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Yaspelkis III, Benedict B.
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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., Saito, Misato, Lessard, Sarah J., Yaspelkis III, Benedict B., and Limon, Jose J.
- Description:
- The aims of this investigation were 1) to determine whether endurance exercise training could reverse impairments in insulin-stimulated compartmentalization and/or activation of aPKCzeta/lambda and Akt2 in skeletal muscle from high-fat-fed rodents and 2) to assess whether the PPARgamma agonist rosiglitazone could reverse impairments in skeletal muscle insulin signaling typically observed after high-fat feeding. Sprague-Dawley rats were placed on chow (NORCON, n = 16) or high-fat (n = 64) diets for 4 wk. During a subsequent 4-wk experimental period, high-fat-fed rats were allocated (n = 16/group) to either sedentary control (HFC), exercise training (HFX), rosiglitazone treatment (HFRSG), or a combination of both exercise training and rosiglitazone (HFRX). Following the 4-wk experimental period, animals underwent hindlimb perfusions. Insulin-stimulated plasma membrane-associated aPKCzeta and -lambda protein concentration, aPKCzeta/lambda activity, GLUT4 protein concentration, cytosolic Akt2, and aPKCzeta/lambda activities were reduced (P < 0.05) in HFC compared with NORCON. Cytosolic Akt2, aPKCzeta, and aPKClambda protein concentrations were not affected in HFC compared with NORCON. Exercise training reversed the deleterious effects of the high-fat diet such that insulin-stimulated compartmentalization and activation of components of the insulin-signaling cascade in HFX were normalized to NORCON. High-fat diet-induced impairments to skeletal muscle glucose metabolism were not reversed by rosiglitazone administration, nor did rosiglitazone augment the effect of exercise. Our findings indicate that chronic exercise training, but not rosiglitazone, reverses high-fat diet induced impairments in compartmentalization and activation of components of the insulin-signaling cascade in skeletal muscle.
- Resource Type:
- Article
- Identifier:
- 0193-1849
- Campus Tesim:
- Northridge
- Creator:
- Britton, Steven L., Koch, Lauren G., Lessard, Sarah J., Stephenson, Erin J., Watt, Matthew J., Hawley, John A., Rivas, Donato A., and Yaspelkis III, Benedict B.
- Description:
- Impaired visceral white adipose tissue (WAT) metabolism has been implicated in the pathogenesis of several lifestyle-related disease states, with diminished expression of several WAT mitochondrial genes reported in both insulin-resistant humans and rodents. We have used rat models selectively bred for low- (LCR) or high-intrinsic running capacity (HCR) that present simultaneously with divergent metabolic phenotypes to test the hypothesis that oxidative enzyme expression is reduced in epididymal WAT from LCR animals. Based on this assumption, we further hypothesized that short-term exercise training (6 wk of treadmill running) would ameliorate this deficit. Approximately 22-wk-old rats (generation 22) were studied. In untrained rats, the abundance of mitochondrial respiratory complexes I–V, citrate synthase (CS), and PGC-1 was similar for both phenotypes, although CS activity was greater than 50% in HCR (P = 0.09). Exercise training increased CS activity in both phenotypes but did not alter mitochondrial protein content. Training increased the expression and phosphorylation of proteins with roles in β-adrenergic signaling, including β3-adrenergic receptor (16% increase in LCR; P < 0.05), NOR1 (24% decrease in LCR, 21% decrease in HCR; P < 0.05), phospho-ATGL (25% increase in HCR; P < 0.05), perilipin (25% increase in HCR; P < 0.05), CGI-58 (15% increase in LCR; P < 0.05), and GLUT4 (16% increase in HCR; P < 0.0001). A training effect was also observed for phospho-p38 MAPK (12% decrease in LCR, 20% decrease in HCR; P < 0.05) and phospho-JNK (29% increase in LCR, 20% increase in HCR; P < 0.05). We conclude that in the LCR-HCR model system, mitochondrial protein expression in WAT is not affected by intrinsic running capacity or exercise training. However, training does induce alterations in the activity and expression of several proteins that are essential to the intracellular regulation of WAT metabolism.
