Long-term divergent selection on body fatness in mice indicates a regulation system that is independent of leptin production and reception

L Bunger, J Forsting, K L McDonald, S Horvat, J Duncan, S Hochscheid, C A Baile, W G Hill, J R Speakman

Research output: Contribution to journalArticle

Abstract

Divergent selection in mice on fatness over 60 generations produced a fat (F) and a lean (L) line, having about 22% and 4% body fat, respectively. To elucidate the importance of the leptin regulatory feedback loop in the genetic changes produced by this selection, Lep(ob) and Lepr(db) mutations causing leptin production and leptin receptor deficiency, respectively, were introgressed individually into both lines by repeated backcrossing. The fat amount increased significantly in homozygotes for Lep(ob) or Lepr(db) in both lines, for example, in F and L males from 8.5 to 18.8 and 17.2 g (P<0.001) and from 1.25 to 18.0 and 12.7 g (P<0.001), respectively. Line differences were, however, mostly maintained after introgression. Concentrations of circulating leptin were relatively independent of the original lines but heavily dependent on the introgressed genotype. Introgression of leptin production and receptor deficiencies had separate effects from long-term selection, indicating that the genes responsible for the line divergence must act independently of the leptin regulatory system. Energy budget analysis indicated that the major line differences were in the level of energy expended on physical activity, and these differences were preserved following introgression, suggesting that multiple pathways regulate fatness, which may be independently responsive to intervention.

Original languageEnglish
Pages (from-to)85
Number of pages15
JournalThe FASEB Journal
Volume16
DOIs
Publication statusPublished - 2002

Keywords

  • obesity
  • mutation
  • selection
  • polygenic model
  • introgression
  • genetics
  • FAT-CONTENT
  • FOOD-INTAKE
  • PCR-RFLP
  • OBESITY
  • MOUSE
  • LINES
  • WEIGHT
  • MUTATION
  • LEP(OB)
  • GROWTH

Cite this

Long-term divergent selection on body fatness in mice indicates a regulation system that is independent of leptin production and reception. / Bunger, L ; Forsting, J ; McDonald, K L ; Horvat, S ; Duncan, J ; Hochscheid, S ; Baile, C A ; Hill, W G ; Speakman, J R .

In: The FASEB Journal, Vol. 16, 2002, p. 85.

Research output: Contribution to journalArticle

Bunger, L ; Forsting, J ; McDonald, K L ; Horvat, S ; Duncan, J ; Hochscheid, S ; Baile, C A ; Hill, W G ; Speakman, J R . / Long-term divergent selection on body fatness in mice indicates a regulation system that is independent of leptin production and reception. In: The FASEB Journal. 2002 ; Vol. 16. pp. 85.
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AU - Forsting, J

AU - McDonald, K L

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AU - Duncan, J

AU - Hochscheid, S

AU - Baile, C A

AU - Hill, W G

AU - Speakman, J R

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AB - Divergent selection in mice on fatness over 60 generations produced a fat (F) and a lean (L) line, having about 22% and 4% body fat, respectively. To elucidate the importance of the leptin regulatory feedback loop in the genetic changes produced by this selection, Lep(ob) and Lepr(db) mutations causing leptin production and leptin receptor deficiency, respectively, were introgressed individually into both lines by repeated backcrossing. The fat amount increased significantly in homozygotes for Lep(ob) or Lepr(db) in both lines, for example, in F and L males from 8.5 to 18.8 and 17.2 g (P<0.001) and from 1.25 to 18.0 and 12.7 g (P<0.001), respectively. Line differences were, however, mostly maintained after introgression. Concentrations of circulating leptin were relatively independent of the original lines but heavily dependent on the introgressed genotype. Introgression of leptin production and receptor deficiencies had separate effects from long-term selection, indicating that the genes responsible for the line divergence must act independently of the leptin regulatory system. Energy budget analysis indicated that the major line differences were in the level of energy expended on physical activity, and these differences were preserved following introgression, suggesting that multiple pathways regulate fatness, which may be independently responsive to intervention.

KW - obesity

KW - mutation

KW - selection

KW - polygenic model

KW - introgression

KW - genetics

KW - FAT-CONTENT

KW - FOOD-INTAKE

KW - PCR-RFLP

KW - OBESITY

KW - MOUSE

KW - LINES

KW - WEIGHT

KW - MUTATION

KW - LEP(OB)

KW - GROWTH

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JO - The FASEB Journal

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