title: Resistance to diet-induced obesity in mice globally overexpressing OGH/GPB5.
abstract: We identified a glycoprotein hormone beta-subunit (OGH, also called GPB5) that, as a heterodimer with the alpha-subunit GPA2, serves as a second ligand for the thyroid-stimulating hormone receptor. Mice in which the OGH gene is deleted (OGH-/-) are indistinguishable from WT littermates in body weight, response to high-fat diet, metabolic parameters, body composition, and insulin tolerance. Mice engineered to transgenically globally overexpress OGH (OGH-TG) develop approximately 2-fold elevations in their basal thyroid levels and weigh slightly less than WT littermates despite increased food intake because of an increase in their metabolic rates. Moreover, when OGH-TG mice are challenged with a high-fat diet, they gain significantly less weight and body fat than their WT littermates. The OGH-TG mice also have reduced blood glucose, insulin, cholesterol, and triglycerides. In contrast to other approaches in which the thyroid axis is activated, OGH-TG mice exhibit only minor changes in heart rate and blood pressure. Our findings suggest that constitutive low-level activation of the thyroid axis (via OGH or other means) may provide a beneficial therapeutic approach for combating diet-induced obesity.
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA. lynn.macdonald@regeneron.com
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Macdonald
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Wortley
authors.forename: Lori C
authors.initials: LC
authors.lastname: Gowen
authors.forename: Keith D
authors.initials: KD
authors.lastname: Anderson
authors.forename: Jane D
authors.initials: JD
authors.lastname: Murray
authors.forename: William T
authors.initials: WT
authors.lastname: Poueymirou
authors.forename: Mary V
authors.initials: MV
authors.lastname: Simmons
authors.forename: Dianna
authors.initials: D
authors.lastname: Barber
authors.forename: David M
authors.initials: DM
authors.lastname: Valenzuela
authors.forename: Aris N
authors.initials: AN
authors.lastname: Economides
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Wiegand
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: Mark W
authors.initials: MW
authors.lastname: Sleeman
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
mesh_terms: D000818:Animals; D001835:Body Weight; D004041:Dietary Fats / Q000008:administration & dosage; D015870:Gene Expression; D017930:Genes, Reporter; D006023:Glycoproteins / Q000235:genetics*; D007763:Lac Operon; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D008969:Molecular Sequence Data; D009765:Obesity / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D036361:Peptide Hormones / Q000235:genetics*; D010641:Phenotype
chemical_list: D004041:Dietary Fats; C559612:GPB5 protein, mouse; D006023:Glycoproteins; D036361:Peptide Hormones