polyunsaturated fatty acids (LC n-3 PUFA) act as natural hypolipidaemics, reduce the risk of cardiovascular disease and could prevent the development of obesity and insulin resistance. We aimed to characterise the effectiveness and underlying mechanisms of the combination treatment with LC n-3 PUFA and 10% calorie restriction in the prevention of obesity and associated disorders in mice. Methods Male mice (C57BL/6J) were habituated to a cornoil-based high-fat diet (cHF) for 2 weeks and then randomly assigned to various dietary treatments for 5 weeks or 15 weeks: (1) cHF, ad libitum; (2) cHF with LC n-3 PUFA concentrate replacing 15% (wt/wt) of dietary lipids (cHF+F), ad libitum; (3) cHF with calorie restriction (CR; cHF+CR); and (4) cHF+F+CR. Mice fed a chow diet were also studied. Results We show that white adipose tissue plays an active role in the amelioration of obesity and the improvement of glucose homeostasis by combining LC n-3 PUFA intake and calorie restriction in cHF-fed mice. Specifically in the epididymal fat in the abdomen, but not in other fat depots, synergistic induction of mitochondrial oxidative capacity and lipid catabolism was observed, resulting in increased oxidation of metabolic fuels in the absence of mitochondrial uncoupling, while low-grade inflammation was suppressed, reflecting changes in tissue levels of anti-inflammatory lipid mediators, namely 15-deoxy-Δ 12,15 -prostaglandin J 2 and protectin D1. Conclusions/interpretation White adipose tissue metabolism linked to its inflammatory status in obesity could be modulated by combination treatment using calorie restriction and dietary LC n-3 PUFA to improve therapeutic strategies for metabolic syndrome.

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“…At 3 months of age mice were randomly assigned to a maize-based high-fat (cHF) diet or the cHF diet with 44% (w/w; D44) of its lipid replaced by n-3 long-chain PUFA concentrate EPAX 1050 TG (EPAX AS, Aalesund, Norway). After 5 weeks of feeding the mice were killed and epididymal adipose tissue collected for the analysis of AMPK and ACC phosphorylation (54,76) . ( n-3 PUFA and adipose tissue functionlevels of inflammatory cytokines (for review, see Yang & Smith (61) ) and secrete higher levels of adiponectin (62) .…”

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confidence: 99%

n-3 PUFA: bioavailability and modulation of adipose tissue function

et al. 2009

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Adipose tissue has a key role in the development of metabolic syndrome (MS), which includes obesity, type 2 diabetes, dyslipidaemia, hypertension and other disorders. Systemic insulin resistance represents a major factor contributing to the development of MS in obesity. The resistance is precipitated by impaired adipose tissue glucose and lipid metabolism, linked to a low-grade inflammation of adipose tissue and secretion of pro-inflammatory adipokines. Development of MS could be delayed by lifestyle modifications, while both dietary and pharmacological interventions are required for the successful therapy of MS. The n-3 long-chain (LC) PUFA, EPA and DHA, which are abundant in marine fish, act as hypolipidaemic factors, reduce cardiac events and decrease the progression of atherosclerosis. Thus, n-3 LC PUFA represent healthy constituents of diets for patients with MS. In rodents n-3 LC PUFA prevent the development of obesity and impaired glucose tolerance. The effects of n-3 LC PUFA are mediated transcriptionally by AMP-activated protein kinase and by other mechanisms. n-3 LC PUFA activate a metabolic switch toward lipid catabolism and suppression of lipogenesis, i.e. in the liver, adipose tissue and small intestine. This metabolic switch improves dyslipidaemia and reduces ectopic deposition of lipids, resulting in improved insulin signalling. Despite a relatively low accumulation of n-3 LC PUFA in adipose tissue lipids, adipose tissue is specifically linked to the beneficial effects of n-3 LC PUFA, as indicated by (1) the prevention of adipose tissue hyperplasia and hypertrophy, (2) the induction of mitochondrial biogenesis in adipocytes, (3) the induction of adiponectin and (4) the amelioration of adipose tissue inflammation by n-3 LC PUFA.

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Possible involvement of AMP‐activated protein kinase in obesity resistance induced by respiratory uncoupling in white fat

Cited by 61 publications

References 45 publications

Metformin induces oxidative stress in white adipocytes and raises uncoupling protein 2 levels

Metformin induces oxidative stress in white adipocytes and raises uncoupling protein 2 levels

Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids

n-3 PUFA: bioavailability and modulation of adipose tissue function

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