Skeletal Muscle Lipolysis Research Articles

Interstitial glycerol concentrations in human skeletal muscle and adipose tissue during graded exercise.

It is not clear how lipolysis changes in skeletal muscle and adipose tissue during exercise of different intensities. We aimed at estimating this by microdialysis and muscle biopsy techniques. Nine healthy, young men were kicking with both legs at 25% of maximal power (Wmax) for 45 min and then simultaneously with one leg at 65% and the other leg at 85% Wmax for 35 min. Glycerol concentrations in skeletal muscle and adipose tissue interstitial fluid and in arterial plasma increased (P<0.001) during low intensity exercise and increased (P<0.05) even more during moderate intensity exercise. The difference between interstitial muscle and arterial plasma water glycerol concentration, which indicates the direction of the glycerol flux, was positive (P<0.05) at rest (21 +/- 9 microM) and during exercise at 25% Wmax (18 +/- 6 microM). The difference decreased (P<0.05) with increasing exercise intensity and was not significantly different from zero during exercise at 65% (-11 +/- 17 microM) and 85% (-12 +/- 13 microM) Wmax. In adipose tissue, the difference between interstitial and arterial plasma water glycerol increased (P<0.001) with increasing intensity. The net triacylglycerol breakdown, measured chemically from the biopsy, did not differ significantly from zero at any exercise intensity although directional changes were similar to microdialysis changes. Skeletal muscle releases glycerol at rest and at low exercise intensity but not at higher intensities. This can be interpreted as skeletal muscle lipolysis peaking at low exercise intensities but could also indicate that glycerol is taken up in skeletal muscle at a rate which is increasing with exercise intensity.

Lipolysis in skeletal muscle is decreased in high-fat-fed rats

The intracellular triglyceride content in skeletal muscle is increased in insulin-resistant states such as obesity or high-fat feeding. It has been hypothesized that increased fatty acid oxidation resulting from increased lipolysis of intramyocellular triglycerides may be responsible for this insulin resistance. This study was undertaken to examine whether insulin resistance is associated with increased lipolysis in skeletal muscle in rats fed a high-fat diet. Sprague-Dawley rats were fed a high-fat diet for 5 weeks. Lipolysis in skeletal muscle and adipose tissue was determined by measuring the interstitial glycerol concentrations using a microdialysis method in basal and hyperinsulinemic-euglycemic clamp conditions. In the basal state, plasma free fatty acid (FFA) levels were higher in high-fat—fed rats than in low fat—fed rats ( P < .05). In contrast, plasma glycerol levels ( P < .001) and interstitial glycerol concentrations of skeletal muscle ( P < .05) and adipose tissue ( P < .01) were lower in high fat—fed rats than in low fat—fed rats. Plasma ( P < .05) and interstitial glycerol concentrations ( P < .05 for skeletal muscle, P < .01 for adipose tissue) during the hyperinsulinemic euglycemic clamps were also lower in the high-fat diet group. These results do not support the idea that increased fatty acid oxidation resulting from increased lipolysis of intramyocellular triglycerides is responsible for the insulin resistance in high fat—fed rats.

Marked heterogeneity of human skeletal muscle lipolysis at rest.

In this study, variations in lipolysis among different muscle groups were examined by measuring local net glycerol release in vivo in healthy, normal-weight subjects (n = 11) during rested, postabsorptive conditions. Microdialysis of the gastrocnemius, deltoid, and vastus lateralis muscle regions revealed that extracellular glycerol concentrations of these three muscle regions were 84.7 +/- 6.7, 59.7 + 7.3, and 56.4 +/- 7.5 micro mol/l, respectively, and the arterial plasma glycerol concentration was 44.8 +/- 2.3 micro mol/l (P = 0.0003-0.006, gastrocnemius vs. others). Local tissue blood flow, as measured by Xe clearance, did not differ among the regions. Net glycerol release was significantly higher in gastrocnemius muscle than in the two other regions. There were no regional differences in glycerol uptake when studied during glycerol infusion. Gastrocnemius muscle showed a dominance of type 1 fibers (70%), whereas the vastus lateralis muscle had equal distribution of fiber types (P = 0.02). No differences in intramuscular triaclyceride content, perimuscular fat, or the adipocyte-specific protein perilipin were observed among the muscle regions. Triglyceride turnover in the gastrocnemius muscle was 3.3 + 1.4% over 24 h, which is about 10 times more rapid than the turnover rate in subcutaneous adipose tissue (P < 0.01). Thus there were marked differences in lipolytic activity among skeletal muscle groups at rest, possibly reflecting variations in fiber type.

