The adipokine zinc-<i>α</i>2-glycoprotein activates AMP kinase in human primary skeletal muscle cells

Eckardt, Kristin; Schober, A.; Platzbecker, B.; Mráček, Tomáš; Chen, Bing; Trayhurn, Paul; Eckel, Jürgen

doi:10.3109/13813455.2011.560950

Cited by 23 publications

(17 citation statements)

References 27 publications

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“…However, ZAG did not display the thermogenic effects of the b-adrenoceptor agonist, nor did it increase b 3 -adrenoceptor or UCP1 (uncoupling protein 1) gene expression in brown adipose tissue, thereby implying that it does not behave as a typical b 3/2 -adrenoceptor agonist (209) . Thus, ZAG has emerged as a novel adipokine, being identified as an additional adipose tissue factor closely related to body weight loss not only via modulation of lipolysis in fat cells but also by activating AMPK in skeletal muscle cells (208,210) . The octapeptide angiotensin II (Ang II) is the active component of the renin-angiotensin system (RAS).…”

Section: Cytokines and Other 'Newcomers'mentioning

confidence: 99%

Regulation of adipocyte lipolysis

et al. 2014

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In adipocytes the hydrolysis of TAG to produce fatty acids and glycerol under fasting conditions or times of elevated energy demands is tightly regulated by neuroendocrine signals, resulting in the activation of lipolytic enzymes. Among the classic regulators of lipolysis, adrenergic stimulation and the insulin-mediated control of lipid mobilisation are the best known. Initially, hormone-sensitive lipase (HSL) was thought to be the rate-limiting enzyme of the first lipolytic step, while we now know that adipocyte TAG lipase is the key enzyme for lipolysis initiation. Pivotal, previously unsuspected components have also been identified at the protective interface of the lipid droplet surface and in the signalling pathways that control lipolysis. Perilipin, comparative gene identification-58 (CGI-58) and other proteins of the lipid droplet surface are currently known to be key regulators of the lipolytic machinery, protecting or exposing the TAG core of the droplet to lipases. The neuroendocrine control of lipolysis is prototypically exerted by catecholaminergic stimulation and insulin-induced suppression, both of which affect cyclic AMP levels and hence the protein kinase A-mediated phosphorylation of HSL and perilipin. Interestingly, in recent decades adipose tissue has been shown to secrete a large number of adipokines, which exert direct effects on lipolysis, while adipocytes reportedly express a wide range of receptors for signals involved in lipid mobilisation. Recently recognised mediators of lipolysis include some adipokines, structural membrane proteins, atrial natriuretic peptides, AMP-activated protein kinase and mitogen-activated protein kinase. Lipolysis needs to be reanalysed from the broader perspective of its specific physiological or pathological context since basal or stimulated lipolytic rates occur under diverse conditions and by different mechanisms.

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Section: Cytokines and Other 'Newcomers'mentioning

confidence: 99%

Regulation of adipocyte lipolysis

et al. 2014

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“…Treatment with ZAG stimulates lipolysis in isolated mouse and human adipocytes, and it selectively reduces body fat in both with adiposity, triglycerides (TG), and the key components of metabolic syndrome (8). Additionally, ZAG expression and protein levels have been reported to be down-regulated in subcutaneous and visceral adipose tissue of obese men and women in comparison with the lean controls (9). Very recently, we have demonstrated that circulating ZAG levels are lower in the patients with impaired glucose tolerance (IGT) and patients with newly diagnosed type 2 diabetes mellitus (nT2DM) than in control subjects.…”

Section: Introductionmentioning

confidence: 99%

Effects of sitagliptin on circulating zinc-α2-glycoprotein levels in newly diagnosed type 2 diabetes patients: a randomized trial

