The Role of Atypical Cannabinoid Ligands O-1602 and O-1918 on Skeletal Muscle Homeostasis with a Focus on Obesity

O-1602 and O-1918 are atypical cannabinoid ligands for GPR55 and GPR18, which may be novel pharmaceuticals for the treatment of obesity by targeting energy homeostasis regulation in skeletal muscle. This study aimed to determine the effect of O-1602 or O-1918 on markers of oxidative capacity and fatty acid metabolism in the skeletal muscle. Diet-induced obese (DIO) male Sprague Dawley rats were administered a daily intraperitoneal injection of O-1602, O-1918 or vehicle for 6 weeks. C2C12 myotubes were treated with O-1602 or O-1918 and human primary myotubes were treated with O-1918. GPR18 mRNA was expressed in the skeletal muscle of DIO rats and was up-regulated in red gastrocnemius when compared with white gastrocnemius. O-1602 had no effect on mRNA expression on selected markers for oxidative capacity, fatty acid metabolism or adiponectin signalling in gastrocnemius from DIO rats or in C2C12 myotubes, while APPL2 mRNA was up-regulated in white gastrocnemius in DIO rats treated with O-1918. In C2C12 myotubes treated with O-1918, PGC1α, NFATc1 and PDK4 mRNA were up-regulated. There were no effects of O-1918 on mRNA expression in human primary myotubes derived from obese and obese T2DM individuals. In conclusion, O-1602 does not alter mRNA expression of key pathways important for skeletal muscle energy homeostasis in obesity. In contrast, O-1918 appears to alter markers of oxidative capacity and fatty acid metabolism in C2C12 myotubes only. GPR18 is expressed in DIO rat skeletal muscle and future work could focus on selectively modulating GPR18 in a tissue-specific manner, which may be beneficial for obesity-targeted therapies.

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IDH2 Deficiency Is Critical in Myogenesis and Fatty Acid Metabolism in Mice Skeletal Muscle

International Journal of Molecular Sciences ◽

10.3390/ijms21165596 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5596

Author(s):

Jeong Hoon Pan ◽

Jingsi Tang ◽

Young Jun Kim ◽

Jin Hyup Lee ◽

Eui-Cheol Shin ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Energy Homeostasis ◽

Muscle Development ◽

Acid Metabolism ◽

Uncoupling Protein ◽

Acid Oxidation ◽

Oxidative Decarboxylation ◽

Muscle Weight

Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) catalyzes the oxidative decarboxylation of isocitrate into α-ketoglutarate with concurrent reduction of NADP+ to NADPH. However, it is not fully understood how IDH2 is intertwined with muscle development and fatty acid metabolism. Here, we examined the effects of IDH2 knockout (KO) on skeletal muscle energy homeostasis. Calf skeletal muscle samples from 10-week-old male IDH2 KO and wild-type (WT; C57BL/6N) mice were harvested, and the ratio of skeletal muscle weight to body and the ratio of mitochondrial to nucleic DNA were measured. In addition, genes involved in myogenesis, mitochondria biogenesis, adipogenesis, and thermogenesis were compared. Results showed that the ratio of skeletal muscle weight to body weight was lower in IDH2 KO mice than those in WT mice. Of note, a noticeable shift in fiber size distribution was found in IDH2 KO mice. Additionally, there was a trend of a decrease in mitochondrial content in IDH2 KO mice than in WT mice (p = 0.09). Further, mRNA expressions for myogenesis and mitochondrial biogenesis were either decreased or showed a trend of decrease in IDH2 KO mice. Moreover, genes for adipogenesis pathway (Pparg, Znf423, and Fat1) were downregulated in IDH2 KO mice. Interestingly, mRNA and protein expression of uncoupling protein 1 (UCP1), a hallmark of thermogenesis, were remarkably increased in IDH2 KO mice. In line with the UCP1 expression, IDH2 KO mice showed higher rectal temperature than WT mice under cold stress. Taken together, IDH2 deficiency may affect myogenesis, possibly due to impairments of muscle generation and abnormal fatty acid oxidation as well as thermogenesis in muscle via upregulation of UCP1.

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17β-estradiol upregulates oxytocin and the oxytocin receptor in C2C12 myotubes

PeerJ ◽

10.7717/peerj.3124 ◽

2017 ◽

Vol 5 ◽

pp. e3124 ◽

Cited By ~ 6

Author(s):

Enrica Berio ◽

Sara Divari ◽

Laura Starvaggi Cucuzza ◽

Bartolomeo Biolatti ◽

Francesca Tiziana Cannizzo

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Fatty Acid Binding Protein ◽

Acid Metabolism ◽

Muscle Cells ◽

Oxytocin Receptor ◽

C2c12 Myotubes ◽

Fatty Acid Binding ◽

Acid Binding Protein

BackgroundThe endocrinology of skeletal muscle is highly complex and many issues about hormone action in skeletal muscle are still unresolved. Aim of the work is to improve our knowledge on the relationship between skeletal muscle and 17β-estradiol.MethodsThe skeletal muscle cell line C2C12 was treated with 17β-estradiol, the oxytocin peptide and a combination of the two hormones. The mRNA levels of myogenic regulatory factors, myosin heavy chain, oxytocin, oxytocin receptor and adipogenic factors were analysed in C2C12 myotubes.ResultsIt was demonstrated that C2C12 myoblasts and myotubes express oxytocin and its receptor, in particular the receptor levels physiologically increase in differentiated myotubes. Myotubes treated with 17β-estradiol overexpressed oxytocin and oxytocin receptor genes by approximately 3- and 29-fold, respectively. A decrease in the expression of fatty acid binding protein 4 (0.62-fold), a fat metabolism-associated gene, was observed in oxytocin-treated myotubes. On the contrary, fatty acid binding protein 4 was upregulated (2.66-fold) after the administration of the combination of 17β-estradiol and oxytocin. 17β-estradiol regulates oxytocin and its receptor in skeletal muscle cells and they act in a synergic way on fatty acid metabolism.DiscussionOxytocin and its receptor are physiologically regulated along differentiation. 17β-estradiol regulates oxytocin and its receptor in skeletal muscle cells. 17β-estradiol and oxytocin act in a synergic way on fatty acid metabolism. A better understanding of the regulation of skeletal muscle homeostasis by estrogens and oxytocin peptide could contribute to increase our knowledge of muscle and its metabolism.

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Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1207605109 ◽

2012 ◽

Vol 109 (38) ◽

pp. 15330-15335 ◽

Cited By ~ 178

Author(s):

Michele Carrer ◽

Ning Liu ◽

Chad E. Grueter ◽

Andrew H. Williams ◽

Madlyn I. Frisard ◽

...

Keyword(s):

Metabolic Syndrome ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Energy Homeostasis ◽

Hormone Receptors ◽

Acid Metabolism ◽

Oxidative Capacity ◽

Nuclear Hormone Receptor ◽

Peroxisome Proliferator ◽

Mitochondrial Fatty Acid

Obesity and metabolic syndrome are associated with mitochondrial dysfunction and deranged regulation of metabolic genes. Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) is a transcriptional coactivator that regulates metabolism and mitochondrial biogenesis through stimulation of nuclear hormone receptors and other transcription factors. We report that the PGC-1β gene encodes two microRNAs (miRNAs), miR-378 and miR-378*, which counterbalance the metabolic actions of PGC-1β. Mice genetically lacking miR-378 and miR-378* are resistant to high-fat diet-induced obesity and exhibit enhanced mitochondrial fatty acid metabolism and elevated oxidative capacity of insulin-target tissues. Among the many targets of these miRNAs, carnitine O-acetyltransferase, a mitochondrial enzyme involved in fatty acid metabolism, and MED13, a component of the Mediator complex that controls nuclear hormone receptor activity, are repressed by miR-378 and miR-378*, respectively, and are elevated in the livers of miR-378/378* KO mice. Consistent with these targets as contributors to the metabolic actions of miR-378 and miR-378*, previous studies have implicated carnitine O-acetyltransferase and MED13 in metabolic syndrome and obesity. Our findings identify miR-378 and miR-378* as integral components of a regulatory circuit that functions under conditions of metabolic stress to control systemic energy homeostasis and the overall oxidative capacity of insulin target tissues. Thus, these miRNAs provide potential targets for pharmacologic intervention in obesity and metabolic syndrome.

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Evidence against a sexual dimorphism in glucose and fatty acid metabolism in skeletal muscle cultures from age-matched men and post-menopausal women

Acta Physiologica ◽

10.1111/j.1748-1716.2009.02010.x ◽

2009 ◽

Vol 197 (3) ◽

pp. 207-215 ◽

Cited By ~ 20

Author(s):

A. Rune ◽

F. Salehzadeh ◽

F. Szekeres ◽

I. Kühn ◽

M. E. Osler ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Sexual Dimorphism ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Menopausal Women ◽

Muscle Cultures ◽

Post Menopausal

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Role of the AMP-activated protein kinase in regulating fatty acid metabolism during exerciseThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

Applied Physiology Nutrition and Metabolism ◽

10.1139/h09-009 ◽

2009 ◽

Vol 34 (3) ◽

pp. 315-322 ◽

Cited By ~ 26

Author(s):

Gregory R. Steinberg

Keyword(s):

Skeletal Muscle ◽

Fatty Acids ◽

Adipose Tissue ◽

Fatty Acid ◽

Protein Kinase ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Moderate Intensity ◽

Amp Activated Protein Kinase

During moderate-intensity exercise, fatty acids are the predominant substrate for working skeletal muscle. The release of fatty acids from adipose tissue stores, combined with the ability of skeletal muscle to actively fine tune the gradient between fatty acid and carbohydrate metabolism, depending on substrate availability and energetic demands, requires a coordinated system of metabolic control. Over the past decade, since the discovery that AMP-activated protein kinase (AMPK) was increased in accordance with exercise intensity, there has been significant interest in the proposed role of this ancient stress-sensing kinase as a critical integrative switch controlling metabolic responses during exercise. In this review, studies examining the role of AMPK as a regulator of fatty acid metabolism in both adipose tissue and skeletal muscle during exercise will be discussed. Exercise induces activation of AMPK in adipocytes and regulates triglyceride hydrolysis and esterfication through phosphorylation of hormone sensitive lipase (HSL) and glycerol-3-phosphate acyl-transferase, respectively. In skeletal muscle, exercise-induced activation of AMPK is associated with increases in fatty acid uptake, phosphorylation of HSL, and increased fatty acid oxidation, which is thought to occur via the acetyl-CoA carboxylase-malony-CoA-CPT-1 signalling axis. Despite the importance of AMPK in regulating fatty acid metabolism under resting conditions, recent evidence from transgenic models of AMPK deficiency suggest that alternative signalling pathways may also be important for the control of fatty acid metabolism during exercise.

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