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1.  Adiponectin is not required for exercise training‐induced improvements in glucose and insulin tolerance in mice 
Physiological Reports  2014;2(9):e12146.
Adiponectin (Ad) is a potent insulin‐sensitizing adipokine that has been found to activate pathways involved in the adaptation to exercise. Therefore, we examined whether Ad is required for the increased insulin response observed following exercise training in Ad knockout mice (AdKO). Eight weeks of exercise training significantly increased glucose and insulin tolerance in both wild type (WT) and AdKO mice. There were no differences in glucose tolerance between genotypes but insulin tolerance was improved to a greater extent in AdKO compared to WT mice following exercise training (+26%, P < 0.05). There were no genotype differences in the insulin‐stimulated phosphorylation of AKT or AS160 in red or white gastrocnemius muscle (RG, WG). Exercise training increased total AKT and AS160 protein content in RG and total AS160 protein content in WG. There were no genotype differences in total AKT or AS160. However, exercise training induced a more robust increase in total AS160 in RG from AdKO (+44 ± 8%, P < 0.05) compared to WT mice (+28 ± 7%, P = 0.06). There were no differences in total GLUT4 or FAT/CD36 in RG or WG in WT or AdKO, with or without exercise training. Similarly, there were no differences in RER, VO2, or activity between any groups. Our results indicate the presence of Ad is not required for exercise‐induced increases in insulin response. Furthermore, it appears that exercise may improve insulin sensitivity to a greater extent in the absence of Ad, suggesting the presence of an unknown compensatory mechanism.
Collectively, our results demonstrate that the absence of Ad does not impair the capacity of endurance exercise training to increase glucose and insulin tolerance in AdKO mice. In addition, there were no impairments in insulin signaling or in the protein content of AKT or AS160. Taken together with previous findings, our data indicate that AdKO mice may have sufficient compensations to override the absence of Ad.
PMCID: PMC4270243  PMID: 25214523
Adiponectin; adiponectin knockout mice; exercise training; glucose and insulin tolerance; insulin response; skeletal muscle
2.  Feeding butter with elevated content of trans-10, cis-12 conjugated linoleic acid to lean rats does not impair glucose tolerance or muscle insulin response 
Numerous studies have investigated the effects of isolated CLA supplementation on glucose homeostasis in humans and rodents. However, both the amount and relative abundance of CLA isomers in supplemental form are not representative of what is consumed from natural sources. No study to date has examined the effects of altered CLA isomer content within a natural food source. Our goal was to increase the content of the insulin desensitizing CLAt10,c12 isomer relative to the CLAc9,t11 isomer in cow’s milk by inducing subacute rumenal acidosis (SARA), and subsequently investigate the effects of this milk fat on parameters related to glucose and insulin tolerance in rats.
We fed female rats (~2.5 to 3 months of age) CLA t10,c12 –enriched (SARA) butter or non-SARA butter based diets for 4 weeks in either low (10% of kcal from fat; 0.18% total CLA by weight) or high (60% of kcal from fat; 0.55% total CLA by weight) amounts. In an effort to extend these findings, we then fed rats high (60% kcal) amounts of SARA or non-SARA butter for a longer duration (8 weeks) and assessed changes in whole body glucose, insulin and pyruvate tolerance in comparison to low fat and 60% lard conditions.
There was a main effect for increased fasting blood glucose and insulin in SARA vs. non-SARA butter groups after 4 weeks of feeding (p < 0.05). However, blood glucose and insulin concentration, and maximal insulin-stimulated glucose uptake in skeletal muscle were similar in all groups. Following 8 weeks of feeding, insulin tolerance was impaired by the SARA butter, but not glucose or pyruvate tolerance. The non-SARA butter did not impair tolerance to glucose, insulin or pyruvate.
This study suggests that increasing the consumption of a naturally enriched CLAt10,c12 source, at least in rats, has minimal impact on whole body glucose tolerance or muscle specific insulin response.
PMCID: PMC4083370  PMID: 24956949
Conjugated linoleic acid; Butter; Rats; Glucose tolerance; Insulin tolerance; Insulin-stimulated glucose uptake
3.  Identification of a novel malonyl-CoA IC50 for CPT-1: implications for predicting in vivo fatty acid oxidation rates 
The Biochemical journal  2012;448(1):10.1042/BJ20121110.
Published values regarding the sensitivity (IC50) of carnitine palmitoyl transferase I (CPT-I) to malonyl-CoA (M-CoA) inhibition in isolated mitochondria are inconsistent with predicted in vivo rates of fatty acid oxidation. Therefore, we have re-examined M-CoA inhibition kinetics under varying palmitoyl-CoA (P-CoA) concentrations in both isolated mitochondria and permeabilized muscle fibres (PMF). PMF have an 18-fold higher IC50 (0.61 vs 0.034 μM) in the presence of 25 μM P-CoA and a 13-fold higher IC50 (6.3 vs 0.49 μM) in the presence of 150 μM P-CoA compared to isolated mitochondria. M-CoA inhibition kinetics determined in PMF predicts that CPT-I activity is inhibited by 33% in resting muscle compared to >95% in isolated mitochondria. Additionally, the ability of M-CoA to inhibit CPT-I appears to be dependent on P-CoA concentration, as the relative inhibitory capacity of M-CoA is decreased with increasing P-CoA concentrations. Altogether, the use of PMF appears to provide a M-CoA IC50 that better reflects the predicted in vivo rates of fatty acid oxidation. These findings also demonstrate the ratio of [P-CoA]/[M-CoA] is critical for regulating CPT-I activity and may partially rectify the in vivo disconnect between M-CoA content and CPT-I flux within the context of exercise and type II diabetes.
