title: Anti-obesity and anti-hyperglycemic effects of the dietary citrus limonoid nomilin in mice fed a high-fat diet.
abstract: TGR5 is a member of the G protein-coupled receptor family and is activated by bile acids (BAs). TGR5 is thought to be a promising drug target for metabolic diseases because the activation of TGR5 prevents obesity and hyperglycemia in mice fed a high-fat diet (HFD). In the present study, we identified a naturally occurring limonoid, nomilin, as an activator of TGR5. Unlike BAs, nomilin did not exhibit the farnesoid X receptor ligand activity. Although the nomilin derivative obacunone was capable of activating TGR5, limonin (the most abundant limonoid in citrus seeds) was not a TGR5 activator. When male C57BL/6J mice fed a HFD for 9 weeks were further fed a HFD either alone or supplemented with 0.2%w/w nomilin for 77 days, nomilin-treated mice had lower body weight, serum glucose, serum insulin, and enhanced glucose tolerance. Our results suggest a novel biological function of nomilin as an agent having anti-obesity and anti-hyperglycemic effects that are likely to be mediated through the activation of TGR5.
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Ono
authors.forename: Jun
authors.initials: J
authors.lastname: Inoue
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hashidume
authors.forename: Makoto
authors.initials: M
authors.lastname: Shimizu
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Sato
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage*; D001584:Benzoxepins / Q000008:administration & dosage* / Q000737:chemistry; D001786:Blood Glucose / Q000187:drug effects; D002957:Citrus / Q000737:chemistry*; D004032:Diet / Q000009:adverse effects; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy* / Q000209:etiology; D000960:Hypolipidemic Agents / Q000008:administration & dosage*; D007328:Insulin / Q000097:blood; D007453:Iodide Peroxidase / Q000235:genetics; D008024:Ligands; D036701:Limonins / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D051379:Mice; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D019440:Anti-Obesity Agents; D001584:Benzoxepins; D001786:Blood Glucose; D004041:Dietary Fats; D000960:Hypolipidemic Agents; D007328:Insulin; D007453:Iodide Peroxidase; D008024:Ligands; D036701:Limonins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; D014157:Transcription Factors; D000097564:Iodothyronine Deiodinase Type II; C513561:Gpbar1 protein, mouse; C485290:Ppargc1a protein, mouse; C067207:obacunone; C059405:nomilin