No apparent suppression by insulin of in vivo skeletal muscle lipolysis in nonobese women.

To investigate the antilipolytic effect of insulin in skeletal muscle and adipose tissue in vivo, the rates of glycerol release from the two tissues were compared in 10 nonobese women during a two-step euglycemic hyperinsulinemic clamp. Tissue interstitial glycerol levels were determined by microdialysis, and tissue blood flow was assessed with the (133)Xe clearance technique. Absolute rates of glycerol release were estimated according to Fick's principle. In both adipose tissue and muscle, glycerol levels decreased significantly already during the low insulin infusion rate. The fractional release of glycerol (difference between interstitial glycerol and arterialized venous plasma glycerol) was reduced by more than one-half in adipose tissue (P < 0.0001) in response to insulin, whereas it remained unaltered in skeletal muscle. Muscle blood flow rates increased by 60% (P < 0.02) during insulin infusion; in adipose tissue, blood flow rates did not change significantly in response to insulin. The basal rate of glycerol release from skeletal muscle amounted to approximately 15% of that from adipose tissue. After insulin infusion, the rate of adipose tissue glycerol release was markedly suppressed, whereas in skeletal muscle the rate of glycerol mobilization did not change significantly in response to insulin. It is concluded that insulin does not inhibit the rate of lipolysis in skeletal muscle of nonobese women.

Evidence for a major role of skeletal muscle lipolysis in the regulation of lipid oxidation during caloric restriction in vivo.

A lipolytic process in skeletal muscle has recently been demonstrated. However, the physiological importance of this process is unknown. We investigated the role of skeletal muscle lipolysis for lipid utilization during caloric restriction in eight obese women before and after 11 days of very low-calorie diet (VLCD) (2.2 MJ per day). Subjects were studied with indirect calorimetry and microdialysis of skeletal muscle and adipose tissue in order to analyze substrate utilization and glycerol (lipolysis index) in connection with a two-step euglycemic-hyperinsulinemic (12 and 80 mU/m(2). min) clamp. Local blood flow rates in the two tissues were determined with (133)Xe-clearance. Circulating free fatty acids and glycerol decreased to a similar extent during insulin infusion before and during VLCD, and there was a less marked insulin-induced reduction in lipid oxidation during VLCD. Adipose tissue glycerol release was hampered by insulin infusion to the same extent ( approximately 40%) before and during VLCD. Skeletal muscle glycerol release was not influenced by insulin before VLCD. However, during VLCD insulin caused a marked (fivefold) (P < 0.01) increase in skeletal muscle glycerol release. The effect was accompanied by a fourfold stimulation of skeletal muscle blood flow (P < 0.01). We propose that, during short-term caloric restriction, the reduced ability of insulin to inhibit lipids, despite a preserved antilipolytic effect of the hormone in adipose tissue, is caused by an augmented mobilization of fat from skeletal muscle, and that a physiological role of muscle lipolysis provides a local source of fatty acids.

Action of Glucagon and Glucagon-Like Peptide-1-(7-36) Amide on Lipolysis in Human Subcutaneous Adipose Tissue and Skeletal Muscle in Vivo

Action of Glucagon and Glucagon-Like Peptide-1-(7-36) Amide on Lipolysis in Human Subcutaneous Adipose Tissue and Skeletal Muscle in Vivo

Action of glucagon and glucagon-like peptide-1-(7-36) amide on lipolysis in human subcutaneous adipose tissue and skeletal muscle in vivo.

In vitro and animal studies have shown that glucagon and glucagon-like peptide-1 (GLP-1)-(7-36) amide may participate in the regulation of lipolysis. However, results on human subjects in vivo are inconclusive. To avoid confounding effects, such as changes in insulin secretion when perfusing hormones iv, we used the in situ microdialysis to analyze the impact of human glucagon and GLP-1 on lipolysis rates and local blood flow. Nine healthy volunteers were given an 80-min local perfusion of each hormone (10(-6) mol/L), both in skeletal muscle (gastrocnemius) and in sc abdominal adipose tissue, after a basal period with perfusion of Ringer's solution. Variations in the lipolysis rate and blood flow, respectively, were assessed by measuring of the dialysate glycerol content and the ethanol ratio (outgoing-to-ingoing ethanol concentration). The in vitro relative recovery of the microdialysis probes was 5.2 +/- 1.2%. No significant effects of either GLP-1 or glucagon on either lipolysis rate or blood flow were detected in muscle or adipose tissue. Isoprenaline (10(-6) mol/L), which was perfused after glucagon or GLP-1 in the same catheters, significantly increased the lipolysis rate (a 249% increase of dialysate glycerol in adipose tissue and a 72% increase in skeletal muscle). Furthermore, isoprenaline, but not glucagon or GLP-1, stimulated lipolysis in vitro in isolated human sc adipose tissue. We conclude that neither glucagon nor GLP-1 affect the lipolysis rate of human sc adipose tissue or skeletal muscle.

