Long-chain acyl-CoA esters as indicators of lipid metabolism and insulin sensitivity in rat and human muscle

Long-chain acyl-CoAs (LCACoA) are an activated lipid species that are key metabolites in lipid metabolism; they also have a role in the regulation of other cellular processes. However, few studies have linked LCACoA content in rat and human muscle to changes in nutritional status and insulin action. Fasting rats for 18 h significantly elevated the three major LCACoA species in muscle ( P < 0.001), whereas high-fat feeding of rats with a safflower oil (18:2) diet produced insulin resistance and increased total LCACoA content ( P < 0.0001) by specifically increasing 18:2-CoA. The LCACoA content of red muscle from rats (4–8 nmol/g) was 4- to 10-fold higher than adipose tissue (0.4–0.9 nmol/g, P < 0.001), suggesting that any contamination of muscle samples with adipocytes would contribute little to the LCACoA content of muscle. In humans, the LCACoA content of muscle correlated significantly with a measure of whole body insulin action in 17 male subjects ( r 2 = 0.34, P = 0.01), supporting a link between muscle lipid metabolism and insulin action. These results demonstrate that the LCACoA pool reflects lipid metabolism and nutritional state in muscle. We conclude that the LCACoA content of muscle provides a direct index of intracellular lipid metabolism and its links to insulin action, which, unlike triglyceride content, is not subject to contamination by closely associated adipose tissue.

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Effects of cold acclimation on lipid metabolism in adipose tissue

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1961.200.4.847 ◽

1961 ◽

Vol 200 (4) ◽

pp. 847-850 ◽

Cited By ~ 82

Author(s):

Judith K. Patkin ◽

E. J. Masoro

Keyword(s):

Fatty Acids ◽

Adipose Tissue ◽

Fatty Acid ◽

Lipid Metabolism ◽

Cold Acclimation ◽

Long Chain Fatty Acids ◽

Synthetic Capacity ◽

And Control ◽

Long Chain ◽

Chain Fatty Acids

Cold acclimation is known to alter hepatic lipid metabolism. Liver slices from cold-acclimated rats have a greatly depressed capacity to synthesize long-chain fatty acids from acctate-1-C14. Since adipose tissue is the major site of lipogenic activity in the intact animal, its fatty acid synthetic capacity was studied. In contrast to the liver, it was found that adipose tissue from the cold-acclimated rat synthesized three to six times as much long-chain fatty acids per milligram of tissue protein as the adipose tissue from the control rat living at 25°C. Evidence is presented indicating that adipose tissue from cold-acclimated and control rats esterify long-chain fatty acids at the same rate. The ability of adipose tissue to oxidize palmitic acid to CO2 was found to be unaltered by cold acclimation. The fate of the large amount of fatty acid synthesized in the adipose tissue of cold-acclimated rats is discussed.

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Reduced malonyl-CoA content in recovery from exercise correlates with improved insulin-stimulated glucose uptake in human skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90556.2008 ◽

2009 ◽

Vol 296 (4) ◽

pp. E787-E795 ◽

Cited By ~ 15

Author(s):

Christian Frøsig ◽

Carsten Roepstorff ◽

Nina Brandt ◽

Stine J. Maarbjerg ◽

Jesper B. Birk ◽

...

Keyword(s):

Glucose Uptake ◽

Insulin Action ◽

Acute Exercise ◽

Glycogen Synthase ◽

Knee Extensor ◽

Human Muscle ◽

Whole Body ◽

Euglycemic Hyperinsulinemic Clamp ◽

Malonyl Coa ◽

Before And After

This study evaluated whether improved insulin-stimulated glucose uptake in recovery from acute exercise coincides with reduced malonyl-CoA (MCoA) content in human muscle. Furthermore, we investigated whether a high-fat diet [65 energy-% (Fat)] would alter the content of MCoA and insulin action compared with a high-carbohydrate diet [65 energy-% (CHO)]. After 4 days of isocaloric diet on two occasions (Fat/CHO), 12 male subjects performed 1 h of one-legged knee extensor exercise (∼80% peak workload). Four hours after exercise, insulin-stimulated glucose uptake was determined in both legs during a euglycemic-hyperinsulinemic clamp. Muscle biopsies were obtained in both legs before and after the clamp. Four hours after exercise, insulin-stimulated glucose uptake was improved (∼70%, P < 0.001) independent of diet composition and despite normal insulin-stimulated regulation of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase, Akt, GSK-3, and glycogen synthase. Interestingly, exercise resulted in a sustained reduction (∼20%, P < 0.05) in MCoA content 4 h after exercise that correlated ( r = 0.65, P < 0.001) with improved insulin-stimulated glucose uptake. Four days of Fat diet resulted in an increased content of intramyocellular triacylglycerol ( P < 0.01) but did not influence muscle MCoA content or whole body insulin-stimulated glucose uptake. However, at the muscular level proximal insulin signaling and insulin-stimulated glucose uptake appeared to be compromised, although to a minor extent, by the Fat diet. Collectively, this study indicates that reduced muscle MCoA content in recovery from exercise may be part of the adaptive response leading to improved insulin action on glucose uptake after exercise in human muscle.

