Muscle type-specific fatty acid metabolism in insulin resistance: an integrated in vivo study in Zucker diabetic fatty rats

Intramyocellular lipid content (IMCL) serves as a good biomarker of skeletal muscle insulin resistance (IR). However, intracellular fatty acid metabolites [malonyl-CoA, long-chain acyl-CoA (LCACoA)] rather than IMCL are considered to be responsible for IR. This study aimed to investigate dynamics of IMCL and fatty acid metabolites during fed-to-starved-to-refed transition in lean and obese (IR) Zucker diabetic fatty rats in the following different muscle types: soleus (oxidative), extensor digitorum longus (EDL, intermediary), and white tibialis anterior (wTA, glycolytic). In the fed state, IMCL was significantly elevated in obese compared with lean rats in all three muscle types (soleus: 304%, EDL: 333%, wTA: 394%) in the presence of elevated serum triglycerides but similar levels of free fatty acids (FFA), malonyl-CoA, and total LCACoAs. During starvation, IMCL in soleus remained relatively constant, whereas in both rat groups IMCL increased significantly in wTA and EDL after comparable dynamics of starvation-induced FFA availability. The decreases of malonyl-CoA in wTA and EDL during starvation were more pronounced in lean than in obese rats, although there were no changes in soleus muscles for both groups. The concomitant increase in IMCL with the fall of malonyl-CoA support the concept that, as a reaction to starvation-induced FFA availability, muscle will activate lipid oxidation more the lower its oxidative capacity and then store the rest as IMCL.

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Abstract 228: FADS2 Regulates Cardiometabolic Risk Phenotypes in Mice

Circulation Research ◽

10.1161/res.121.suppl_1.228 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Adam J Chicco ◽

Christopher M Mulligan ◽

Catherine H Le ◽

Melissa A Routh ◽

Dina Nemr ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Hepatic Steatosis ◽

Cardiometabolic Risk ◽

Elevated Serum ◽

Loss Of Function ◽

Serum Triglycerides ◽

Serum Fatty Acid ◽

Tissue Phospholipid

Single nucleotide polymorphisms of the FADS2 gene associate with cardiometabolic risk in humans. Additionally, serum fatty acid profiles reflecting hepatic hyperactivity of the FADS2 gene product, delta-6 desaturase (D6D), correspond to cardiometabolic syndrome (CMS) phenotypes in humans and animal models. D6D catalyzes rate-limiting steps in essential polyunsaturated fatty acid (PUFA) metabolism, but its role in the pathogenesis of CMS has not been defined. In the present study, we employed pharmacological and genetic gain- and loss-of-function approaches to investigate the links between D6D activity and CMS phenotypes in mice. Transgenic overexpression (TG) of FADS2 in normal (FVB) mice modestly increases hepatic D6D protein expression and serum PUFA product/precursor ratios reflecting greater enzyme activity in vivo . FADS2 TG mice develop a mild, but progressive obesity and insulin resistance with age compared to WT mice, as well as elevated serum triglycerides and LDL/HDL and hepatic macrophage infiltration, but not hepatic steatosis. Global FADS2 ablation prevents obesity/insulin resistance and hyperlipidemia induced by high-fat feeding in C57Bl/6J mice, but promotes severe hepatic steatosis. Pharmacological D6D inhibition in vivo with SC-26196 (100 mpk 4-8 weeks) ameliorates hepatic inflammation and glucose intolerance in FADS2 TG mice and leptin-deficient ( ob ) mice, and prevents severe hyperlipidemia and atherosclerosis in ldlr -/- mice fed an atherogenic diet; despite augmenting hepatic steatosis in all cases. Tissue phospholipid analyses across these models revealed consistent positive relationships between D6D activity, pro-inflammatory eicosanoid accumulation, and a higher phosphatdiylcholine/phosphatidylethanolamine (PC/PE) ratio previously linked to increased hepatic VLDL synthesis and release. These studies establish an important role of D6D activity in the development of CMS and inflammation, and reveal novels links with tissue phospholipid class distribution and metabolism relevant to the development an atherogenic serum lipid profile, hepatic lipid homeostasis, and perhaps other aspects of cardiovascular risk currently under investigation in our laboratory.

