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

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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The RabGAPs TBC1D1 and TBC1D4 control uptake of long-chain fatty acids into skeletal muscle via fatty acid transporter SLC27A4/FATP4 Short title: RabGAPs in skeletal muscle lipid metabolism

10.2337/figshare.12857771 ◽

2020 ◽

Author(s):

Ada Admin ◽

Tim Benninghoff ◽

Lena Espelage ◽

Samaneh Eickelschulte ◽

Isabel Zeinert ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acids ◽

Fatty Acid ◽

Lipid Metabolism ◽

Long Chain Fatty Acids ◽

Muscle Lipid ◽

Skeletal Muscle Lipid ◽

Fatty Acid Transporter ◽

Acid Transporter ◽

Long Chain

The two closely related RabGTPase-activating proteins (RabGAPs) TBC1D1 and TBC1D4 play a crucial role in the regulation of GLUT4 translocation in response to insulin and contraction in skeletal muscle. In mice, deficiency in one or both RabGAPs leads to reduced insulin and contraction-stimulated glucose uptake, and to elevated fatty acid uptake and oxidation in both glycolytic and oxidative muscle fibers without altering mitochondrial copy number and the abundance of OXPHOS proteins. Here we present evidence for a novel mechanism of skeletal muscle lipid utilization involving the two RabGAPs and the fatty acid transporter SLC27A4/FATP4. Both RabGAPs control the uptake of saturated and unsaturated long-chain fatty acids (LCFAs) into skeletal muscle and knockdown of a subset of RabGAP substrates, Rab8, Rab10 or Rab14, decreased LCFA uptake into these cells. In skeletal muscle from Tbc1d1/Tbc1d4 knockout animals, SLC27A4/FATP4 abundance was increased and depletion of SLC27A4/FATP4 but not FAT/CD36 completely abrogated the enhanced fatty acid oxidation in RabGAP-deficient skeletal muscle and cultivated C2C12 myotubes. Collectively, our data demonstrate that RabGAP-mediated control of skeletal muscle lipid metabolism converges with glucose metabolism at the level of downstream RabGTPases and involves regulated transport of LCFAs via SLC27A4/FATP4.

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Dietary Sphingomyelin Attenuates Adipose Inflammation and Skeletal Muscle Lipid Accumulation in C57BL/6J Mice Fed an Obesogenic Diet

The FASEB Journal ◽

10.1096/fasebj.31.1_supplement.966.17 ◽

2017 ◽

Vol 31 ◽

pp. 966.17-966.17

Author(s):

Gregory H Norris ◽

Christina Jiang ◽

Caitlin M Porter ◽

Courtney L. Millar ◽

Christopher N Blesso

Keyword(s):

Skeletal Muscle ◽

Lipid Accumulation ◽

Muscle Lipid ◽

Skeletal Muscle Lipid ◽

Obesogenic Diet ◽

Adipose Inflammation

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Impaired Insulin Resistance in IF1-Deficient Mice Subjected to a High-Fat Diet with Reduced-Fat Mass and Skeletal Muscle Lipid Accumulation

Diabetes ◽

10.2337/db18-1748-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 1748-P ◽

Cited By ~ 1

Author(s):

FENGYUAN HUANG ◽

KEVIN YANG ◽

KAMALAMMA SAJA ◽

YICHENG HUANG ◽

QINGQIANG LONG ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Lipid Accumulation ◽

High Fat Diet ◽

High Fat ◽

Muscle Lipid ◽

Reduced Fat ◽

Impaired Insulin ◽

Skeletal Muscle Lipid ◽

Deficient Mice

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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2008-2565 ◽

2009 ◽

Vol 94 (12) ◽

pp. 5053-5061 ◽

Cited By ~ 31

Author(s):

A. Brianne Thrush ◽

David N. Brindley ◽

Adrian Chabowski ◽

George J. Heigenhauser ◽

David J. Dyck

Keyword(s):

Skeletal Muscle ◽

Protein Expression ◽

Retinol Binding Protein ◽

Metabolic Complications ◽

Muscle Lipid ◽

Lipid Species ◽

Skeletal Muscle Lipid ◽

Phosphatase 2A ◽

Potential Factor ◽

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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The RabGAPs TBC1D1 and TBC1D4 control uptake of long-chain fatty acids into skeletal muscle via fatty acid transporter SLC27A4/FATP4 Short title: RabGAPs in skeletal muscle lipid metabolism

10.2337/figshare.12857771.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Tim Benninghoff ◽

Lena Espelage ◽

Samaneh Eickelschulte ◽

Isabel Zeinert ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acids ◽

Fatty Acid ◽

Lipid Metabolism ◽

Long Chain Fatty Acids ◽

Muscle Lipid ◽

Skeletal Muscle Lipid ◽

Fatty Acid Transporter ◽

Acid Transporter ◽

Long Chain

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Dyslipidemia is the hallmark of the metabolic syndrome in postmenopausal women

Annals of Medical Physiology ◽

10.23921/amp.2020v4i2.115684 ◽

2020 ◽

Vol 4 (2) ◽

pp. 18-21

Author(s):

Asim Alaaeldin Osman ◽

Ahmed Mohamed Fadlalla

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Total Cholesterol ◽

Postmenopausal Women ◽

Lipid Accumulation ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Significant Negative Correlation ◽

Very Low Density Lipoprotein ◽

Low Density

The incidence of cardiovascular diseases (CVD) increases after menopause and may be due to changes in the plasma lipid-lipoprotein levels that occur following menopausal transition. Physiological estrogen withdrawal during menopause plays a major role in abnormal lipid metabolism such as elevated low-density lipoprotein concentration. The aim of this study was to determine the relationship between dyslipidemia and the causative factors of metabolic syndrome in postmenopausal women. In this cross-sectional study, 290 postmenopausal Sudanese women were included. Lipid profiles were measured by spectrophotometer, estrogen hormone determined by ELISA, insulin resistance determined by HOMA-2 calculator and lipid accumulation product was calculated by the following equation (waist circumference in cm X triglyceride concentration in mM). The results revealed that total cholesterol, triglycerides, low-density lipoprotein levels and very low-density lipoprotein levels were significantly higher in the postmenopausal women with metabolic syndrome (MS) in comparison to those without the MS. Elevated total cholesterol levels were seen in 51.7 %, elevated triglycerides were seen in 49.7% and elevated low-density lipoprotein levels were seen in 29.3% whereas reduced high density lipoprotein levels were seen in 16.89% of the postmenopausal women. Total cholesterol, triglycerides and very low-density lipoprotein values showed a significant positive correlation with insulin resistance and lipid accumulation and a significant negative correlation with the estrogen hormone level. In addition, high density lipoproteins showed a significant negative correlation with lipid accumulation levels.

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