Microdialysis: use in human exercise studies.

Microdialysis has been used for 25 years to study brain function in vivo. Recently, it has been developed for investigations on peripheral tissues. A microdialysis catheter is an artificial blood vessel system which can be placed in the extracellular space of various tissues such as adipose tissue and skeletal muscle in order to examine these tissues in situ. Molecules are collected from the tissue by the device and their true interstitial concentration can be estimated. Metabolically-active molecules can be delivered to the interstitial space through the microdialysis probe and their action on the tissue can be investigated locally without producing generalized effects. It is also possible to study local tissue blood flow with microdialysis by adding a flow marker (usually ethanol) to the microdialysis solvent. The microdialysis technique is particularly useful for studies of small and water-soluble molecules. A number of important observations on the in vivo regulation of lipolysis, carbohydrate metabolism and blood flow in human skeletal muscle and adipose tissue have been made recently using microdialysis.

Lipolysis in skeletal muscle is rapidly regulated by low physiological doses of insulin.

Both patients with Type II (non-insulin-dependent) diabetes mellitus and normoglycaemic, insulin resistant subjects were shown to have an increased lipid content in skeletal muscle, which correlates negatively with insulin sensitivity. Recently, it was shown that during a hyperinsulinaemic euglycaemic clamp interstitial glycerol was reduced not only in adipose tissue but also in skeletal muscle. To assess whether lipolysis of muscular lipids is also regulated by low physiological concentrations of insulin, we used the microdialysis technique in combination with a 3-step hyperinsulinaemic glucose clamp. Nineteen lean, healthy subjects (12 m/7 f) underwent a glucose clamp with various doses of insulin (GC I = 0.1, GC II = 0.25 and GC III = 1.0 mU x kg(-1) x min(-1)). Two double lumen microdialysis catheters each were inserted in the paraumbilical subcutaneous adipose tissue and in skeletal muscle (tibialis anterior) to measure interstitial glycerol concentration (index of lipolysis) and ethanol outflow (index of tissue flow). During the different steps of the glucose clamp, glycerol in adipose tissue was reduced to 81 +/- 7 % (GC I), 55 +/- 8 % (GC II) and 25 +/- 5 % (GC III), respectively, of basal. In contrast, glycerol in skeletal muscle declined to 73 +/- 5 % (GC I) and to 57 +/- 6 % (GC II) but was not further reduced at GC III. Tissue flow was higher in the skeletal muscle and remained unchanged in both compartments throughout the experiment. This study confirms the presence of glycerol release in skeletal muscle. Lipolysis in skeletal muscle and adipose tissue are suppressed similarly by minute and physiological increases in insulin but differently by supraphysiological increases. Inadequate suppression of intramuscular lipolysis resulting in increased availability of non-esterified fatty acids, could represent a potential mechanism involved in the pathogenesis of impaired glucose disposal, i. e. insulin resistance, in muscle. [Diabetologia (1999) 42: 1171-1174]

Beta-Adrenergic regulation of lipolysis and blood flow in human skeletal muscle in vivo.

Little is known about the regulation of catecholamine-stimulated lipolysis in human skeletal muscle. Therefore, beta-adrenergic regulation of lipolysis and blood flow was investigated in healthy subjects in vivo by use of microdialysis of the gastrocnemius muscle. First, during a hypoglycemic, hyperinsulinemic clamp, which induces a lipolytic response in skeletal muscle tissue, the muscle was locally perfused with beta-adrenoceptor blocking agents. Perfusion with nonselective (propranolol) and beta2-selective (ICI-118551) blocking agents counteracted the hypoglycemia-induced lipolysis (P < 0.01), but perfusion with metoprolol (beta1-blocker) did not affect the glycerol response. Second, selective beta-adrenoceptor agonists were perfused in situ into skeletal muscle during resting conditions. beta2-Adrenoceptor stimulation with terbutaline induced a concentration-dependent increase in skeletal muscle glycerol levels and in tissue blood flow, whereas perfusion with beta1- or beta3-adrenoceptor agonists (dobutamine or CGP-12177) did not influence the glycerol concentration or blood flow. In conclusion, in skeletal muscle tissue, only the beta2-subtype is of importance among beta-adrenoceptors for regulation of lipolysis and blood flow. This is in contrast to adipose tissue, where beta1- and beta3-adrenoceptors are also involved.

Interstitial fluid concentrations of glycerol, glucose, and amino acids in human quadricep muscle and adipose tissue. Evidence for significant lipolysis in skeletal muscle.

To determine the relationship between circulating metabolic fuels and their local concentrations in peripheral tissues we measured glycerol, glucose, and amino acids by microdialysis in muscle and adipose interstitium of 10 fasted, nonobese human subjects during (a) baseline, (b) euglycemic hyperinsulinemia (3 mU/kg per min for 3 h) and, (c) local norepinephrine reuptake blockade (NOR). At baseline, interstitial glycerol was strikingly higher (P < 0.0001) in muscle (3710 microM) and adipose tissue (2760 microM) compared with plasma (87 microM), whereas interstitial glucose (muscle 3.3, fat 3.6 mM) was lower (P < 0.01) than plasma levels (4.8 mM). Taurine, glutamine, and alanine levels were higher in muscle than in adipose or plasma (P < 0.05). Euglycemic hyperinsulinemia did not affect interstitial glucose, but induced a fall in plasma glycerol and amino acids paralleled by similar changes in the interstitium of both tissues. Local NOR provoked a fivefold increase in glycerol (P < 0.001) and twofold increase in norepinephrine (P < 0.01) in both muscle and adipose tissues. To conclude, interstitial substrate levels in human skeletal muscle and adipose tissue differ substantially from those in the circulation and this disparity is most pronounced for glycerol which is raised in muscle as well as adipose tissue. In muscle, insulin suppressed and NOR increased interstitial glycerol concentrations. Our data suggest unexpectedly high rates of intramuscular lipolysis in humans that may play an important role in fuel metabolism.

Evidence for a substrate regulation of triglyceride lipolysis in human skeletal muscle.

Glycerol release from the human forearm which is generally used as a semiquantitative index of intramuscular lipolysis was studied under different hormonal influence and substrate supply in healthy volunteers and juvenile diabetics using the forearm technique. Acute insulin deficiency in juvenile diabetics failed stimulating the rate of muscular lipolysis since the rates of glycerol release in normals and diabetics were the same. In addition, in normal volunteers high physiological levels of insulin caused by an intraarterial infusion of the hormone exhibited no effect on the glycerol release from deep forearm tissue. Similarly, an intraarterial infusion of metaproterenol did not accelerate muscular glycerol release in normal man. However, in juvenile diabetics in acute insulin deficiency the same dose of the catecholamine increased the rate of muscular glycerol production. Elevated substrate supply during intravenous infusion of glucose or fructose yielded increased uptake of glucose and fructose into the deep forearm tissue and thereby promptly blocked muscular glycerol release in normal volunteers and in juvenile diabetics. These findings suggest that the rate of lipolysis in muscle tissue is not primarily under the control of hormones but rather by substrate supply.

Influence of experimental hyperthyroidism on skeletal muscle metabolism in the rat.

In this study hind-limb perfusion was used to investigate the influence of thyroid hormones on some metabolic parameters in the skeletal muscle of the rat. Daily injection of 20 microng L-thyroxine (T4) per 100 g b. w. for a week caused a 25% increase in oxygen consumption. Further enlargement of the T4 dose had little additive effect. In the dose range 20--80 microng T4/100g b.w., no important changes occurred in lactate production or glucose consumption. Only at the highest T4 dose did the glucose consumption increase significantly. The most profound effect of T4 was on lipolysis. A daily dose of 20 microng T4/100 g b. w. gave a doubling of glycerol production rate, the maximum occuring at a dose of 40 microng T4/100 g b. w. Inactivation of the nervous system was without influence on the T4-induced increase in oxygen consumption. However, the T4-induced elevation of lipolysis disappeared after abolition of the nervous activity. This raises the possibility that the T4 effect on lipolysis in skeletal muscle is a potentiation of catecholamine effects. The T4-induced oxygen consumption increase might be dependent not on the lipolytic process but rather on other energy-consuming cell processes.