PMCID: PMC3863641  PMID: 22928974
skeletal muscle; carnitine palmitoyl transferase-I; malonyl-CoA; palmitoyl-CoA; isolated mitochondria; permeabilized fibres
4.  Correction: IL-6 Indirectly Modulates the Induction of Glyceroneogenic Enzymes in Adipose Tissue during Exercise 
PLoS ONE  2013;8(4):10.1371/annotation/3029d433-8e4e-41ca-a2da-6561aa0701bd.
PMCID: PMC3622696
5.  IL-6 Is Not Necessary for the Regulation of Adipose Tissue Mitochondrial Content 
PLoS ONE  2012;7(12):e51233.
Adipose tissue mitochondria have been implicated as key mediators of systemic metabolism. We have shown that IL-6 activates AMPK, a mediator of mitochondrial biogenesis, in adipose tissue; however, IL-6−/− mice fed a high fat diet have been reported to develop insulin resistance. These findings suggest that IL-6 may control adipose tissue mitochondrial content in vivo, and that reductions in adipose tissue mitochondria may be causally linked to the development of insulin resistance in IL-6−/− mice fed a high fat diet. On the other hand, IL-6 has been implicated as a negative regulator of insulin action. Given these discrepancies the purpose of the present investigation was to further evaluate the relationship between IL-6, adipose tissue mitochondrial content and whole body insulin action.
Methodology and Principal Findings
In cultured epididymal mouse adipose tissue IL-6 (75 ng/ml) induced the expression of the transcriptional co-activators PGC-1α and PRC, reputed mediators of mitochondrial biogenesis. Similarly, IL-6 increased the expression of COXIV and CPT-1. These effects were absent in cultured subcutaneous adipose tissue and were associated with lower levels of GP130 and IL-6 receptor alpha protein content. Markers of mitochondrial content were intact in adipose tissue from chow fed IL-6−/− mice. When fed a high fat diet IL-6−/− mice were more glucose and insulin intolerant than controls fed the same diet; however this was not explained by decreases in adipose tissue mitochondrial content or respiration.
Conclusions and Significance
Our findings demonstrate depot-specific differences in the ability of IL-6 to induce PGC-1α and mitochondrial enzymes and demonstrate that IL-6 is not necessary for the maintenance of adipose tissue mitochondrial content in vivo. Moreover, reductions in adipose tissue mitochondria do not explain the greater insulin resistance in IL-6−/− mice fed a high fat diet. These results question the role of adipose tissue mitochondrial dysfunction in the etiology of insulin resistance.
PMCID: PMC3519867  PMID: 23240005
6.  Increased hypolipidemic benefits of cis-9, trans-11 conjugated linoleic acid in combination with trans-11 vaccenic acid in a rodent model of the metabolic syndrome, the JCR:LA-cp rat 
Conjugated linoleic acid (cis-9, trans-11 CLA) and trans-11 vaccenic acid (VA) are found naturally in ruminant-derived foods. CLA has been shown to have numerous potential health related effects and has been extensively investigated. More recently, we have shown that VA has lipid-lowering properties associated with reduced hepatic lipidogenesis and chylomicron secretion in the JCR:LA-cp rat. The aim of this study was to evaluate potential additional hypolipidemic effects of purified forms of CLA and VA in an animal model of the metabolic syndrome (the JCR:LA-cp rat).
Twenty four obese JCR:LA-cp rats were randomized and assigned to one of three nutritionally adequate iso-caloric diets containing 1% w/w cholesterol and 15% w/w fat for 16 wk: 1) control diet (CD), 2) 1.0% w/w cis-9, trans-11 CLA (CLA), 3) 1.0% w/w VA and 1% w/w cis-9, trans-11 CLA (VA+CLA). Lean rats were fed the CD to represent normolipidemic conditions.
Fasting plasma triglyceride (TG), total cholesterol and LDL-cholesterol concentrations were reduced in obese rats fed either the CLA diet or the VA+CLA diet as compared to the obese control group (p < 0.05, p < 0.001; p < 0.001, p < 0.01; p < 0.01, p < 0.001, respectively). The VA+CLA diet reduced plasma TG and LDL-cholesterol to the level of the normolipidemic lean rats and further decreased nonesterified fatty acids compared to the CLA diet alone. Interestingly, rats fed the VA+CLA diet had a higher food intake but lower body weight than the CLA fed group (P < 0.05). Liver weight and TG content were lower in rats fed either CLA (p < 0.05) or VA+CLA diets (p < 0.001) compared to obese control, consistent with a decreased relative protein abundance of hepatic acetyl-CoA carboxylase in both treatment groups (P < 0.01). The activity of citrate synthase was increased in liver and adipose tissue of rats fed, CLA and VA+CLA diets (p < 0.001) compared to obese control, suggesting increased mitochondrial fatty acid oxidative capacity.
We demonstrate that the hypolipidemic effects of chronic cis-9, trans-11 CLA supplementation on circulating dyslipidemia and hepatic steatosis are enhanced by the addition of VA in the JCR:LA-cp rat.
PMCID: PMC3161353  PMID: 20633302

Results 1-7 (7)