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

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 beta-subunit (IR-beta) and insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation and phosphorylation of Akt Ser473 and glycogen synthase kinase-3beta (GSK-3beta) 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-3beta 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-3beta 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-3beta overactivity.

• Authors: Erik J Henriksen, Mary K Teachey, Katherine A Lindborg, Cody J Diehl, Alan N Beneze
• Journal: American journal of physiology. Regulatory, integrative and comparative physiology (Am J Physiol Regul Integr Comp Physiol) Vol. 294 Issue 6 Pg. R1813-21 (Jun 2008) ISSN: 0363-6119 [Print] United States
• PMID: 18385470 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Blood Glucose
• Dietary Fats
• Insulin
• Glycogen Synthase Kinase 3

Topics

• Animals
• Blood Glucose (metabolism)
• Dietary Fats (pharmacology)
• Disease Models, Animal
• Female
• Glycogen Synthase Kinase 3 (metabolism)
• Insulin (blood)
• Insulin Resistance (physiology)
• Muscle, Skeletal (drug effects, enzymology, physiopathology)
• Rats
• Rats, Zucker
• Signal Transduction (physiology)