- Resource Type:
- Article
- Identifier:
- 0193-1849
- Campus Tesim:
- Northridge
- Creator:
- Singh, Mohenish K., Abdelkerim, Ashraf, Arends, Julie C., Krisan, Adam D., Kwong, Connie C., Barrack, Michelle T., Seeger, Leanne L., Bernard, Jeffrey Richard, Crain, Andrew M., Nattiv, Aurelia, Kennedy, Gannon, Goolsby, Marci A., Yaspelkis III, Benedict B., and Collins, Dale E.
- Description:
- Our laboratory recently reported that chronic resistance training (RT) improved insulin-stimulated glucose transport in normal rodent skeletal muscle, owing, in part, to increased GLUT-4 protein concentration (Yaspelkis BB III, Singh MK, Trevino B, Krisan AD, and Collins DE. Acta Physiol Scand 175: 315-323, 2002). However, it remained to be determined whether these improvements resulted from alterations in the insulin signaling cascade as well. In addition, the possibility existed that RT might improve skeletal muscle insulin resistance. Thirty-two male Sprague-Dawley rats were assigned to four groups: control diet (Con)-sedentary (Sed); Con-RT; high-fat diet (HF)-Sed; and HF-RT. Animals consumed their respective diets for 9 wk; then RT animals performed 12 wk of training (3 sets, 10 repetitions at 75% one-repetition maximum, 3x/wk). Animals remained on their dietary treatments over the 12-wk period. After the training period, animals were subjected to hindlimb perfusions. Insulin-stimulated insulin receptor substrate-1-associated phosphatidylinositol-3 kinase activity was enhanced in the red gastrocnemius and quadriceps of Con-RT and HF-RT animals. Atypical PKC-zeta/lambda and Akt activities were reduced in HF-Sed and normalized in HF-RT animals. Resistance training increased GLUT-4 protein concentration in red gastrocnemius and quadriceps of Con-RT and HF-RT animals. No differences were observed in total protein concentrations of insulin receptor substrate-1, Akt, atypical PKC-zeta/lambda, or phosphorylation of Akt. Collectively, these findings suggest that resistance training increases insulin-stimulated carbohydrate metabolism in normal skeletal muscle and reverses high-fat diet-induced skeletal muscle insulin resistance by altering components of both the insulin signaling cascade and glucose transporter effector system.
- Resource Type:
- Article
- Identifier:
- 1522-1601, 8750-7587, 0161-7567
- Campus Tesim:
- Northridge
- Creator:
- Kelly, Scott A., Lytle, Christian, Malisch, Jessica L., Lee, Sun K., Rivas, Donato A., Yaspelkis III, Benedict B., Rezende, Enrico L., Gomes, Fernando R., and Garland, Theodore
- Description:
- To examine the evolution of endurance-exercise behaviour, we have selectively bred four replicate lines of laboratory mice (Mus domesticus) for high voluntary wheel running (`high runner' or HR lines), while also maintaining four non-selected control (C) lines. By generation 16, HR mice ran ∼2.7-fold more than C mice, mainly by running faster (especially in females), a differential maintained through subsequent generations, suggesting an evolutionary limit of unknown origin. We hypothesized that HR mice would have higher glycogen levels before nightly running, show greater depletion of those depots during their more intense wheel running, and have increased glycogen synthase activity and GLUT-4 protein in skeletal muscle. We sampled females from generation 35 at three times (photophase 07:00 h–19:00 h) during days 5–6 of wheel access, as in the routine selection protocol: Group 1, day 5, 16:00 h–17:30 h, wheels blocked from 13:00 h; Group 2, day 6, 02:00 h–03:30 h (immediately after peak running); and Group 3, day 6, 07:00 h–08:30 h. An additional Group 4, sampled 16:00 h–17:30 h, never had wheels. HR individuals with the mini-muscle phenotype (50% reduced hindlimb muscle mass) were distinguished for statistical analyses comparing C, HR normal, and HR mini. HR mini ran more than HR normal, and at higher speeds, which might explain why they have been favored by the selective-breeding protocol. Plasma glucose was higher in Group 1 than in Group 4, indicating a training effect (phenotypic plasticity). Without wheels, no differences in gastrocnemius GLUT-4 were observed. After 5 days with wheels, all mice showed elevated GLUT-4, but HR normal and mini were 2.5-fold higher than C. At all times and irrespective of wheel access, HR mini showed approximately three-fold higher [glycogen] in gastrocnemius and altered glycogen synthase activity. HR mini also showed elevated glycogen in soleus when sampled during peak running. All mice showed some glycogen depletion during nightly wheel running, in muscles and/or liver, but the magnitude of this depletion was not large and hence does not seem to be limiting to the evolution of even-higher wheel running.
- Resource Type:
- Article
- Identifier:
- 0022-0949
- Campus Tesim:
- Northridge
- Creator:
- Kvasha, Ilya A., Figueroa, Tania Y., and Yaspelkis III, Benedict B.
- Description:
- High-fat feeding increases insulin receptor and IRS-1 coimmunoprecipitation with SOCS-3, IKK / phosphorylation and decreases PI-3 kinase activity in muscle. Am J Physiol Regul Integr Comp Physiol 296: R1709-R1715, 2009. First published April 22, 2009
- Resource Type:
- Article
- Identifier:
- http://ajpregu.physiology.org/content/ajpregu/296/6/R1709.full.pdf, 0363-6119
- Campus Tesim:
- Northridge
- Creator:
- Figueroa, Tania Y., Zolotnik, Ilya A., and Yaspelkis III, Benedict B.
- Description:
- AIMS: We evaluated if selected pro-inflammatory cytokines and/or the protein suppressor of cytokine signaling 3 (SOCS-3) could account for decreased insulin-stimulated phosphatidylinositol 3-kinase (PI3-K) activity in the skeletal muscle of the obese Zucker rat. MAIN METHODS: Eight lean and eight obese Zucker rats ~4weeks of age were obtained and allowed to feed ad libitum for 4weeks before undergoing hind limb perfusion in the presence of 500μU/ml insulin. KEY FINDINGS: Insulin-stimulated skeletal muscle PI3-K activity and 3-O-methylglucose transport rates were reduced (P<0.05) in obese compared to lean animals. IRS-1 concentration remained unchanged although IRS-1 tyrosine phosphorylation was decreased (P<0.05), and IRS-1 serine phosphorylation (pS) was increased (P<0.05) in obese animals compared to lean animals. IKKα/β pS and JNK theronine/tyrosine phosphorylation was increased (P<0.05) in the obese animals. IκBα concentration was decreased (P<0.05) and IκBα pS was increased (P<0.05) in the obese compared to lean Zucker animals. SOCS-3 concentration and SOCS-3 co-immunoprecipitation with both insulin receptor β-subunit (IR-β) and IRS-1 were elevated (P<0.05) in obese compared to lean animals. IRS-1 co-immunoprecipitation with IR-β was reduced 56% in the obese animals. SIGNIFICANCE: Increased IKKα/β and JNK serine phosphorylation may contribute to increasing IRS-1 serine phosphorylation, while concurrent co-localization of SOCS-3 with both IR-β and IRS-1 may prevent IRS-1 from interacting with IR-β. These two mechanisms thusly may independently contribute to impairing insulin-stimulated PI3-K activation in the skeletal muscle of the obese Zucker rat.
- Resource Type:
- Article
- Identifier:
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478879/pdf/nihms407937.pdf, 1878-5565
- Campus Tesim:
- Northridge
- Creator:
- Kvasha, Ilya A., Figueroa, Tania Y., and Yaspelkis III, Benedict B.
