Research Article Details
| Article ID: | A12390 |
| PMID: | 30473057 |
| Source: | Metabolism |
| Title: | Adiponectin homolog novel osmotin protects obesity/diabetes-induced NAFLD by upregulating AdipoRs/PPARα signaling in ob/ob and db/db transgenic mouse models. |
| Abstract: | BACKGROUND: In metabolic disorders, adiponectin and adiponectin receptors (AdipoR1/R2) signaling has a key role in improving nonalcoholic fatty liver disease (NAFLD) in obesity-associated diabetes. OBJECTIVE: To the best of our knowledge, here, we reported for the first time the underlying mechanistic therapeutic efficacy of the novel osmotin, a homolog of mammalian adiponectin, against NAFLD in leptin-deficient ob/ob and db/db mice. METHODS: The ob/ob and db/db mice were treated with osmotin at a dose of 5 μg/g three times a week for two weeks. To co-relate the in vivo results we used the human liver carcinoma HepG2 cells, subjected to knockdown with small siRNAs of AdipoR1/R2 and PPARα genes and treated with osmotin and palmitic acid (P.A.). MTT assay, Western blotting, immunohistofluorescence assays, and plasma biochemical analyses were applied. RESULTS: Osmotin stimulated AdipoR1/R2 and its downstream APPL1/PPAR-α/AMPK/SIRT1 pathways in ob/ob and db/db mice, and HepG2 cells exposed to P.A. Mechanistically, we confirmed that knockdown of AdipoR1/R2 and PPARα by their respective siRNAs abolished the osmotin activity in HepG2 cells exposed to P.A. Overall, the in vivo and in vitro results suggested that osmotin protected against NAFLD through activation of AdipoR1/R2 and its downstream APPL1/PPAR-α/AMPK/SIRT1 pathways as shown by the reduced body weight, blood glucose level and glycated hemoglobin, improved glucose tolerance, attenuated insulin resistance and hepatic glucogenesis, regulated serum lipid parameters, and increased fatty acid oxidation and mitochondrial functions. CONCLUSION: Our findings strongly suggest that novel osmotin might be a potential novel therapeutic tool against obesity/diabetes-induced NAFLD and other metabolic disorders. |
| DOI: | 10.1016/j.metabol.2018.10.004 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | Details |
| S07 | Anti-lipogenesis | de novo lipogenesis; de novo lipogenesis; DNL; anti-lipogenic mechanisms; adipogenesis; anti-obesity | stearoyl-CoA desaturase 1 (SCD-1); Acetyl-coenzyme carboxylase; acyl-CoA carboxylase inhibitor (ACC inhibitor); stearoyl Coenzyme A desaturase inhibitor (SCD inhibitor); THR-beta selective agonist; DGAT2 inhibitor; FASN inhibitor | Aramchol; Firsocostat (GS-0976); VK-2809; ION 224 | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T01 | 5'-AMP-activated protein kinase subunit beta-1 | PRKAB1 | activator | Kinase | Q9Y478 | AAKB1_HUMAN | Details |
| T10 | Caspase-1 | CASP1 | inhibitor | Enzyme | P29466 | CASP1_HUMAN | Details |
| T03 | Peroxisome proliferator-activated receptor alpha | PPARA | agonist | Nuclear hormone receptor | Q07869 | PPARA_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| I14 | 9970 | Obesity | An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity | disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D589 | Minor allele-specific small interfering RNA | Miscellany | -- | PNPLA3-rs738409 (I148M) variant inhibitor | -- | Under investigation | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |