CrossTalk opposing view: Intramuscular lipid accumulation does not cause insulin resistance

Abstract Background The skeletal muscle plays a central role in glucose homeostasis through the uptake of glucose from the extracellular medium in response to insulin. A number of factors are known to disrupt the normal response to insulin leading to the emergence of insulin resistance (IR). Advanced age and a high-fat diet are factors that increase the susceptibility to IR, with lipid accumulation in the skeletal muscle being a key driver of this phenomenon. It is debated, however, whether lipid accumulation arises due to dietary lipid overload or from a decline of mitochondrial function. To gain insights into the interplay of diet and age in the flexibility of muscle lipid and glucose handling, we combined lipidomics, proteomics, mitochondrial function analysis and computational modelling to investigate young and aged mice on a low- or high-fat diet (HFD). Results As expected, aged mice were more susceptible to IR when given a HFD than young mice. The HFD induced intramuscular lipid accumulation specifically in aged mice, including C18:0-containing ceramides and diacylglycerols. This was reflected by the mitochondrial β-oxidation capacity, which was upregulated by the HFD in young, but not in old mice. Conspicuously, most β-oxidation proteins were upregulated by the HFD in both groups, but carnitine palmitoyltransferase 1B (CPT1B) declined in aged animals. Computational modelling traced the flux control mostly to CPT1B, suggesting a CPT1B-driven loss of flexibility to the HFD with age. Finally, in old animals, glycolytic protein levels were reduced and less flexible to the diet. Conclusion We conclude that intramuscular lipid accumulation and decreased insulin sensitivity are not due to age-related mitochondrial dysfunction or nutritional overload alone, but rather to their combined effects. Moreover, we identify CPT1B as a potential target to counteract age-dependent intramuscular lipid accumulation and thereby IR.

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Age-related susceptibility to insulin resistance is due to a combination of CPT1B decline and lipid overload

10.1101/2021.02.04.429529 ◽

2021 ◽

Author(s):

Marcel A. Vieira-Lara ◽

Marleen B. Dommerholt ◽

Wenxuan Zhang ◽

Maaike Blankestijn ◽

Justina C. Wolters ◽

...

Keyword(s):

Insulin Resistance ◽

Lipid Accumulation ◽

Computational Modelling ◽

Dietary Lipid ◽

Aged Mice ◽

Protein Levels ◽

Age Related ◽

Intramuscular Lipid ◽

Key Driver ◽

Old Mice

AbstractBACKGROUNDAdvanced age increases the susceptibility to diet-induced insulin resistance (IR). A key driver of this phenomenon is lipid accumulation in the skeletal muscle. It is debated, however, whether this is due to dietary lipid overload or decline of mitochondrial function. To address the interplay of diet and age in the flexibility of muscle lipid and glucose handling, we put young and aged mice on a low- or high-fat diet (HFD).RESULTSAs expected, aged mice were more susceptible to IR when given a HFD than young mice. The HFD induced intramuscular lipid accumulation specifically in aged mice, including C18:0-containing ceramides and diacylglycerols. This was reflected by the mitochondrial β-oxidation capacity, which was upregulated by the HFD in young, but not in old mice. Conspicuously, most β-oxidation proteins were upregulated by the HFD in both groups, but carnitine palmitoyltransferase 1B (CPT1B) declined in aged animals. Computational modelling traced the flux control mostly to CPT1B, suggesting a CPT1B-driven loss of flexibility to the HFD with age. Finally, in old animals glycolytic protein levels were reduced and less flexible to the diet.CONCLUSIONWe conclude that intramuscular lipid accumulation and decreased insulin sensitivity are not due to age-related mitochondrial dysfunction or nutritional overload alone, but rather to their interaction. Moreover, we identify CPT1B as a potential target to counteract age-dependent intramuscular lipid accumulation and thereby IR.

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Two phases of palmitate-induced insulin resistance in skeletal muscle: impaired GLUT4 translocation is followed by a reduced GLUT4 intrinsic activity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00685.2006 ◽

2007 ◽

Vol 293 (3) ◽

pp. E783-E793 ◽

Cited By ~ 62

Author(s):

Hakam Alkhateeb ◽

Adrian Chabowski ◽

Jan F. C. Glatz ◽

Joost F. P. Luiken ◽

Arend Bonen

Keyword(s):

Insulin Resistance ◽

Glucose Transport ◽

Insulin Signaling ◽

Lipid Accumulation ◽

Early Phase ◽

Intrinsic Activity ◽

Signaling Proteins ◽

Glut4 Translocation ◽

Intramuscular Lipid ◽

Two Phases

We examined, in soleus muscle, the effects of prolonged palmitate exposure (0, 6, 12, 18 h) on insulin-stimulated glucose transport, intramuscular lipid accumulation and oxidation, activation of selected insulin-signaling proteins, and the insulin-stimulated translocation of GLUT4. Insulin-stimulated glucose transport was progressively reduced after 6 h (−33%), 12 h (−66%), and 18 h (−89%) of palmitate exposure. These decrements were closely associated with concurrent reductions in palmitate oxidation at 6 h (−40%), 12 h (−60%), and 18 h (−67%). In contrast, intramuscular ceramide (+24%) and diacylglycerol (+32%) concentrations, insulin-stimulated AS160 (−36%) and PRAS40 (−33%) phosphorylations, and Akt (−40%), PKCθ (−50%), and GLUT4 translocation (−40%) to the plasma membrane were all maximally altered within the first 6 h of palmitate treatment. No further changes were observed in any of these parameters after 12 and 18 h of palmitate exposure. Thus, the intrinsic activity of GLUT4 was markedly reduced after 12 and 18 h of palmitate treatment. During this reduced GLUT4 intrinsic activity phase at 12 and 18 h, the reduction in glucose transport was twofold greater compared with the early phase (≤6 h), when only GLUT4 translocation was impaired. Our study indicates that palmitate-induced insulin resistance is provoked by two distinct mechanisms: 1) an early phase (≤6 h), during which lipid-mediated impairments in insulin signaling and GLUT4 translocation reduce insulin-stimulated glucose transport, followed by 2) a later phase (12 and 18 h), during which the intrinsic activity of GLUT4 is markedly reduced independently of any further alterations in intramuscular lipid accumulation, insulin signaling and GLUT4 translocation.

