Skeletal Muscle Lipogenic Protein Expression Is Not Different between Lean and Obese Individuals: A Potential Factor in Ceramide Accumulation

Context: Skeletal muscle lipid content is increased in obesity. Recent evidence suggests that fatty acid (FA) storage as triacylglycerol (TAG) represents a metabolically safe pool compared to the more bioactive diacylglycerol (DAG) and ceramide. Objective/Design: The purpose of this study was to compare the expression of lipogenic proteins and ceramide and DAG content in skeletal muscle of lean and obese humans. We hypothesized that lipogenic protein expression would be increased in obese to facilitate the storage of excess FA as TAG. Participants: Eighteen lean (BMI ≤26 kg/m2) and 15 obese (BMI >29 kg/m2) women participated in this study. Results: There was no difference in the expression of any lipogenic (stearoyl-CoA desaturase-1, stearoyl retinol binding protein-1c, mitochondrial glycerol-3-phosphate acyltransferase, diacylglycerol acyltransferase-1) or sphingolipid proteins measured between lean and obese humans. Total ceramide was increased in muscle from obese humans (lean vs. obese, 529.4 ± 54.8 vs. 672.4 ± 57.4 nmol/g; P < 0.05), but there was no difference in total DAG content (lean vs. obese, 2244.1 ± 278.2 vs. 1941.4 ± 165.0 nmol/g). Content of protein phosphatase 2A, a ceramide target, was increased in muscle of obese humans (P < 0.05). Conclusions: We propose that in muscle of obese humans there is an insufficient lipogenic response to the lipid oversupply, allowing more FA to be stored as reactive lipid species, particularly ceramide, potentially contributing to subsequent metabolic complications.

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Skeletal Muscle Lipogenic Protein Expression Is Not Different Between Lean And Obese Humans; A Potential Factor In Ceramide Accumulation.

Medicine & Science in Sports & Exercise ◽

10.1249/01.mss.0000353387.27428.9a ◽

2009 ◽

Vol 41 ◽

pp. 40

Author(s):

A. Brianne Thrush ◽

David N. Brindley ◽

Adrian Chabowski ◽

George J. Heigenhauser ◽

David J. Dyck

Keyword(s):

Skeletal Muscle ◽

Protein Expression ◽

Potential Factor ◽

Ceramide Accumulation

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SUN-582 Effect of the Combination of Conjugated Estrogens and Bazedoxifene on Muscle and Serum Lipidome in Obese Postmenopausal Women: A Placebo-Controlled Randomized Pilot Trial

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.443 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Dragana Lovre ◽

Kara Marlatt ◽

Robbie A Beyl ◽

Charles F Burant ◽

Eric Ravussin ◽

...

Keyword(s):

Skeletal Muscle ◽

Postmenopausal Women ◽

Lipid Accumulation ◽

Pilot Trial ◽

Density Lipoprotein ◽

Low Density ◽

Muscle Lipid ◽

Lipid Species ◽

Skeletal Muscle Lipid ◽

Long Chain

Abstract Background and Objectives: Menopause is characterized by estrogen deficiency and predisposes women to weight gain and metabolic disturbances including lipid abnormalities. Orally-administered estrogens increase high-density lipoprotein (HDL) and triglycerides (TG) cholesterol and decreases low-density lipoprotein (LDL) cholesterol levels. The increase in serum TGs is not well understood. The objective of this study was to assess the effect of CE/BZA on serum and skeletal muscle lipid species in obese postmenopausal women. Methods: Randomized double-blind crossover pilot trial in 8 obese postmenopausal women (53± 3 years, BMI 35.7±3.2 kg/m2) assigned to 8 weeks of CE/BZA or placebo with 8 weeks washout in between. At the end of each 8-week treatment period, intrahepatic and skeletal muscle lipids were measured by proton magnetic resonance spectroscopy (1H-MRS) while serum and skeletal muscle lipidomics were assayed by ultrahigh performance liquid chromatography/mass spectrometry (UHPLC/MS). Results: No treatment differences were observed in intrahepatic lipid, soleus intramyocellular lipid (IMCL) or extramyocellular lipid (EMCL) as well as tibialis anterior IMCL or EMCL. The serum metabolome and lipidome comprised a total of 2002 biochemicals. Treatment with CE/BZA was associated with higher levels of diacylglycerols (DAGs) and triacylglycerols (TAGs) composed of long-chain saturated fatty acids (SFA, palmitic C16:0 and arachidic C20:0), monounsaturated FAs (MUFA, palmitoleic C16:1, oleic C18:1 and ecosenoic C20:1), and polyunsaturated FAs (PUFA, linoleic C18:2, arachidonic C20:4, eicosapentaenoic C20:5, and docosahexaenoic C22:6) compared to placebo (all p<0.05). Treatment with CE/BZA was also associated with lower levels of several acylcarnitine species, which are markers of FA oxidation, including long-chain SFA (C14, C16 and C18), MUFA (C18:1 and C24:1) and PUFA (C18:2, C20:2 and C20:4). In addition, treatment with CE/BZA was associated with higher levels of phosphatidylcholines (PCs), phosphatidylinositols (PIs), phosphatidylethanolamines (PEs), sphingomyelins (SMs), and ceramides (CER), as well as lower levels of lysophophatidylcholines (LPCs). There were no treatment differences in carnitine or ketones levels. The skeletal muscle analysis comprised a total of 652 biochemicals, but unlike in serum, no significant treatment differences were observed in the skeletal muscle lipidome. Conclusions: Our lipidomic analysis supports a model in which CE/BZA (and likely all oral estrogens) increases hepatic de novo FA synthesis and esterification into TAGs for export into TAG-rich very low-density lipoproteins, as well as decreased FA oxidation, respectively. Although CE/BZA treatment inhibits FA oxidation, it is not associated with hepatic lipid accumulation as measured by MRS, or skeletal muscle lipid accumulation measured by MRS and lipidomics.

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Intramyocellular fat storage in metabolic diseases

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2015-0045 ◽

2016 ◽

Vol 26 (1) ◽

Cited By ~ 3

Author(s):

Claire Laurens ◽

Cedric Moro

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Metabolic Diseases ◽

Recent Literature ◽

Lipid Storage ◽

Muscle Lipid ◽

The Past ◽

Skeletal Muscle Lipid ◽

Ectopic Lipid Storage

AbstractOver the past decades, obesity and its metabolic co-morbidities such as type 2 diabetes (T2D) developed to reach an endemic scale. However, the mechanisms leading to the development of T2D are still poorly understood. One main predictor for T2D seems to be lipid accumulation in “non-adipose” tissues, best known as ectopic lipid storage. A growing body of data suggests that these lipids may play a role in impairing insulin action in metabolic tissues, such as liver and skeletal muscle. This review aims to discuss recent literature linking ectopic lipid storage and insulin resistance, with emphasis on lipid deposition in skeletal muscle. The link between skeletal muscle lipid content and insulin sensitivity, as well as the mechanisms of lipid-induced insulin resistance and potential therapeutic strategies to alleviate lipotoxic lipid pressure in skeletal muscle will be discussed.

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The effect of short-term fasting on liver and skeletal muscle lipid, glucose, and energy metabolism in healthy women and men

The Journal of Lipid Research ◽

10.1194/jlr.p020867 ◽

2011 ◽

Vol 53 (3) ◽

pp. 577-586 ◽

Cited By ~ 44

Author(s):

Jeffrey D. Browning ◽

Jeannie Baxter ◽

Santhosh Satapati ◽

Shawn C. Burgess

Keyword(s):

Skeletal Muscle ◽

Energy Metabolism ◽

Short Term ◽

Muscle Lipid ◽

Healthy Women ◽

Skeletal Muscle Lipid

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Responses of skeletal muscle lipid metabolism in rat gastrocnemius to hypothyroidism and iodothyronine administration: a putative role for FAT/CD36

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00037.2012 ◽

2012 ◽

Vol 303 (10) ◽

pp. E1222-E1233 ◽

Cited By ~ 21

Author(s):

Assunta Lombardi ◽

Rita De Matteis ◽

Maria Moreno ◽

Laura Napolitano ◽

Rosa Anna Busiello ◽

...

Keyword(s):

Skeletal Muscle ◽

Lipid Metabolism ◽

Protein Level ◽

Oxidation Rate ◽

Mitochondrial Protein ◽

Acid Oxidation ◽

Mrna Levels ◽

Muscle Lipid ◽

Mitochondrial Fatty Acid ◽

Skeletal Muscle Lipid

Iodothyronines such as triiodothyronine (T3) and 3,5-diiodothyronine (T2) influence energy expenditure and lipid metabolism. Skeletal muscle contributes significantly to energy homeostasis, and the above iodothyronines are known to act on this tissue. However, little is known about the cellular/molecular events underlying the effects of T3 and T2 on skeletal muscle lipid handling. Since FAT/CD36 is involved in the utilization of free fatty acids by skeletal muscle, specifically in their import into that tissue and presumably their oxidation at the mitochondrial level, we hypothesized that related changes in lipid handling and in FAT/CD36 expression and subcellular redistribution would occur due to hypothyroidism and to T3 or T2 administration to hypothyroid rats. In gastrocnemius muscles isolated from hypothyroid rats, FAT/CD36 was upregulated (mRNA levels and total tissue, sarcolemmal, and mitochondrial protein levels). Administration of either T3 or T2 to hypothyroid rats resulted in 1) little or no change in FAT/CD36 mRNA level, 2) a decreased total FAT/CD36 protein level, and 3) further increases in FAT/CD36 protein level in sarcolemma and mitochondria. Thus, the main effect of each iodothyronine seemed to be exerted at the level of FAT/CD36 cellular distribution. The effect of further increases in FAT/CD36 protein level in sarcolemma and mitochondria was already evident at 1 h after iodothyronine administration. Each iodothyronine increased the mitochondrial fatty acid oxidation rate. However, the mechanisms underlying their rapid effects seem to differ; T2 and T3 each induce FAT/CD36 translocation to mitochondria, but only T2 induces increases in carnitine palmitoyl transferase system activity and in the mitochondrial substrate oxidation rate.

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Effects of epinephrine on lipid metabolism in resting skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1998.275.2.e300 ◽

1998 ◽

Vol 275 (2) ◽

pp. E300-E309 ◽

Cited By ~ 27

Author(s):

Sandra J. Peters ◽

David J. Dyck ◽

Arend Bonen ◽

Lawrence L. Spriet

Keyword(s):

Skeletal Muscle ◽

Lipid Metabolism ◽

Lipid Synthesis ◽

Hormone Sensitive Lipase ◽

Simultaneous Estimation ◽

Lipid Hydrolysis ◽

Muscle Lipid ◽

Triacylglycerol Hydrolysis ◽

Skeletal Muscle Lipid ◽

Glycogen Breakdown

The effects of physiological (0, 0.1, 2.5, and 10 nM) and pharmacological (200 nM) epinephrine concentrations on resting skeletal muscle lipid metabolism were investigated with the use of incubated rat epitrochlearis (EPT), flexor digitorum brevis (FDB), and soleus (SOL) muscles. Muscles were chosen to reflect a range of oxidative capacities: SOL > EPT > FDB. The muscles were pulsed with [1-14C]palmitate and chased with [9,10-3H]palmitate. Incorporation and loss of the labeled palmitate from the triacylglycerol pool (as well as mono- and diacylglycerol, phospholipid, and fatty acid pools) permitted the simultaneous estimation of lipid hydrolysis and synthesis. Endogenous and exogenous fat oxidation was quantified by14CO2and3H2O production, respectively. Triacylglycerol breakdown was elevated above control at all epinephrine concentrations in the oxidative SOL muscle, at 2.5 and 200 nM (at 10 nM, P= 0.066) in the FDB, and only at 200 nM epinephrine in the EPT. Epinephrine stimulated glycogen breakdown in the EPT at all concentrations but only at 10 and 200 nM in the FDB and had no effect in the SOL. We further characterized muscle lipid hydrolysis potential and measured total hormone-sensitive lipase content by Western blotting (SOL > FDB > EPT). This study demonstrated that physiological levels of epinephrine cause measurable increases in triacylglycerol hydrolysis at rest in oxidative but not in glycolytic muscle, with no change in the rate of lipid synthesis or oxidation. Furthermore, epinephrine caused differential stimulation of carbohydrate and fat metabolism in glycolytic vs. oxidative muscle. Epinephrine preferentially stimulated glycogen breakdown over triacylglycerol hydrolysis in the glycolytic EPT muscle. Conversely, in the oxidative SOL muscle, epinephrine caused an increase in endogenous lipid hydrolysis over glycogen breakdown.

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