Therapeutic potential of panduratin A, LKB1-dependent AMP-activated protein kinase stimulator, with activation of PPARα/δ for the treatment of obesity

2011 ◽  
Vol 13 (7) ◽  
pp. 584-593 ◽  
Author(s):  
D. Kim ◽  
M.-S. Lee ◽  
K. Jo ◽  
K.-E. Lee ◽  
J.-K. Hwang
Keyword(s):  
Protein Kinase ◽  
Therapeutic Potential ◽  
Treatment Of Obesity ◽  
Amp Activated Protein Kinase ◽  
Panduratin A

scholarly journals Angiotensin AT1 receptor antagonism by losartan stimulates adipocyte browning via induction of apelin

2020 ◽  
Vol 295 (44) ◽  
pp. 14878-14892
Author(s):  
Dong Young Kim ◽  
Mi Jin Choi ◽  
Tae Kyung Ko ◽  
Na Hyun Lee ◽  
Ok-Hee Kim ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Kinase ◽  
Metabolic Disorders ◽  
Angiotensin Ii Receptor ◽  
Adeno Associated Virus ◽  
Receptor Antagonism ◽  
White Adipocytes ◽  
Treatment Of Obesity ◽  
Amp Activated Protein Kinase

Adipocyte browning appears to be a potential therapeutic strategy to combat obesity and related metabolic disorders. Recent studies have shown that apelin, an adipokine, stimulates adipocyte browning and has negative cross-talk with angiotensin II receptor type 1 (AT1 receptor) signaling. Here, we report that losartan, a selective AT1 receptor antagonist, induces browning, as evidenced by an increase in browning marker expression, mitochondrial biogenesis, and oxygen consumption in murine adipocytes. In parallel, losartan up-regulated apelin expression, concomitant with increased phosphorylation of protein kinase B and AMP-activated protein kinase. However, the siRNA-mediated knockdown of apelin expression attenuated losartan-induced browning. Angiotensin II cotreatment also inhibited losartan-induced browning, suggesting that AT1 receptor antagonism-induced activation of apelin signaling may be responsible for adipocyte browning induced by losartan. The in vivo browning effects of losartan were confirmed using both C57BL/6J and ob/ob mice. Furthermore, in vivo apelin knockdown by adeno-associated virus carrying–apelin shRNA significantly inhibited losartan-induced adipocyte browning. In summary, these data suggested that AT1 receptor antagonism by losartan promotes the browning of white adipocytes via the induction of apelin expression. Therefore, apelin modulation may be an effective strategy for the treatment of obesity and its related metabolic disorders.

Abstract 533: Salicylate Restores Macrophage Cholesterol Homeostasis via Activation of AMP-Activated Protein Kinase

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Morgan D Fullerton ◽  
Chelsea P McGregor ◽  
Nicholas D LeBlond ◽  
Shayne A Snider ◽  
Rebecca J Ford ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cholesterol Efflux ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Foam Cell ◽  
Cholesterol Homeostasis ◽  
Dependent Manner ◽  
Cholesterol Uptake ◽  
Gene And Protein Expression ◽  
Amp Activated Protein Kinase

Objectives: Atherosclerosis stems from imbalances in lipid metabolism and leads to maladaptive inflammatory responses. AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine kinase that regulates many aspects of lipid and energy metabolism, although its specific role in controlling macrophage foam cell cholesterol homeostasis remains unclear. Methods: We sought to address this question by testing the effects of AMPK-specific activators in primary bone marrow-derived macrophages from AMPK β1-deficient (β1-/-) mice. Results: Macrophages from AMPK β1-/- mice had enhanced lipogenic potential and diminished cholesterol efflux, although cholesterol uptake was unaffected. Specific activation of Ampk β1 via salicylate (the unacetylated form of aspirin) or A-769662 (a small molecule activator), decreased the synthesis of both fatty acids and sterols in WT but not AMPK β1-/- macrophages. In lipid-laden macrophage foam cells, salicylate and A-769662 decreased cholesterol uptake and increased cholesterol efflux to HDL and apoA-I, effects that occurred in an AMPK β1-dependent manner. Increased cholesterol efflux was also associated with increased gene and protein expression of the ATP binding cassette transporters, ABCG1 and ABCA1. Moreover, in vivo reverse cholesterol transport was significantly suppressed in mice that received AMPK β1-/- macrophages compared to WT control. Conclusion: Our data highlight the therapeutic potential of targeting macrophage AMPK with new or existing drugs for the restoration of cholesterol homeostasis during the early stages of atherosclerosis.