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ChREBP-Mediated Regulation of Lipid Metabolism: Involvement of the Gut Microbiota, Liver, and Adipose Tissue

Frontiers in Endocrinology ◽

10.3389/fendo.2020.587189 ◽

2020 ◽

Vol 11 ◽

Author(s):

Katsumi Iizuka ◽

Ken Takao ◽

Daisuke Yabe

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Lipid Metabolism ◽

Gut Microbiota ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Acid Synthesis ◽

Whole Body ◽

Acetyl Coa ◽

Alcoholic Fatty Liver

Carbohydrate response element-binding protein (ChREBP) plays an important role in the development of type 2 diabetes, dyslipidemia, and non-alcoholic fatty liver disease, as well as tumorigenesis. ChREBP is highly expressed in lipogenic organs, such as liver, intestine, and adipose tissue, in which it regulates the production of acetyl CoA from glucose by inducing Pklr and Acyl expression. It has recently been demonstrated that ChREBP plays a role in the conversion of gut microbiota-derived acetate to acetyl CoA by activating its target gene, Acss2, in the liver. ChREBP regulates fatty acid synthesis, elongation, and desaturation by inducing Acc1 and Fasn, elongation of long-chain fatty acids family member 6 (encoded by Elovl6), and Scd1 expression, respectively. ChREBP also regulates the formation of very low-density lipoprotein by inducing the expression of Mtp. Furthermore, it plays a crucial role in peripheral lipid metabolism by inducing Fgf21 expression, as well as that of Angptl3 and Angptl8, which are known to reduce peripheral lipoprotein lipase activity. In addition, ChREBP is involved in the production of palmitic-acid-5-hydroxystearic-acid, which increases insulin sensitivity in adipose tissue. Curiously, ChREBP is indirectly involved in fatty acid β-oxidation and subsequent ketogenesis. Thus, ChREBP regulates whole-body lipid metabolism by controlling the transcription of lipogenic enzymes and liver-derived cytokines.

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Mechanisms of Insulin Action and Insulin Resistance

Physiological Reviews ◽

10.1152/physrev.00063.2017 ◽

2018 ◽

Vol 98 (4) ◽

pp. 2133-2223 ◽

Cited By ~ 276

Author(s):

Max C. Petersen ◽

Gerald I. Shulman

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Insulin Action ◽

Big Bang ◽

Whole Body ◽

Detailed Knowledge ◽

Bioactive Lipids ◽

Mechanistic Investigation ◽

The Impact

The 1921 discovery of insulin was a Big Bang from which a vast and expanding universe of research into insulin action and resistance has issued. In the intervening century, some discoveries have matured, coalescing into solid and fertile ground for clinical application; others remain incompletely investigated and scientifically controversial. Here, we attempt to synthesize this work to guide further mechanistic investigation and to inform the development of novel therapies for type 2 diabetes (T2D). The rational development of such therapies necessitates detailed knowledge of one of the key pathophysiological processes involved in T2D: insulin resistance. Understanding insulin resistance, in turn, requires knowledge of normal insulin action. In this review, both the physiology of insulin action and the pathophysiology of insulin resistance are described, focusing on three key insulin target tissues: skeletal muscle, liver, and white adipose tissue. We aim to develop an integrated physiological perspective, placing the intricate signaling effectors that carry out the cell-autonomous response to insulin in the context of the tissue-specific functions that generate the coordinated organismal response. First, in section II, the effectors and effects of direct, cell-autonomous insulin action in muscle, liver, and white adipose tissue are reviewed, beginning at the insulin receptor and working downstream. Section III considers the critical and underappreciated role of tissue crosstalk in whole body insulin action, especially the essential interaction between adipose lipolysis and hepatic gluconeogenesis. The pathophysiology of insulin resistance is then described in section IV. Special attention is given to which signaling pathways and functions become insulin resistant in the setting of chronic overnutrition, and an alternative explanation for the phenomenon of ‟selective hepatic insulin resistanceˮ is presented. Sections V, VI, and VII critically examine the evidence for and against several putative mediators of insulin resistance. Section V reviews work linking the bioactive lipids diacylglycerol, ceramide, and acylcarnitine to insulin resistance; section VI considers the impact of nutrient stresses in the endoplasmic reticulum and mitochondria on insulin resistance; and section VII discusses non-cell autonomous factors proposed to induce insulin resistance, including inflammatory mediators, branched-chain amino acids, adipokines, and hepatokines. Finally, in section VIII, we propose an integrated model of insulin resistance that links these mediators to final common pathways of metabolite-driven gluconeogenesis and ectopic lipid accumulation.

