Research Article Details
| Article ID: | A18204 |
| PMID: | 27288055 |
| Source: | J Endocrinol |
| Title: | Metformin increases hepatic leptin receptor and decreases steatosis in mice. |
| Abstract: | In addition to the ascertained efficacy as antidiabetic drug, metformin is increasingly being used as weight-loss agent in obesity, and as insulin sensitizer in nonalcoholic fatty liver disease (NAFLD). However, the mechanisms underlying these effects are still incompletely understood. Emerging evidence suggest metformin as leptin sensitizer to mediate the weight-loss effect in the brain. In this study, we investigated effects of metformin on expression of leptin receptors in liver and kidney in mice. C57BL/6 mice were fed with chow diet (CD) or high-fat diet (HF) for 5months. Afterward, mice were treated with metformin (50mg/kg or 200mg/kg) for 15days. Metabolic parameters and hepatic gene expression were analyzed at the end of the treatment. We also tested the effects of metformin on plasma-soluble leptin receptor (sOB-R) levels in newly diagnosed type 2 diabetes mellitus (T2DM) patients, and assessed its effect on hepatosteatosis in mice. Results showed that metformin upregulates the expression of leptin receptors (OB-Ra, -Rb, -Rc, and -Rd) in liver but not kidney. The stimulation effect is dose-dependent in both chow and HF mice. Upregulation of OB-Rb, long signaling isoform, needs a relatively higher dose of metformin. This effect was paralleled by increased sOBR levels in mice and T2DM patients, and decreased hepatic triglyceride (TG) content and lipogenic gene expression, including sterol regulatory element-binding protein 1c (SREBP-1c), fatty acid synthase (FAS) and acetyl-CoA carboxylase-1 (ACC-1). Taken together, these data identify hepatic leptin receptor as target gene being upregulated by metformin which may enhance leptin sensitivity in liver to alleviate steatosis. |
| DOI: | 10.1530/JOE-16-0142 |
| 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 |
| 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 | |
|---|---|---|---|---|---|---|---|
| D248 | Obeticholic Acid | Chemical drug | DB05990 | NR1H4 activator; NR1H4 agonist; FXR agonist | Enhance lipid metabolism | Approval rejected | Details |
| D225 | Metformin | Chemical drug | DB00331 | PRKAB1 inducer activator; ETEDH inhibitor; GPD1 inhibitor | Improve insulin resistance | Under clinical trials | Details |
| D157 | Glucophage | Chemical drug | DB00331 | -- | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |