title: Responses of brown adipose tissue to diet-induced obesity, exercise, dietary restriction and ephedrine treatment.
abstract: Drug-induced weight loss in humans has been associated with undesirable side effects not present in weight loss from lifestyle interventions (caloric restriction or exercise). To investigate the mechanistic differences of weight loss by drug-induced and lifestyle interventions, we examined the gene expression (mRNA) in brown adipose tissue (BAT) and conducted histopathologic assessments in diet-induced obese (DIO) mice given ephedrine (18 mg/kg/day orally), treadmill exercise (10 m/min, 1-h/day), and dietary restriction (DR: 26% dietary restriction) for 7 days. Exercise and DR mice lost more body weight than controls and both ephedrine and exercise reduced percent body fat. All treatments reduced BAT and liver lipid accumulation (i.e., cytoplasmic lipids in brown adipocytes and hepatocytes) and increased oxygen consumption (VO2 ml/kg/h) compared with controls. Mitochondrial biogenesis/function-related genes (TFAM, NRF1 and GABPA) were up-regulated in the BAT of all groups. UCP-1 was up-regulated in exercise and ephedrine groups, whereas MFSD2A was up-regulated in ephedrine and DR groups. PGC-1α up-regulation was observed in exercise and DR groups but not in ephedrine group. In all experimental groups, except for ephedrine, fatty acid transport and metabolism genes were up-regulated, but the magnitude of change was higher in the DR group. PRKAA1 was up-regulated in all groups but not significantly in the ephedrine group. ADRß3 was slightly up-regulated in the DR group only, whereas ESRRA remained unchanged in all groups. Although our data suggest a common pathway of BAT activation elicited by ephedrine treatment, exercise or DR, mRNA changes were indicative of additional nutrient-sensing pathways in exercise and DR.
authors.affiliation: Safety Assessment, GlaxoSmithKline, Research Triangle Park, NC 27709-3398, USA.
authors.forename: Nikki
authors.initials: N
authors.lastname: Slocum
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Durrant
authors.forename: David
authors.initials: D
authors.lastname: Bailey
authors.forename: Lawrence
authors.initials: L
authors.lastname: Yoon
authors.forename: Holly
authors.initials: H
authors.lastname: Jordan
authors.forename: Joanna
authors.initials: J
authors.lastname: Barton
authors.forename: Roger H
authors.initials: RH
authors.lastname: Brown
authors.forename: Lisa
authors.initials: L
authors.lastname: Clifton
authors.forename: Tula
authors.initials: T
authors.lastname: Milliken
authors.forename: Wallace
authors.initials: W
authors.lastname: Harrington
authors.forename: Carie
authors.initials: C
authors.lastname: Kimbrough
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Faber
authors.forename: Neal
authors.initials: N
authors.lastname: Cariello
authors.forename: Chandikumar S
authors.initials: CS
authors.lastname: Elangbam
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D031204:Caloric Restriction; D004041:Dietary Fats / Q000008:administration & dosage*; D004734:Energy Metabolism / Q000187:drug effects; D004809:Ephedrine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010101:Oxygen Consumption / Q000187:drug effects; D013566:Sympathomimetics / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D004041:Dietary Fats; D024101:Mitochondrial Proteins; D013566:Sympathomimetics; D004809:Ephedrine