Abstract | BACKGROUND AND PURPOSE: EXPERIMENTAL APPROACH: The anti-diabetic and anti- obesity effects of NaB treatment were measured by comparing phenotypes and physiologies of C57BL/6J mice fed a low-fat diet (LF), high-fat diet (HF) or high-fat diet plus NaB (HF + NaB) for 10 weeks. We determined a possible mechanism of NaB action through induction of beneficial skeletal muscle mitochondrial adaptations and applied microccocal nuclease digestion with sequencing (MNase-seq) to assess whole genome differences in nucleosome occupancy or positioning and to identify associated epigenetic targets of NaB. KEY RESULTS: NaB prevented HF diet-induced increases in body weight and adiposity without altering food intake or energy expenditure, improved insulin sensitivity as measured by glucose and insulin tolerance tests, and decreased respiratory exchange ratio. In skeletal muscle, NaB increased the percentage of type 1 fibres, improved acylcarnitine profiles as measured by metabolomics and produced a chromatin structure, determined by MNase-seq, similar to that seen in LF. Targeted analysis of representative nuclear-encoded mitochondrial genes showed specific repositioning of the -1 nucleosome in association with altered gene expression. CONCLUSIONS AND IMPLICATIONS: NaB treatment may be an effective pharmacological approach for type 2 diabetes and obesity by inducing -1 nucleosome repositioning within nuclear-encoded mitochondrial genes, causing skeletal muscle mitochondrial adaptations that result in more complete β-oxidation and a lean, insulin sensitive phenotype.
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Authors | Tara M Henagan, Barbara Stefanska, Zhide Fang, Alexandra M Navard, Jianping Ye, Natalie R Lenard, Prasad P Devarshi |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 172
Issue 11
Pg. 2782-98
(Jun 2015)
ISSN: 1476-5381 [Electronic] England |
PMID | 25559882
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | © 2015 The British Pharmacological Society. |
Chemical References |
- Blood Glucose
- Nucleosomes
- acylcarnitine
- Butyric Acid
- Carnitine
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Topics |
- Adaptation, Physiological
- Adiposity
(drug effects)
- Animals
- Blood Glucose
(drug effects, metabolism)
- Body Weight
(drug effects)
- Butyric Acid
(pharmacology)
- Carnitine
(analogs & derivatives, metabolism)
- Diet, High-Fat
- Eating
- Energy Metabolism
- Epigenesis, Genetic
(drug effects)
- Insulin Resistance
(genetics)
- Mice
- Mice, Inbred C57BL
- Mitochondria
(drug effects, metabolism)
- Mitochondria, Muscle
(drug effects, metabolism)
- Muscle Fibers, Slow-Twitch
(drug effects)
- Muscle, Skeletal
(drug effects, metabolism)
- Nucleosomes
(drug effects, metabolism)
- Obesity
(genetics)
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