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Enhanced glycogen metabolism in adipose tissue decreases triglyceride mobilization

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00741.2009 ◽

2010 ◽

Vol 299 (1) ◽

pp. E117-E125 ◽

Cited By ~ 6

Author(s):

Kathleen R. Markan ◽

Michael J. Jurczak ◽

Margaret B. Allison ◽

Honggang Ye ◽

Maria M. Sutanto ◽

...

Keyword(s):

Adipose Tissue ◽

Lipid Metabolism ◽

Lactate Production ◽

Transgenic Animals ◽

Whole Body ◽

Nonesterified Fatty Acids ◽

Transgenic Mouse Line ◽

Whole Body Metabolism

Adipose tissue is a primary site for lipid storage containing trace amounts of glycogen. However, refeeding after a prolonged partial fast produces a marked transient spike in adipose glycogen, which dissipates in coordination with the initiation of lipid resynthesis. To further study the potential interplay between glycogen and lipid metabolism in adipose tissue, the aP2-PTG transgenic mouse line was utilized since it contains a 100- to 400-fold elevation of adipocyte glycogen levels that are mobilized upon fasting. To determine the fate of the released glucose 1-phosphate, a series of metabolic measurements were made. Basal and isoproterenol-stimulated lactate production in vitro was significantly increased in adipose tissue from transgenic animals. In parallel, basal and isoproterenol-induced release of nonesterified fatty acids (NEFAs) was significantly reduced in transgenic adipose tissue vs. control. Interestingly, glycerol release was unchanged between the genotypes, suggesting that enhanced triglyceride resynthesis was occurring in the transgenic tissue. Qualitatively similar results for NEFA and glycerol levels between wild-type and transgenic animals were obtained in vivo during fasting. Additionally, the physiological upregulation of the phospho enolpyruvate carboxykinase cytosolic isoform (PEPCK-C) expression in adipose upon fasting was significantly blunted in transgenic mice. No changes in whole body metabolism were detected through indirect calorimetry. Yet weight loss following a weight gain/loss protocol was significantly impeded in the transgenic animals, indicating a further impairment in triglyceride mobilization. Cumulatively, these results support the notion that the adipocyte possesses a set point for glycogen, which is altered in response to nutritional cues, enabling the coordination of adipose glycogen turnover with lipid metabolism.

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Peroxisome Proliferator-induced Long Chain Acyl-CoA Thioesterases Comprise a Highly Conserved Novel Multi-gene Family Involved in Lipid Metabolism

Journal of Biological Chemistry ◽

10.1074/jbc.274.48.34317 ◽

1999 ◽

Vol 274 (48) ◽

pp. 34317-34326 ◽

Cited By ~ 82

Author(s):

Mary C. Hunt ◽

Sari E. B. Nousiainen ◽

Merja K. Huttunen ◽

Kenji E. Orii ◽

L. Thomas Svensson ◽

...

Keyword(s):

Lipid Metabolism ◽

Gene Family ◽

Peroxisome Proliferator ◽

Chain Acyl ◽

Long Chain

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Role of long-chain acyl-CoA synthetase 4 in formation of polyunsaturated lipid species in hepatic stellate cells

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ◽

10.1016/j.bbalip.2014.12.003 ◽

2015 ◽

Vol 1851 (2) ◽

pp. 220-230 ◽

Cited By ~ 22

Author(s):

Maidina Tuohetahuntila ◽

Bart Spee ◽

Hedwig S. Kruitwagen ◽

Richard Wubbolts ◽

Jos F. Brouwers ◽

...