The role of AMP-activated protein kinase in the coordination of skeletal muscle turnover and energy homeostasis

2012 ◽  
Vol 303 (5) ◽  
pp. C475-C485 ◽  
Author(s):  
Anthony M. J. Sanchez ◽  
Robin B. Candau ◽  
Alfredo Csibi ◽  
Allan F. Pagano ◽  
Audrey Raibon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Energy Homeostasis ◽  
Therapeutic Potential ◽  
Energy Status ◽  
Muscle Plasticity ◽  
Glucose And Lipid Metabolism ◽  
Muscle Homeostasis ◽  
Amp Activated Protein Kinase

The AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that acts as a sensor of cellular energy status switch regulating several systems including glucose and lipid metabolism. Recently, AMPK has been implicated in the control of skeletal muscle mass by decreasing mTORC1 activity and increasing protein degradation through regulation of ubiquitin-proteasome and autophagy pathways. In this review, we give an overview of the central role of AMPK in the control of skeletal muscle plasticity. We detail particularly its implication in the control of the hypertrophic and atrophic signaling pathways. In the light of these cumulative and attractive results, AMPK appears as a key player in regulating muscle homeostasis and the modulation of its activity may constitute a therapeutic potential in treating muscle wasting syndromes in humans.

scholarly journals Nuts and bolts of the salt-inducible kinases (SIKs)

2021 ◽  
Vol 478 (7) ◽  
pp. 1377-1397
Author(s):  
Nicola J. Darling ◽  
Philip Cohen
Keyword(s):  
Protein Kinase ◽  
Histone Deacetylases ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Skin Pigmentation ◽  
Physiological Processes ◽  
Dependent Inactivation ◽  
Catalytically Active ◽  
Dependent Protein ◽  
Amp Activated Protein Kinase

The salt-inducible kinases, SIK1, SIK2 and SIK3, most closely resemble the AMP-activated protein kinase (AMPK) and other AMPK-related kinases, and like these family members they require phosphorylation by LKB1 to be catalytically active. However, unlike other AMPK-related kinases they are phosphorylated by cyclic AMP-dependent protein kinase (PKA), which promotes their binding to 14-3-3 proteins and inactivation. The most well-established substrates of the SIKs are the CREB-regulated transcriptional co-activators (CRTCs), and the Class 2a histone deacetylases (HDAC4/5/7/9). Phosphorylation by SIKs promotes the translocation of CRTCs and Class 2a HDACs to the cytoplasm and their binding to 14-3-3s, preventing them from regulating their nuclear binding partners, the transcription factors CREB and MEF2. This process is reversed by PKA-dependent inactivation of the SIKs leading to dephosphorylation of CRTCs and Class 2a HDACs and their re-entry into the nucleus. Through the reversible regulation of these substrates and others that have not yet been identified, the SIKs regulate many physiological processes ranging from innate immunity, circadian rhythms and bone formation, to skin pigmentation and metabolism. This review summarises current knowledge of the SIKs and the evidence underpinning these findings, and discusses the therapeutic potential of SIK inhibitors for the treatment of disease.

scholarly journals HL156A, a novel AMP-activated protein kinase activator, is protective against peritoneal fibrosis in an in vivo and in vitro model of peritoneal fibrosis

2016 ◽  
Vol 310 (5) ◽  
pp. F342-F350 ◽  
Author(s):  
Kyung Don Ju ◽  
Hyo Jin Kim ◽  
Bodokhsuren Tsogbadrakh ◽  
Jinho Lee ◽  
Hyunjin Ryu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Protective Mechanism ◽  
Peritoneal Fibrosis ◽  
Mesenchymal Transition ◽  
Amp Activated Protein Kinase

HL156A is a novel AMP-activated protein kinase (AMPK) activator. We aimed to investigate the protective mechanism of HL156A against peritoneal fibrosis (PF) in in vivo and in vitro models. The rat PF model was induced by daily intraperitoneally injection of chlorhexidine (CHX) solution containing 0.1% CHX gluconate and 15% ethanol for 4 wk. The rats in the treatment group were treated with HL156A (1 mg·kg−1·day−1). Control rats were injected with vehicle alone. In vitro, cultured rat peritoneal mesothelial cells (RPMCs) were treated with either high glucose (HG; 50 mM), normal glucose (NG; 5 mM), NG+HL156A, or HG+HL156A. HL156A in supplemented rats ameliorated peritoneal calcification, cocoon formation, bowel obstruction, and PF. Immunohistochemistry showed reduced fibronectin accumulation in the peritoneum of HL156A-treated rats compared with those injected with CHX alone. HL156A treatment of RPMCs inhibited HG-induced myofibroblast transdifferentiation and markers of epithelial-mesenchymal transition (EMT). Moreover, HL156A ameliorated HG-induced transforming growth factor-β1, Smad3, Snail, and fibronectin expression in the RPMCs via AMPK upregulation. These results suggest that HL156A exhibits a protective effect in PF progression. Further research is warranted to seek the therapeutic potential of HL156A as an antifibrotic agent in peritoneal dialysis patients.

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