The high-fat-fed lean Zucker rat: a spontaneous isocaloric model of fat-induced insulin resistance associated with muscle GSK-3 overactivity.
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.
Henriksen
Erik J
EJ
Department of Physiology, Univeristy of Arizona, Tucson, AZ 85721-0093, USA. ejhenrik@u.arizona.edu
Teachey
Mary K
MK
Lindborg
Katherine A
KA
Diehl
Cody J
CJ
Beneze
Alan N
AN
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000502:physiology
D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D038362:Glycogen Synthase Kinase 3