Keyword(s):

Hepatic Stellate Cells ◽

Stellate Cells ◽

Lipid Species ◽

Chain Acyl ◽

Long Chain

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Multiple effects of cold exposure on livers of male mice

Journal of Endocrinology ◽

10.1530/joe-18-0076 ◽

2018 ◽

Vol 238 (2) ◽

pp. 91-106 ◽

Cited By ~ 3

Author(s):

Aldo Grefhorst ◽

Johanna C van den Beukel ◽

Wieneke Dijk ◽

Jacobie Steenbergen ◽

Gardi J Voortman ◽

...

Keyword(s):

Adipose Tissue ◽

Lipid Metabolism ◽

Cold Exposure ◽

Ldl Receptor ◽

Whole Body ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid ◽

Hepatic Expression ◽

Brown Adipose ◽

Whole Body Metabolism

Cold exposure of mice is a common method to stimulate brown adipose tissue (BAT) activity and induce browning of white adipose tissue (WAT) that has beneficial effects on whole-body lipid metabolism, including reduced plasma triglyceride (TG) concentrations. The liver is a key regulatory organ in lipid metabolism as it can take up as well as oxidize fatty acids. The liver can also synthesize, store and secrete TGs in VLDL particles. The effects of cold exposure on murine hepatic lipid metabolism have not been addressed. Here, we report the effects of 24-h exposure to 4°C on parameters of hepatic lipid metabolism of male C57BL/6J mice. Cold exposure increased hepatic TG concentrations by 2-fold (P < 0.05) but reduced hepatic lipogenic gene expression. Hepatic expression of genes encoding proteins involved in cholesterol synthesis and uptake such as the LDL receptor (LDLR) was significantly increased upon cold exposure. Hepatic expression of Cyp7a1 encoding the rate-limiting enzyme in the classical bile acid (BA) synthesis pathway was increased by 4.3-fold (P < 0.05). Hepatic BA concentrations and fecal BA excretion were increased by 2.8- and 1.3-fold, respectively (P < 0.05 for both). VLDL-TG secretion was reduced by approximately 50% after 24 h of cold exposure (P < 0.05). In conclusion, cold exposure has various, likely intertwined effects on the liver that should be taken into account when studying the effects of cold exposure on whole-body metabolism.

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Codon-optimized FAM132b prevents diet-induced obesity by modulating adrenergic response and insulin action

10.1101/2020.08.31.275503 ◽

2020 ◽

Author(s):

Zhengtang Qi ◽

Jie Xia ◽

Xiangli Xue ◽

Wenbin Liu ◽

Zhuochun Huang ◽

...

Keyword(s):

Adipose Tissue ◽

Gene Transfer ◽

Insulin Action ◽

Metabolic Disorders ◽

Codon Optimization ◽

Whole Body ◽

Therapeutic Effects ◽

Glycemic Response ◽

Adrenergic Response

AbstractFAM132b, also known as myonectin, has been identified as a myokine produced by exercise. It is a secreted protein precursor that belongs to the adipolin/erythroferrone family, and has hormone activity in circulation to regulate cellular iron homeostasis and lipid metabolism via unknown receptors. Here, adeno-associated viral vectors (AAV9) were engineered to induce overexpression of FAM132b with 2 codon mutations (A136T and P159A). Treatment of mice under high-fat diet feeding with FAM132b gene transfer resulted in marked reductions in body weight, fat depot, adipocytes size, glucose intolerance and insulin resistance. Moreover, FAM132b overproduction reduced glycemic response to epinephrine (EPI) in whole body and increased lipolytic response to EPI in adipose tissues. This adrenergic response of adipose tissue led to the result that gene transfer reduced glycogen utilization and increased fat consumption in skeletal muscle during exercise. FAM132b knockdown by shRNA significantly increased glycemic response to EPI in vivo and reduced adipocytes response to EPI and adipose tissue browning. Structural analysis suggested that FAM132b mutants delivered by AAV9 may form a weak bond with ADRB2, and potentially bind to insulin against insulin receptor by blocking the receptor binding sites on insulin B-chain. Our study underscores the potential of FAM132b gene therapy with codon optimization to treat obesity by modulating adrenergic response and interfering insulin action.SignificanceWe show here that AAV9-mediated expression of FAM132b with A136T and P159A is a safe and effective therapeutic strategy for improving glucose homeostasis. This is the first demonstration of a therapeutic effect on metabolic disorders in mice with FAM132b codon optimization. These therapeutic effects indicate that FAM132b gene transfer with selective codon mutants in vivo might be a valid therapy for diabetes that can be extended to other metabolic disorders.

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