Wheel running prevents the accumulation of monounsaturated fatty acids in the liver of ovariectomized mice by attenuating changes in SCD-1 content

Jackson, Kathryn C.; Wohlers, Lindsay M.; Valencia, Ana P.; Cilenti, Michelle; Borengasser, Sarah J.; Thyfault, John P.; Spangenburg, Espen E.

doi:10.1139/h11-099

Cited by 18 publications

(43 citation statements)

References 73 publications

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“…Isolation of RNA and subsequent cDNA synthesis from the gastrocnemius or plantaris muscles and mouse testes (positive control) was performed according to the previously described techniques ( 15,16 ). Specifi c primers for mouse Brca1 were as follows: forward 5 ′ -CAC AGC GTA TGC CAG AGA AA-3 ′ and reverse 5 ′ -ATC CTG GGA GTT TGC ATT TG-3 ′ .…”

Section: Mouse Mrna Analysismentioning

confidence: 99%

“…Mouse skeletal muscle was mechanically homogenized according to previously described techniques ( 15,19 ). Human skeletal muscle biopsies were homogenized on ice using glass-on-glass homogenizers in RIPA buffer [150 mM NaCl, 10 mM Tris-HCl, 5 mM EDTA, 0.5% Na deoxycholate, 0.1% SDS, 1% Triton X-100, and protein inhibitor cocktail complete mini (Roche Diagnostics)].…”

Section: Homogenizationmentioning

confidence: 99%

“…Immunoblotting for either BRCA1 immunoprecipitation solution or whole muscle homogenate protein was performed as previously described ( 15,20,22 ). Membranes were probed with an antibody specifi c for BRCA1 (I-20 or D-20, 1:200; Santa Cruz Biotechnology), ACC-p or ACC total (1:1,000; Cell Signal, Boston, MA), Akt-p or Akt total (1:1,000; Cell Signal), ␣ -actinin (1:5,000; Sigma-Aldrich, Saint Louis, MO), red fl uorescent protein (RFP) (1:2,000; Thermo Scientifi c, Waltham, MA).…”

Section: Immunoblotting Analysismentioning

confidence: 99%

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BRCA1 is a novel regulator of metabolic function in skeletal muscle

Jackson

Gidlund

Norrbom

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org breast cancer and/or tumorigenesis in reproductive tissues ( 3 ). The BRCA1 gene produces either a full-length breast cancer type 1 susceptibility protein (BRCA1) or through alternatively splicing two documented variants, BRCA1 ⌬ 11 or BRCA1 ⌬ 11b, both of which lack a nuclear localization signal ( 4 ). Recently, BRCA1 was identifi ed as a regulator of lipid metabolism in human breast cancer cells (MCF7) as a result of direct interaction with the phosphorylated form of acetylCoA carboxylase (ACC-p) at the BRCA1 C-terminal (BRCT) domains ( 5, 6 ). The interaction encourages the maintenance of the phosphorylated state of ACC thereby altering lipid metabolism in the cancer cell line ( 5, 6 ).ACC has two isoforms, ACC1 or ACC2, with ACC2 containing an extra 146 amino acids in the NH 2 -terminal region. ACC activity is negatively regulated by phosphorylation of residue Ser 79 on ACC1 and Ser 221 on ACC2 ( 7,8 ). In the active form (i.e., dephosphorylated), ACC catalyzes the carboxylation of acetyl-CoA into malonyl-CoA (MaCoA). Changes in cellular MaCoA content alter intracellular lipid dynamics in two specifi c manners ( 9, 10 ). MaCoA directly contributes to de novo synthesis of palmitate via FAS and MaCoA also allosterically inhibits carnitine palmitoyltransferase-1 (CPT-1), a mitochondrial long chain fatty acid transporter ( 11 ). Thus, in mammary tissue the ability of BRCA1 to affect ACC activity alters cellular lipid concentrations by indirectly regulating rates of fatty acid synthesis and/or the fl ux of fatty acids into the mitochondria.Abstract Breast cancer type 1 (BRCA1) susceptibility protein is expressed across multiple tissues including skeletal muscle. The overall objective of this investigation was to defi ne a functional role for BRCA1 in skeletal muscle using a translational approach. For the fi rst time in both mice and humans, we identifi ed the presence of multiple isoforms of BRCA1 in skeletal muscle. In response to an acute bout of exercise, we found increases in the interaction between the native forms of BRCA1 and the phosphorylated form of acetyl-CoA carboxylase. Decreasing BRCA1 content using a shRNA approach in cultured primary human myotubes resulted in decreased oxygen consumption by the mitochondria and increased reactive oxygen species production. The decreased BRCA1 content also resulted in increased storage of intracellular lipid and reduced insulin signaling. These results indicate that BRCA1 plays a critical role in the regulation of metabolic function in skeletal muscle. Collectively, these data reveal BRCA1 as a novel target to consider in our understanding of metabolic function and risk for development of metabolic-based diseases. -Jackson, K. C., E-K. Gidlund, J. Abbreviations: ACC, acetyl-CoA carboxylase; ACC-p, phosphorylated form of acetyl-CoA carboxylase; AICAR, 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide; AMPK, AMP-activated protein kinase; BRCA1, Breast Cancer 1, early onset; BRCA1 MG KO, mammary gland tissue fr...

