Research Article Details
| Article ID: | A17067 |
| PMID: | 28011892 |
| Source: | Gut |
| Title: | Adipose type I interferon signalling protects against metabolic dysfunction. |
| Abstract: | OBJECTIVE: Low-grade chronic inflammation emerges as a potent driver of insulin resistance and glucose dysregulation in obesity and associated non-alcoholic fatty liver disease (NAFLD). The liver, subcutaneous fat and the immune system participate in disturbances of metabolism. Type I interferon (IFN) signalling initiated by innate and adaptive immunity modulates inflammatory responses consequent to infection. However, little is known about the role of type I IFN signalling in metabolic diseases and the development of NAFLD. DESIGN: We determined the impact of type I IFN signalling by tissue-specific deletion of interferon (α and β) receptor 1 (Ifnar1) in hepatocytes (Ifnar1Δhep ), adipocytes (Ifnar1Δat ), intestinal epithelial cells (Ifnar1ΔIEC ) or myelocytes (Ifnar1Δmyel ) on glucose metabolism, obesity and hepatic disease in mice exposed to a high-fat or methionine-choline-deficient (MCD) diet. Furthermore, we investigated the expression of type I IFN-regulated genes in patients with obesity undergoing laparoscopic adjustable gastric banding (LAGB). RESULTS: Long chain fatty acids induce type I IFN responses in murine hepatocytes and macrophages and exposure to a high-fat diet elicited type I IFN-regulated gene expression in the liver of wild-type mice. Hepatocyte-specific, but not adipose tissue-specific deletion of Ifnar1 worsened steatosis and inflammation induced by the MCD diet. In contrast, adipose-specific, but not hepatocyte-specific deletion of Ifnar1 deteriorated metabolic dysregulation induced by a high-fat diet, indicated by increased weight gain, insulin resistance and an impaired glucose tolerance. Abrogated type I IFN signalling in myeloid or intestinal epithelial cells did not modulate susceptibility to metabolic or hepatic disease. Improved metabolic control in patients with obesity after LAGB was associated with increased expression of type I IFN-regulated genes in subcutaneous adipose tissue and liver. CONCLUSIONS: Our study implicates a role for adipose and hepatocyte type I IFN signalling in diet-induced metabolic dysregulation and hepatic disease. Further studies on type I IFN signalling in metabolic diseases are warranted. |
| DOI: | 10.1136/gutjnl-2016-313155 |
| 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 |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | 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 | |
|---|---|---|---|---|---|---|---|
| D080 | Citrulline | Chemical drug | DB00155 | -- | -- | Under clinical trials | Details |
| D075 | Choline | Supplement | DB00122 | PLD2 product of; PLD1 product of | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |