Increased abundance of the adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif (APPL1) in patients with obesity and type 2 diabetes: evidence for altered adiponectin signalling

Holmes, Richard; Yi, Zhengping; Filippis, Eleanna De; Berria, Rachele; Shahani, Sadeka; Sathyanarayana, Padma; Sherman, Vadim; Fujiwara, Kunisato; Meyer, Christian; Christ-Roberts, Christine Y.; Hwang, Hyun Sook; Finlayson, Jean; Dong, Lily Q.; Mandarino, Lawrence J.; Bajaj, Mandeep S

doi:10.1007/s00125-011-2173-x

Cited by 33 publications

(21 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, we found increased AMPK signaling in adipose tissue but not in skeletal muscle following RYGB. It could be speculated whether results by Holmes et al (26) were influenced by fat contamination of their muscle preparation, since no dissection of excess fat from the muscles biopsies was reported. Interestingly, we found a positive association between the increase (presurgery to 12 mo) in plasma adiponectin and basal phosphorylation of AMPK and ACC in adipose tissue, supporting the idea of AMPK signaling being regulated by adiponectin (24,60).…”

Section: Discussionmentioning

confidence: 97%

“…Holmes et al (26) reported that RYGB led to a marked increase in AMPK phosphorylation/protein-ratio in skeletal muscle from obese nondiabetic subjects. In contrast, we found increased AMPK signaling in adipose tissue but not in skeletal muscle following RYGB.…”

Section: Discussionmentioning

confidence: 99%

“…In mice, AMP-activated protein kinase (AMPK) has been implicated in the improved insulin-stimulated glucose uptake in skeletal muscle following caloric restriction (58). Further, enhanced AMPK signaling has been reported in human skeletal muscle 6 mo after RYGB (26), implying a role of AMPK in postsurgery changes in peripheral insulin sensitivity. In line with this observation, Gauthier et al (21) found improved AMPK signaling in adipose tissue of morbidly obese insulin-sensitive subjects compared with weight-matched, insulin-resistant subjects.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Enhanced insulin signaling in human skeletal muscle and adipose tissue following gastric bypass surgery

Albers

Bojsen‐Møller

Dirksen

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Enhanced insulin signaling in human skeletal muscle and adipose tissue following gastric bypass surgery

Albers

Bojsen‐Møller

Dirksen

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

show abstract

“…MHC, major histocompatibility complex. conditions (7,(33)(34)(35)(36)(37). However, conflicting data about AdipoR1 mRNA expression suggest that transcriptional regulation cannot fully account for AdipoR1 protein expression.…”

Section: Discussionmentioning

confidence: 99%

RNA-Binding Protein PTB and MicroRNA-221 Coregulate AdipoR1 Translation and Adiponectin Signaling

et al. 2014

View full text Add to dashboard Cite

Adiponectin receptor 1 (AdipoR1) mediates adiponectin's pleiotropic effects in muscle and liver and plays an important role in the regulation of insulin resistance and diabetes. Here, we demonstrate a pivotal role for microRNA-221 (miR-221) and the RNA-binding protein polypyrimidine tract-binding protein (PTB) in posttranscriptional regulation of AdipoR1 during muscle differentiation and in obesity. RNA-immunoprecipitation and luciferase reporter assays illustrated that both PTB and miR-221 bind AdipoR1-39UTR and cooperatively inhibit AdipoR1 translation. Depletion of PTB or miR-221 increased, while overexpression of these factors decreased, AdipoR1 protein synthesis in both muscle and liver cells. During myogenesis, downregulation of PTB and miR-221 robustly induced AdipoR1 translation, providing a mechanism for enhanced AdipoR1 protein expression and activation in differentiated muscle cells. In addition, since both PTB and miR-221 are upregulated in liver and muscle of genetic and dietary mouse models of obesity, this novel translational mechanism may be at least partly responsible for the reduction in AdipoR1 protein levels in obesity. These findings highlight the importance of translational control in regulating AdipoR1 protein expression and adiponectin signaling. Given that adiponectin is reduced in obesity, induction of AdipoR1 could potentially enhance adiponectin beneficial effects and ameliorate insulin resistance and diabetes. Adiponectin, an adipocyte-derived abundant plasma protein (1-4) with insulin-sensitizing and antiinflammatory properties, gained recognition as a potential mediator between obesity, insulin resistance, and diabetes (5): Adiponectin levels are reduced in obesity (1), and mice lacking adiponectin develop insulin resistance, glucose intolerance, hyperglycemia, and hypertension-all characteristics of the metabolic syndrome (5,6). Adiponectin's biological effects depend not only on the relative circulating concentrations of the hormone but also on the expression level and function of its receptors (5,7-9). To date, two receptors for adiponectin have been identified (AdipoR1 and AdipoR2), which mediate adiponectin pleoitropic effects (10). Downregulation of the receptors in obesity is involved in the development of insulin resistance and diabetes (11).Skeletal muscle and liver are important targets of adiponectin and its receptors in the regulation of energy metabolism (12). Adiponectin, through AdipoR1, METABOLISMactivates AMP-activated protein kinase (AMPK) in vivo and in vitro, which increases fatty acid oxidation and glucose utilization and leads to an improvement in insulin sensitivity (10,11,(13)(14)(15). Recently, overexpression of AdipoR1 in rat skeletal muscle was shown to enhance insulin sensitivity in vivo through phosphatidylinositol 3-kinase-and AMPK-signaling pathways (16). In addition, specific deletion of AdipoR1 in mouse skeletal muscle demonstrated that AdipoR1 is involved in the regulation of Ca 2+ signaling, peroxisome proliferator-activated receptor g coactivat...

show abstract

“…Indeed, APPL1 levels were significantly decreased in endothelium of Zucker diabetic fatty rats (38), and a recent study suggested that chronic exercise in mice increased hepatic APPL1 expression, which, at least in part, accounted for improved insulin sensitivity (28). However, in a human study, there was higher APPL1 expression in type 2 diabetic muscle, and weight loss in these individuals was associated with reduced skeletal muscle APPL1 level (22). The limitations of mouse models that constitutively overexpress or lack a specific protein include the fact that potential compensatory effects may ensue, and this must be borne in mind when interpreting data from this and other studies.…”

Section: E801mentioning

confidence: 84%

APPL1 transgenic mice are protected from high-fat diet-induced cardiac dysfunction

Park

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

APPL1 (adaptor protein containing PH domain, PTB domain, and leucine zipper motif 1) has been established as an important mediator of insulin and adiponectin signaling. Here, we investigated the influence of transgenic (Tg) APPL1 overexpression in mice on high-fat diet (HFD)-induced cardiomyopathy in mice. Wild-type (WT) mice fed an HFD for 16 wk showed cardiac dysfunction, determined by echocardiography, with decreased ejection fraction, decreased fractional shortening, and increased end diastolic volume. HFD-fed APPL1 Tg mice were significantly protected from this dysfunction. Speckle tracking echocardiography to accurately assess cardiac tissue deformation strain and wall motion also indicated dysfunction in WT mice and a similar improvement in Tg vs. WT mice on HFD. APPL1 Tg mice had less HFD-induced increase in circulating nonesteridied fatty acid levels and myocardial lipid accumulation. Lipidomic analysis using LC-MS-MS showed HFD significantly increased myocardial contents of distinct ceramide, sphingomyelin, and diacylglycerol (DAG) species, of which increases in C16:0 and C18:0 ceramides plus C16:0 and C18:1 DAGs were attenuated in Tg mice. A glucose tolerance test indicated less peripheral insulin resistance in response to HFD in Tg mice, which was also apparent by measuring cardiac Akt phosphorylation and cardiomyocyte glucose uptake. In summary, APPL1 Tg mice exhibit improved peripheral metabolism, reduced cardiac lipotoxicity, and improved insulin sensitivity. These cellular effects contribute to protection from HFD-induced cardiomyopathy.

show abstract

Increased abundance of the adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif (APPL1) in patients with obesity and type 2 diabetes: evidence for altered adiponectin signalling

Cited by 33 publications

References 39 publications

Enhanced insulin signaling in human skeletal muscle and adipose tissue following gastric bypass surgery

Enhanced insulin signaling in human skeletal muscle and adipose tissue following gastric bypass surgery

RNA-Binding Protein PTB and MicroRNA-221 Coregulate AdipoR1 Translation and Adiponectin Signaling

APPL1 transgenic mice are protected from high-fat diet-induced cardiac dysfunction

Contact Info

Product

Resources

About