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Section: Mouse Mrna Analysismentioning

confidence: 99%

Section: Homogenizationmentioning

confidence: 99%

Section: Immunoblotting Analysismentioning

confidence: 99%

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BRCA1 is a novel regulator of metabolic function in skeletal muscle

Jackson

Gidlund

Norrbom

et al. 2014

Journal of Lipid Research

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“…Exercise stimulates glucose uptake by skeletal muscle from the blood (Goldstein et al 1953), decreases fat content from the adipose tissue (Gollisch et al 2009), and prevents fat accumulation in the liver (Jackson et al 2011). Besides the effects of exercise on peripheral tissues, voluntary exercise also improves brain function.…”

Section: Introductionmentioning

confidence: 99%

Voluntary exercise improves hypothalamic and metabolic function in obese mice

Laing¹,

Do²,

Matsubara³

et al. 2016

Journal of Endocrinology

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Exercise plays a critical role in regulating glucose homeostasis and body weight. However, the mechanism of exercise on metabolic functions associated with the CNS has not been fully understood. C57BL6 male mice (n = 45) were divided into three groups: normal chow diet, high-fat diet (HFD) treatment, and HFD along with voluntary running wheel exercise training for 12 weeks. Metabolic function was examined by the Comprehensive Lab Animal Monitoring System and magnetic resonance imaging; phenotypic analysis included measurements of body weight, food intake, glucose and insulin tolerance tests, as well as insulin and leptin sensitivity studies. By immunohistochemistry, the amount changes in the phosphorylation of signal transducer and activator of transcription 3, neuronal proliferative maker Ki67, apoptosis positive cells as well as pro-opiomelanocortin (POMC)-expressing neurons in the arcuate area of the hypothalamus was identified. We found that 12 weeks of voluntary exercise training partially reduced body weight gain and adiposity induced by an HFD. Insulin and leptin sensitivity were enhanced in the exercise training group verses the HFD group. Furthermore, the HFD-impaired POMC-expressing neuron is remarkably restored in the exercise training group. The restoration of POMC neuron number may be due to neuroprotective effects of exercise on POMC neurons, as evidenced by altered proliferation and apoptosis. In conclusion, our data suggest that voluntary exercise training improves metabolic symptoms induced by HFD, in part through protected POMC-expressing neuron from HFD and enhanced leptin signaling in the hypothalamus that regulates whole-body energy homeostasis. Exercise restores HFD-impaired POMC-expression neuronb t laing, k do and others

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“…While low aerobic fitness is a powerful independent risk factor for all-cause mortality and metabolic disease risk (24), the impact of aerobic fitness on postmenopausal metabolic function per se is largely unknown. Animal studies have demonstrated that loss of ovarian hormones causes a reduction in physical activity and that exercise can offset these effects (18), but no studies have investigated the unique role played by intrinsic aerobic fitness, independent of exercise, on the changes in energy balance, body composition, and insulin resistance following ovariectomy (OVX). Accordingly, the purpose of the present study was to test the hypothesis that high intrinsic aerobic fitness protects against the metabolic dysfunction associated with OVX in rats.…”

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confidence: 99%

Female rats selectively bred for high intrinsic aerobic fitness are protected from ovariectomy-associated metabolic dysfunction

Vieira‐Potter

Padilla

Park

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Ovariectomized rodents model human menopause in that they rapidly gain weight, reduce spontaneous physical activity (SPA), and develop metabolic dysfunction, including insulin resistance. How contrasting aerobic fitness levels impacts ovariectomy (OVX)-associated metabolic dysfunction is not known. Female rats selectively bred for high and low intrinsic aerobic fitness [high-capacity runners (HCR) and low-capacity runners (LCR), respectively] were maintained under sedentary conditions for 39 wk. Midway through the observation period, OVX or sham (SHM) operations were performed providing HCR-SHM, HCR-OVX, LCR-SHM, and LCR-OVX groups. Glucose tolerance, energy expenditure, and SPA were measured before and 4 wk after surgery, while body composition via dual-energy X-ray absorptiometry and adipose tissue distribution, brown adipose tissue (BAT), and skeletal muscle phenotype, hepatic lipid content, insulin resistance via homeostatic assessment model of insulin resistance and AdipoIR, and blood lipids were assessed at death. Remarkably, HCR were protected from OVX-associated increases in adiposity and insulin resistance, observed only in LCR. HCR rats were ∼30% smaller, had ∼70% greater spontaneous physical activity (SPA), consumed ∼10% more relative energy, had greater skeletal muscle proliferator-activated receptor coactivator 1-alpha, and ∼40% more BAT. OVX did not increase energy intake and reduced SPA to the same extent in both HCR and LCR. LCR were particularly affected by an OVX-associated reduction in resting energy expenditure and experienced a reduction in relative BAT; resting energy expenditure correlated positively with BAT across all animals (r = 0.6; P < 0.001). In conclusion, despite reduced SPA following OVX, high intrinsic aerobic fitness protects against OVX-associated increases in adiposity and insulin resistance. The mechanism may involve preservation of resting energy expenditure.

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Wheel running prevents the accumulation of monounsaturated fatty acids in the liver of ovariectomized mice by attenuating changes in SCD-1 content

Cited by 18 publications

References 73 publications

BRCA1 is a novel regulator of metabolic function in skeletal muscle

BRCA1 is a novel regulator of metabolic function in skeletal muscle

Voluntary exercise improves hypothalamic and metabolic function in obese mice

Female rats selectively bred for high intrinsic aerobic fitness are protected from ovariectomy-associated metabolic dysfunction

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