title: Mesodermal developmental gene Tbx15 impairs adipocyte differentiation and mitochondrial respiration.
abstract: Increased intraabdominal (visceral) fat is associated with a high risk of diabetes and metabolic syndrome. We have previously shown that the mesodermal developmental transcription factor Tbx15 is highly differentially expressed between visceral and subcutaneous (s.c.) fat in both humans and rodents, and in humans visceral fat Tbx15 expression is decreased in obesity. Here we show that, in mice, Tbx15 is 260-fold more highly expressed in s.c. preadipocytes than in epididymal preadipocytes. Overexpression of Tbx15 in 3T3-L1 preadipocytes impairs adipocyte differentiation and decreases triglyceride content. This defect in differentiation can be corrected by stimulating cells with the PPARγ agonist rosiglitazone (Rosi). However, triglyceride accumulation remains decreased by ∼50%, due to a decrease in basal lipogenic rate and increase in basal lipolytic rate. 3T3-L1 preadipocytes overexpressing Tbx15 also have a 15% reduction in mitochondrial mass and a 28% reduction in basal mitochondrial respiration (P = 0.004) and ATP turnover (P = 0.02), and a 45% (P = 0.003) reduction in mitochondrial respiratory capacity. Thus, differential expression of Tbx15 between fat depots plays an important role in the interdepot differences in adipocyte differentiation, triglyceride accumulation, and mitochondrial function that may contribute to the risk of diabetes and metabolic disease.
authors.affiliation: Joslin Diabetes Center, Department of Integrative Physiology and Metabolism, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Stephane
authors.initials: S
authors.lastname: Gesta
authors.forename: Olivier
authors.initials: O
authors.lastname: Bezy
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Mori
authors.forename: Yazmin
authors.initials: Y
authors.lastname: Macotela
authors.forename: Kevin Y
authors.initials: KY
authors.lastname: Lee
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
mesh_terms: D041721:3T3-L1 Cells; D000255:Adenosine Triphosphate / Q000378:metabolism; D017667:Adipocytes / Q000502:physiology*; D000818:Animals; D001391:Azo Compounds; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D019069:Cell Respiration / Q000235:genetics* / Q000502:physiology; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D004734:Energy Metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology*; D010101:Oxygen Consumption / Q000502:physiology; D047495:PPAR gamma / Q000819:agonists; D016133:Polymerase Chain Reaction; D000077154:Rosiglitazone; D050151:Subcutaneous Fat / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D001391:Azo Compounds; D017931:DNA Primers; D047495:PPAR gamma; D020825:T-Box Domain Proteins; C114093:TBX15 protein, mouse; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000255:Adenosine Triphosphate; C011049:oil red O