- Description:
- doi:10.1152/ajpregu.00117.2009.—Suppressor of cytokine signaling (SOCS) proteins and/or activation of the proinflammatory pathway have been postulated as possible mechanisms that may contribute to skeletal muscle insulin resistance. Thus, the aims of the present investigation were to determine in high-fat-fed skeletal muscle: 1) whether SOCS-3 protein concentration is increased, 2) whether coimmunoprecipitation of SOCS-3 with the insulin receptor- subunit and/or IRS-1 is increased, and 3) whether select components of the proinflammatory pathway are altered. Thirtytwo male Sprague-Dawley rats were assigned to either control (CON, n 16) or high-fat-fed (HF, n 16) dietary groups for 12 wk and then subjected to hind limb perfusions in the presence (n 8/group) or absence (n 8/group) of insulin. Insulin-stimulated skeletal muscle 3-MG transport rates and PI-3 kinase activity were greater (P 0.05) in CON. IRS-1 tyrosine phosphorylation was decreased (P 0.05), and IRS-1 serine 307 phosphorylation was increased (P 0.05) in HF. Insulin receptor- (IR-) subunit coimmunoprecipitation with IRS-1 was reduced in HF. SOCS-3 protein concentration and SOCS-3 coimmunoprecipitation with both the IR- subunit and IRS-1 was increased (P 0.05) in HF. IKK / serine phosphorylation was increased (P 0.05), I B protein concentration was decreased (P 0.05) and I B serine phosphorylation was increased (P 0.05) in HF. Increased colocalization of SOCS-3 with both the IR- subunit and IRS-1 may provide steric hindrance that prevents IRS-1 from interacting with IR-, while increased IKK serine phosphorylation may contribute to increasing IRS-1 serine phosphorylation, both of which independently can have deleterious effects on insulin-stimulated PI-3 kinase activation in high-fat-fed rodent skeletal muscle. insulin res and High-fat feeding increases insulin receptor and IRS-1 coimmunoprecipitation with SOCS-3, IKK / phosphorylation and decreases PI-3 kinase activity in muscle. Am J Physiol Regul Integr Comp Physiol 296: R1709 -R1715, 2009. First published April 22, 2009
- Resource Type:
- Article
- Identifier:
- http://ajpregu.physiology.org/content/ajpregu/296/6/R1709.full.pdf, 0363-6119
- Campus Tesim:
- Northridge
- Creator:
- Britton, Steven L., Saito, Misato, Koch, Lauren G., Lessard, Sarah J., Hawley, John A., Rivas, Donato A., Yaspelkis III, Benedict B., and Friedhuber, Anna M.
- Description:
- Chronic metabolic diseases develop from the complex interaction of environmental and genetic factors, although the extent to which each contributes to these disorders is unknown. Here, we test the hypothesis that artificial selection for low intrinsic aerobic running capacity is associated with reduced skeletal muscle metabolism and impaired metabolic health. Rat models for low- (LCR) and high- (HCR) intrinsic running capacity were derived from genetically heterogeneous N:NIH stock for 20 generations. Artificial selection produced a 530% difference in running capacity between LCR/HCR, which was associated with significant functional differences in glucose and lipid handling by skeletal muscle, as assessed by hindlimb perfusion. LCR had reduced rates of skeletal muscle glucose uptake (∼30%; P = 0.04), glucose oxidation (∼50%; P = 0.04), and lipid oxidation (∼40%; P = 0.02). Artificial selection for low aerobic capacity was also linked with reduced molecular signaling, decreased muscle glycogen, and triglyceride storage, and a lower mitochondrial content in skeletal muscle, with the most profound changes to these parameters evident in white rather than red muscle. We show that a low intrinsic aerobic running capacity confers reduced insulin sensitivity in skeletal muscle and is associated with impaired markers of metabolic health compared with high intrinsic running capacity. Furthermore, selection for high running capacity, in the absence of exercise training, endows increased skeletal muscle insulin sensitivity and oxidative capacity in specifically white muscle rather than red muscle. These data provide evidence that differences in white muscle may have a role in the divergent aerobic capacity observed in this generation of LCR/HCR.
- Resource Type:
- Article
- Identifier:
- 0363-6119, 1522-1490
- 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