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Proto-Oncogene Proteins c-akt
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- Creator:
- Yaspelkis III, Benedict B., Crain, Andrew M., Singh, Mohenish K., Collins, Dale E., and Krisan, Adam D.
- Description:
- The aim of this investigation was to evaluate if leptin treatment enhances insulin-stimulated glucose transport in normal (experimental group [EXP]-1) and insulin-resistant skeletal muscle (EXP-2) by altering components of the insulin-signaling cascade and/or glucose transport pathway. In EXP-1, Sprague Dawley rats were assigned to control-chow fed (CON-CF) or leptin treated-chow fed (LEP-CF) groups. Animals were implanted with miniosmotic pumps, which delivered 0.5 mg leptin/kg/d to the LEP-CF animals and vehicle to CON-CF animals for 14 days. For EXP-2, Sprague-Dawley rats consumed normal (CON) or high-fat diets for 3 months. After the dietary lead in, the high-fat diet group was further subdivided into high-fat (HF) and high-fat, leptin-treated (HF-LEP) animals. HF-LEP animals were injected with leptin (0.5 mg leptin/kg/d) for 12 days, while the CON and HF animals were injected with vehicle. After the treatment periods, all animals were prepared for and subjected to hind limb perfusion. In EXP-1, leptin treatment increased insulin-stimulated skeletal muscle glucose transporter (GLUT4) translocation, which appeared to be due to increased phosphatidylinositol 3-kinase (PI3-K) activation and Akt phosphorylation. In EXP-2, the high-fat diet reduced insulin-stimulated glucose transport, in part, by impairing insulin-stimulated PI3-K activation and glucose transporter translocation. Leptin treatment reversed high-fat-diet-induced insulin resistance in skeletal muscle by restoring insulin receptor substrate (IRS)-1-associated PI3-K activity, total GLUT4 protein concentration, and glucose transporter translocation. Collectively, these findings suggest that leptin treatment will enhance components of both the insulin-signaling cascade and glucose transport effector system in normal and insulin-resistant skeletal muscle.
- Resource Type:
- Article
- Identifier:
- 0026-0495
- Campus Tesim:
- Northridge
- Creator:
- Reeder, Donald W., Limon, Jose J., Rivas, Donato A., Herr, Henry James, and Bernard, Jeffrey Richard
- Description:
- Several recent reports using cell lines have suggested that both Akt and atypical protein kinase C (aPKC) ζ/λ are translocated to the plasma membrane (PM) in response to insulin. However, it has yet to be determined in skeletal muscle whether: (1) insulin increases PM‐associated Akt2, aPKC ζ and/or λ protein concentration, (2) the activity of these kinases is altered by insulin at the PM, and (3) high fat feeding alters the insulin‐stimulated PM concentration and/or activity of Akt2 and aPKC ζ/λ. Sprague‐Dawley rats were randomly assigned to either normal (n= 16) or high fat (n= 16) dietary groups. Following a 12 week dietary period, animals were subjected to hind limb perfusions in the presence (n= 8 per group) or absence (n= 8 per group) of insulin. In normal skeletal muscle, total PI3‐kinase, Akt2 and aPKC ζ/λ activities were increased by insulin. PM‐associated aPKC ζ and λ, and aPKC ζ/λ activity, but not Akt2 or Akt2 activity, were increased by insulin in normal muscle. High fat feeding did not alter total skeletal muscle Akt2, aPKC ζ or aPKC λ protein concentration. Insulin‐stimulated total PI3‐kinase, Akt2 and aPKC ζ/λ activities were reduced in the high fat fed animals. Insulin‐stimulated PM aPKC ζ, aPKC λ, aPKC ζ/λ activity and GLUT4 protein concentration were also reduced in high fat fed animals. These findings suggest that in skeletal muscle, insulin stimulates translocation of aPKC ζ and λ, but not Akt2, to the PM. In addition, high fat feeding impairs insulin‐stimulated activation of total aPKC ζ/λ and Akt2, as well as PM association and activation of aPKC ζ and λ.
- Resource Type:
- Article
- Identifier:
- 0022-3751
- Campus Tesim:
- Northridge
- Creator:
- Hawley, J.A, Rivas, Donato A., Yaspelkis III, Benedict B., and Lessard, S.J.
- Description:
- The serine/threonine protein kinase, mammalian target of rapamycin (mTOR) is regulated by insulin and nutrient availability and has been proposed to play a central role as a nutrient sensor in skeletal muscle. mTOR associates with its binding partners, raptor and rictor, to form two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) respectively. We have investigated the assembly of mTORC1/2 and the activation of their downstream substrates (i.e. Akt, S6K1) in response to known effectors of mTOR, excess lipid availability and AMP-activated protein kinase (AMPK) activation/exercise training in rat skeletal muscle. The in vivo formation of mTORC1 and 2 and the activation of their respective downstream substrates were increased in response to chronic (8 weeks) consumption of a high-fat diet. Diet-induced mTORC activation and skeletal muscle insulin resistance were reversed by 4 weeks of exercise training, which was associated with enhanced muscle AMPK activation. In order to determine whether AMPK activation reverses lipid-induced mTOR activation, L6 myotubes were exposed to 0.4 mM palmitate to activate mTORC1/2 in the absence or presence of 5′-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). Palmitate exposure (4 h) increased insulin-stimulated S6K1 Thr389 phosphorylation by 60%, indicating activation of mTORC1. AMPK activation with 1 mM AICAR abolished lipid-induced mTOR activation in vitro. Our data implicates reductions in mTOR complex activation with the reversal of lipid-induced skeletal muscle insulin resistance in response to exercise training or AICAR and identifies mTOR as a potential target for the treatment of insulin resistance.
- Resource Type:
- Article
- Identifier:
- 0022-0795
- Campus Tesim:
- Northridge