Tian¹,

Liang²,

Liu³

et al. 2016

European Journal of Endocrinology

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Objective: Zinc-a 2 -glycoprotein (ZAG) has recently been characterized as a potent metabolic regulator. However, the effects of anti-diabetic agents on circulating ZAG levels in humans remain largely unknown. To explore the possible mechanisms by which the dipeptidyl peptidase-IV (DPP-IV) inhibitor improves insulin resistance, we investigated the effect of sitagliptin, a DPP-IV inhibitor, on circulating cytokine levels in newly diagnosed type 2 diabetes (nT2DM) patients. Design and methods: A subset of 141 subjects with nT2DM were assigned to receive placebo (nZ47) or sitagliptin (nZ94) for 3 months. Before and after treatment, subjects received a 75 g oral glucose tolerance test, euglycemic-hyperinsulinemic clamp (EHC), and measurement of ZAG and adiponectin (ADI) concentrations. Results: Circulating ZAG levels were lower in nT2DM than in control individuals (P!0.01). After 3 months of sitagliptin treatment, HbA1c, fasting plasma glucose, postprandial glucose, 2-h insulin after glucose overload, triglycerides, and homeostasis model assessment of insulin resistance (HOMA-IR) were decreased significantly compared with pre-treatment (P!0.05 or P!0.01), whereas the glucose infusion rate during the stable period of the clamp (M values) during EHC were significantly increased (P!0.01). In addition, circulating ZAG and ADI concentrations were significantly increased along with improved glucose metabolism and insulin sensitivity compared with pre-treatment (both P!0.01) and the change of ZAG (DZAG) was positively associated with DADI, DHOMA-IR, DBMI, Dfasting insulin and negatively associated with D tumor necrosis factor-a (TNF-a). Furthermore, sitagliptin treatment resulted in significantly lowered plasma TNF-a level (P!0.05). Conclusion: A low level of circulating ZAG is associated with insulin resistance and sitagliptin treatment significantly increases circulating ZAG levels. These observations have implications in relation to the mode of action of the DPP-IV inhibitor as an insulin sensitizing agent.

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“…ZAG promotes lipid metabolism through β-AR, stimulates uncoupler proteins in the mitochondria inner membrane to increase energy expenditure, increases number of skeletal muscle glucose transporters, stimulates AMP-activated protein kinase and acetyl-CoA carboxylase activity that promote fatty acid oxidation and glycerol release, and inhibits the activity of several key enzymes in the lipogenesis pathway 1, 4, 8, 12 . Due to its anti-obesity effects, ZAG is now considered a target for future therapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

“…Research shows that the introduction of ZAG producing tumors leads to up-regulation of ZAG in adipose tissue accompanied by profound WL due to fat depletion, without changing FFM or nutrient intake 1, 6 . ZAG knockout animals are more prone to weight gain than their wild-type siblings when given a high-fat diet 7, 8 . In addition, treatment with β-AR agonists stimulates ZAG production while β-AR antagonists suppress it, implying overexpression of ZAG is most likely regulated through β-AR and the sympathetic system in cachectic mice 3, 4 .…”

Section: Introductionmentioning

confidence: 99%

Zinc-α2-Glycoprotein Expression in Adipose Tissue of Obese Postmenopausal Women before and after Weight Loss and Exercise + Weight Loss

Ryan

2014

Metabolism

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Objective Zinc-Alpha 2-Glycoprotein (ZAG) has recently been implicated in the regulation of adipose tissue metabolism due to its negative association with obesity and insulin resistance. The purpose of this study is to investigate the relationships between adipose tissue ZAG expression and central obesity, and the effects of six-months of weight loss (WL) or aerobic exercise + weight loss (AEX+WL) on ZAG expression. Design and Methods A six-month, longitudinal study of 33 healthy, overweight or obese postmenopausal women (BMI: 25–46 kg/m2) was conducted. Abdominal and gluteal adipose tissue samples were obtained before and after AEX+WL (n=17) and WL (n=16). ZAG expression was determined by RT-PCR. Results Prior to interventions, abdominal ZAG expression was negatively correlated with visceral fat (r=−0.50, P<0.005), sagittal diameter (r=−0.42, P<0.05), and positively related to VO2max (r=0.37, P<0.05). Gluteal ZAG expression was negatively correlated with weight, fat-free mass, visceral fat, resting metabolic rate, and fasting insulin (r=−0.39 to −0.50, all P<0.05). Abdominal ZAG mRNA levels increased, though not significantly, 5% after AEX+WL and 11% after WL. Gluteal ZAG mRNA levels also did not change significantly with AEX+WL and WL. Conclusions Abdominal ZAG expression may be important in central fat accumulation and fitness that modestly but not significantly increases with weight reduction alone or with aerobic training in obese postmenopausal women.

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The adipokine zinc-α2-glycoprotein activates AMP kinase in human primary skeletal muscle cells

Abstract: These results show that ZAG leads to phosphorylation of AMPKα and ACC, thereby activating a pathway central to the regulation of energy metabolism. This mechanism may be involved in mediating the effects of ZAG in relation to increased energy utilization.

Cited by 23 publications

References 27 publications

Regulation of adipocyte lipolysis

Regulation of adipocyte lipolysis

Effects of sitagliptin on circulating zinc-α2-glycoprotein levels in newly diagnosed type 2 diabetes patients: a randomized trial

Zinc-α2-Glycoprotein Expression in Adipose Tissue of Obese Postmenopausal Women before and after Weight Loss and Exercise + Weight Loss

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