The high-fat-fed lean Zucker rat: A spontaneous isocaloric model of fat-induced insulin resistance associated with muscle GSK-3 overactivity

Erik J Henriksen, Mary K. Teachey, Katherine A. Lindborg, Cody J. Diehl, Alan N. Beneze

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Abstract

High-fat feeding (HFF) is a well-accepted model for nutritionally-induced insulin resistance. The purpose of this investigation was to assess the metabolic responses of female lean Zucker rats provided regular chow (4% fat) or a high-fat chow (50% fat) for 15 wk. HFF rats spontaneously adjusted food intake so that daily caloric intake matched that of chow-fed (CF) controls. HFF animals consumed more (P < 0.05) calories from fat (31.9 ± 1.2 vs. 2.4 ± 0.2 kcal/day) and had significantly greater final body weights (280 ± 10 vs. 250 ± 5 g) and total visceral fat (24 ± 3 vs. 10 ± 1 g). Fasting plasma insulin was 2.3-fold elevated in HFF rats. Glucose tolerance (58%) and whole body insulin sensitivity (75%) were markedly impaired in HFF animals. In HFF plantaris muscle, in vivo insulin receptor β-subunit (IR-β) and insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation and phosphorylation of Akt Ser473 and glycogen synthase kinase-3β (GSK-3β) Ser9, relative to circulating insulin levels, were decreased by 40-59%. In vitro insulin-stimulated glucose transport in HFF soleus was decreased by 54%, as were IRS-1 tyrosine phosphorylation (26%) and phosphorylation of Akt Ser473 (38%) and GSK-3β Ser9 (25%), the latter indicative of GSK-3 overactivity. GSK-3 inhibition in HFF soleus using CT98014 increased insulin-stimulated glucose transport (28%), IRS-1 tyrosine phosphorylation (28%) and phosphorylation of Akt Ser473 (38%) and GSK-3β Ser9 (48%). In summary, the female lean Zucker rat fed a high-fat diet represents an isocaloric model of nutritionally-induced insulin resistance associated with moderate visceral fat gain, hyperinsulinemia, and impairments of skeletal muscle insulin-signaling functionality, including GSK-3β overactivity.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume294
Issue number6
DOIs
StatePublished - Jun 2008

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Glycogen Synthase Kinase 3
Zucker Rats
Insulin Resistance
Fats
Muscles
Phosphorylation
Insulin Receptor Substrate Proteins
Insulin
Tyrosine
Intra-Abdominal Fat
Glucose
Skeletal Muscle
Insulin Receptor
Hyperinsulinism
High Fat Diet
Energy Intake
Fasting

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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The high-fat-fed lean Zucker rat : A spontaneous isocaloric model of fat-induced insulin resistance associated with muscle GSK-3 overactivity. / Henriksen, Erik J; Teachey, Mary K.; Lindborg, Katherine A.; Diehl, Cody J.; Beneze, Alan N.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 294, No. 6, 06.2008.

Research output: Contribution to journalArticle

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abstract = "High-fat feeding (HFF) is a well-accepted model for nutritionally-induced insulin resistance. The purpose of this investigation was to assess the metabolic responses of female lean Zucker rats provided regular chow (4{\%} fat) or a high-fat chow (50{\%} fat) for 15 wk. HFF rats spontaneously adjusted food intake so that daily caloric intake matched that of chow-fed (CF) controls. HFF animals consumed more (P < 0.05) calories from fat (31.9 ± 1.2 vs. 2.4 ± 0.2 kcal/day) and had significantly greater final body weights (280 ± 10 vs. 250 ± 5 g) and total visceral fat (24 ± 3 vs. 10 ± 1 g). Fasting plasma insulin was 2.3-fold elevated in HFF rats. Glucose tolerance (58{\%}) and whole body insulin sensitivity (75{\%}) were markedly impaired in HFF animals. In HFF plantaris muscle, in vivo insulin receptor β-subunit (IR-β) and insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation and phosphorylation of Akt Ser473 and glycogen synthase kinase-3β (GSK-3β) Ser9, relative to circulating insulin levels, were decreased by 40-59{\%}. In vitro insulin-stimulated glucose transport in HFF soleus was decreased by 54{\%}, as were IRS-1 tyrosine phosphorylation (26{\%}) and phosphorylation of Akt Ser473 (38{\%}) and GSK-3β Ser9 (25{\%}), the latter indicative of GSK-3 overactivity. GSK-3 inhibition in HFF soleus using CT98014 increased insulin-stimulated glucose transport (28{\%}), IRS-1 tyrosine phosphorylation (28{\%}) and phosphorylation of Akt Ser473 (38{\%}) and GSK-3β Ser9 (48{\%}). In summary, the female lean Zucker rat fed a high-fat diet represents an isocaloric model of nutritionally-induced insulin resistance associated with moderate visceral fat gain, hyperinsulinemia, and impairments of skeletal muscle insulin-signaling functionality, including GSK-3β overactivity.",
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