Protein Kinases in Obesity, and the Kinase-Targeted Therapy.
5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK)
Dual-specificity kinases
Extracellular signal-regulated protein kinase (ERK)
Inhibitor of kappaB-kinase (IKK)
Lipoapoptosis
Liver kinase B1 (LKB1)
MAPK phosphatases
Mammalian target of rapamycin (mTOR)
Mitogen-activated protein kinases (MAPK)
Period (Per)-aryl hydrocarbon receptor nuclear translocator (ARNT)- single-minded protein (Sim) (PAS) kinase (PASK)
Protein kinase B (PKB; Akt)
Protein kinase-like endoplasmic reticulum (ER) eukaryotic initiation factor-2 alpha kinase (PERK)
Protein kinases
Protein phosphatases
c-Jun N-terminal kinase (JNK)
Journal
Advances in experimental medicine and biology
ISSN: 0065-2598
Titre abrégé: Adv Exp Med Biol
Pays: United States
ID NLM: 0121103
Informations de publication
Date de publication:
2024
2024
Historique:
medline:
17
9
2024
pubmed:
17
9
2024
entrez:
17
9
2024
Statut:
ppublish
Résumé
The action of protein kinases and protein phosphatases is essential for multiple physiological responses. Each protein kinase displays its own unique substrate specificity and a regulatory mechanism that may be modulated by association with other proteins. Protein kinases are classified as dual-specificity kinases and dual-specificity phosphatases. Dual-specificity phosphatases are important signal transduction enzymes that regulate various cellular processes in coordination with protein kinases and play an important role in obesity. Impairment of insulin signaling in obesity is largely mediated by the activation of the inhibitor of kappa B-kinase beta and the c-Jun N-terminal kinase (JNK). Oxidative stress and endoplasmic reticulum (ER) stress activate the JNK pathway which suppresses insulin biosynthesis. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are important for proper regulation of glucose metabolism in mammals at both the hormonal and cellular levels. Additionally, obesity-activated calcium/calmodulin dependent-protein kinase II/p38 suppresses insulin-induced protein kinase B phosphorylation by activating the ER stress effector, activating transcription factor-4. To alleviate lipotoxicity and insulin resistance, promising targets are pharmacologically inhibited. Nifedipine, calcium channel blocker, stimulates lipogenesis and adipogenesis by downregulating AMPK and upregulating mTOR, which thereby enhances lipid storage. Contrary to the nifedipine, metformin activates AMPK, increases fatty acid oxidation, suppresses fatty acid synthesis and deposition, and thus alleviates lipotoxicity. Obese adults with vascular endothelial dysfunction have greater endothelial cells activation of unfolded protein response stress sensors, RNA-dependent protein kinase-like ER eukaryotic initiation factor-2 alpha kinase (PERK), and activating transcription factor-6. The transcriptional regulation of adipogenesis in obesity is influenced by AGC (protein kinase A (PKA), PKG, PKC) family signaling kinases. Obesity may induce systemic oxidative stress and increase reactive oxygen species in adipocytes. An increase in intracellular oxidative stress can promote PKC-β activation. Activated PKC-β induces growth factor adapter Shc phosphorylation. Shc-generated peroxides reduce mitochondrial oxygen consumption and enhance triglyceride accumulation and lipotoxicity. Liraglutide attenuates mitochondrial dysfunction and reactive oxygen species generation. Co-treatment of antiobesity and antidiabetic herbal compound, berberine with antipsychotic drug olanzapine decreases the accumulation of triglyceride. While low-dose rapamycin, metformin, amlexanox, thiazolidinediones, and saroglitazar protect against insulin resistance, glucagon-like peptide-1 analog liraglutide inhibits palmitate-induced inflammation by suppressing mTOR complex 1 (mTORC1) activity and protects against lipotoxicity.
Identifiants
pubmed: 39287853
doi: 10.1007/978-3-031-63657-8_7
doi:
Substances chimiques
Protein Kinases
EC 2.7.-
Protein Kinase Inhibitors
0
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
199-229Informations de copyright
© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.
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