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Muscle expression of a malonyl-CoA-insensitive carnitine palmitoyltransferase-1 protects mice against high-fat/high-sucrose diet-induced insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00020.2016 ◽

2016 ◽

Vol 311 (3) ◽

pp. E649-E660 ◽

Cited By ~ 5

Author(s):

Eliska Vavrova ◽

Véronique Lenoir ◽

Marie-Clotilde Alves-Guerra ◽

Raphaël G. Denis ◽

Julien Castel ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Fatty Acid ◽

Carnitine Palmitoyltransferase ◽

High Fat ◽

Direct Modulation ◽

Malonyl Coa ◽

Carnitine Palmitoyltransferase 1 ◽

High Sucrose

Impaired skeletal muscle mitochondrial fatty acid oxidation (mFAO) has been implicated in the etiology of insulin resistance. Carnitine palmitoyltransferase-1 (CPT1) is a key regulatory enzyme of mFAO whose activity is inhibited by malonyl-CoA, a lipogenic intermediate. Whereas increasing CPT1 activity in vitro has been shown to exert a protective effect against lipid-induced insulin resistance in skeletal muscle cells, only a few studies have addressed this issue in vivo. We thus examined whether a direct modulation of muscle CPT1/malonyl-CoA partnership is detrimental or beneficial for insulin sensitivity in the context of diet-induced obesity. By using a Cre- LoxP recombination approach, we generated mice with skeletal muscle-specific and inducible expression of a mutated CPT1 form (CPT1mt) that is active but insensitive to malonyl-CoA inhibition. When fed control chow, homozygous CPT1mt transgenic (dbTg) mice exhibited decreased CPT1 sensitivity to malonyl-CoA inhibition in isolated muscle mitochondria, which was sufficient to substantially increase ex vivo muscle mFAO capacity and whole body fatty acid utilization in vivo. Moreover, dbTg mice were less prone to high-fat/high-sucrose (HFHS) diet-induced insulin resistance and muscle lipotoxicity despite similar body weight gain, adiposity, and muscle malonyl-CoA content. Interestingly, these CPT1mt-protective effects in dbTg-HFHS mice were associated with preserved muscle insulin signaling, increased muscle glycogen content, and upregulation of key genes involved in muscle glucose metabolism. These beneficial effects of muscle CPT1mt expression suggest that a direct modulation of the malonyl-CoA/CPT1 partnership in skeletal muscle could represent a potential strategy to prevent obesity-induced insulin resistance.

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Muscle acylcarnitines during short-term fasting in lean healthy men

Clinical Science ◽

10.1042/cs20080433 ◽

2009 ◽

Vol 116 (7) ◽

pp. 585-592 ◽

Cited By ~ 48

Author(s):

Maarten R. Soeters ◽

Hans P. Sauerwein ◽

Marinus Duran ◽

Ronald J. Wanders ◽

Mariëtte T. Ackermans ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Glucose Oxidation ◽

Acid Oxidation ◽

Healthy Humans ◽

Peripheral Insulin Resistance ◽

Acid Metabolites ◽

Fatty Acid Metabolites ◽

Long Chain

The transition from the fed to the fasted resting state is characterized by, among other things, changes in lipid metabolism and peripheral insulin resistance. Acylcarnitines have been suggested to play a role in insulin resistance, as well as other long-chain fatty acid metabolites. Plasma levels of long-chain acylcarnitines increase during fasting, but this is unknown for muscle long-chain acylcarnitines. In the present study we investigated whether muscle long-chain acylcarnitines increase during fasting and we investigated their relationship with glucose/fat oxidation and insulin sensitivity in lean healthy humans. After 14 h and 62 h of fasting, glucose fluxes, substrate oxidation, and plasma and muscle acylcarnitines were measured before and during a hyperinsulinaemic–euglycaemic clamp. Hyperinsulinaemia decreased long-chain muscle acylcarnitines after 14 h of fasting, but not after 62 h of fasting. In both the basal state and during the clamp, glucose oxidation was lower and fatty acid oxidation was higher after 62 h compared with 14 h of fasting. Absolute changes in glucose and fatty acid oxidation in the basal compared with hyperinsulinaemic state were not different. Muscle long-chain acylcarnitines did not correlate with glucose oxidation, fatty acid oxidation or insulin-mediated peripheral glucose uptake. After 62 h of fasting, the suppression of muscle long-chain acylcarnitines by insulin was attenuated compared with 14 h of fasting. Muscle long-chain acylcarnitines do not unconditionally reflect fatty acid oxidation. The higher fatty acid oxidation during hyperinsulinaemia after 62 h compared with 14 h of fasting, although the absolute decrease in fatty acid oxidation was not different, suggests a different set point.

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