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Publisher Correction: Deletion of the diabetes candidate gene Slc16a13 in mice attenuates diet-induced ectopic lipid accumulation and insulin resistance

Communications Biology ◽

10.1038/s42003-021-02425-2 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Tina Schumann ◽

Jörg König ◽

Christian von Loeffelholz ◽

Daniel F. Vatner ◽

Dongyan Zhang ◽

...

Keyword(s):

Insulin Resistance ◽

Candidate Gene ◽

Lipid Accumulation ◽

Diabetes Candidate Gene

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Intramuscular Lipid Metabolism in the Insulin Resistance of Smoking

Diabetes ◽

10.2337/db09-0481 ◽

2009 ◽

Vol 58 (10) ◽

pp. 2220-2227 ◽

Cited By ~ 39

Author(s):

B. C. Bergman ◽

L. Perreault ◽

D. M. Hunerdosse ◽

M. C. Koehler ◽

A. M. Samek ◽

...

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Intramuscular Lipid

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Lipid accumulation product and insulin resistance in Iranian PCOS prevalence study

Clinical Endocrinology ◽

10.1111/cen.12287 ◽

2013 ◽

Vol 81 (1) ◽

pp. 52-57 ◽

Cited By ~ 15

Author(s):

Farhad Hosseinpanah ◽

Maryam Barzin ◽

Hadi Erfani ◽

Sara Serahati ◽

Fahimeh Ramezani Tehrani ◽

...

Keyword(s):

Insulin Resistance ◽

Lipid Accumulation ◽

Prevalence Study ◽

Lipid Accumulation Product

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Black Sesame Seeds Ethanol Extract Ameliorates Hepatic Lipid Accumulation, Oxidative Stress, and Insulin Resistance in Fructose-Induced Nonalcoholic Fatty Liver Disease

Journal of Agricultural and Food Chemistry ◽

10.1021/acs.jafc.8b04210 ◽

2018 ◽

Vol 66 (40) ◽

pp. 10458-10469 ◽

Cited By ~ 9

Author(s):

Yang Yang ◽

Jingjing Wang ◽

Yongmin Zhang ◽

Jing Li ◽

Wenji Sun

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Liver Disease ◽

Fatty Liver ◽

Lipid Accumulation ◽

Fatty Liver Disease ◽

Ethanol Extract ◽

Nonalcoholic Fatty Liver ◽

Sesame Seeds ◽

Hepatic Lipid Accumulation

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Alleviative Effect of Ruellia tuberosa L. on Insulin Resistance and Abnormal Lipid Accumulation in TNF-α-Treated FL83B Mouse Hepatocytes

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/9967910 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Hong-Jie Chen ◽

Chih-Yuan Ko ◽

Jian-Hua Xu ◽

Yu-Chu Huang ◽

James Swi-Bea Wu ◽

...

Keyword(s):

Insulin Resistance ◽

Ethyl Acetate ◽

Glucose Uptake ◽

Insulin Signaling ◽

Lipid Accumulation ◽

Glucose Transporter ◽

Peroxisome Proliferator ◽

Glucose Transporter 2 ◽

Tnf Α ◽

Mouse Hepatocytes

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, and most patients with T2DM develop nonalcoholic fatty liver disease (NAFLD). Both diseases are closely linked to insulin resistance (IR). Our previous studies demonstrated that Ruellia tuberosa L. (RTL) extract significantly enhanced glucose uptake in the skeletal muscles and ameliorated hyperglycemia and IR in T2DM rats. We proposed that RTL might be via enhancing hepatic antioxidant capacity. However, the potent RTL bioactivity remains unidentified. In this study, we investigated the effects of RTL on glucose uptake, IR, and lipid accumulation in vitro to mimic the T2DM accompanied by the NAFLD paradigm. FL83B mouse hepatocytes were treated with tumor necrosis factor-α (TNF-α) to induce IR, coincubated with oleic acid (OA) to induce lipid accumulation, and then, treated with RTL fractions, fractionated with n-hexane or ethyl acetate (EA), from column chromatography, and analyzed by thin-layer chromatography. Our results showed that the ethyl acetate fraction (EAf2) from RTL significantly increased glucose uptake and suppressed lipid accumulation in TNF-α plus OA-treated FL83B cells. Western blot analysis showed that EAf2 from RTL ameliorated IR by upregulating the expression of insulin-signaling-related proteins, including protein kinase B, glucose transporter-2, and peroxisome proliferator-activated receptor alpha in TNF-α plus OA-treated FL83B cells. The results of this study suggest that EAf2 from RTL may improve hepatic glucose uptake and alleviate lipid accumulation by ameliorating and suppressing the hepatic insulin signaling and lipogenesis pathways, respectively, in hepatocytes.

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