Resistance to diet-induced obesity in mice globally overexpressing OGH/GPB5.
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.
Macdonald
Lynn E
LE
Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA. lynn.macdonald@regeneron.com
Wortley
Katherine E
KE
Gowen
Lori C
LC
Anderson
Keith D
KD
Murray
Jane D
JD
Poueymirou
William T
WT
Simmons
Mary V
MV
Barber
Dianna
D
Valenzuela
David M
DM
Economides
Aris N
AN
Wiegand
Stanley J
SJ
Yancopoulos
George D
GD
Sleeman
Mark W
MW
Murphy
Andrew J
AJ
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
D004041:Dietary Fats; C559612:GPB5 protein, mouse; D006023:Glycoproteins; D036361:Peptide Hormones