Jeffrey F. Horowitz

Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid–induced insulin resistance

Fatty acid oversupply is a key mediator of skeletal muscle insulin resistance in obesity, primarily via accumulation of fatty acid metabolites and activation of proinflammatory pathways. Herein, we demonstrate that fatty acid-induced insulin resistance in humans is completely prevented the day after 1 session of endurance exercise. Because skeletal muscle is the primary site for systemic glucose disposal and is highly susceptible to impaired insulin action by elevated fatty acid availability, we obtained skeletal muscle samples to investigate possible mechanisms mediating this protective effect of exercise. Prevention of fatty acid-induced insulin resistance after exercise accompanied enhanced skeletal muscle protein expression of key lipogenic enzymes and an increase in muscle triglyceride synthesis. Partitioning more fatty acids toward triglyceride synthesis within muscle reduced the accumulation of fatty acid metabolites and suppressed the proinflammatory response in skeletal muscle, as evidenced by decreased phosphorylation and activation of JNK and increased abundance of inhibitor of NF-kappaB alpha (I kappa B-alpha) and I kappa B-beta. We believe this is the first study to demonstrate that 1 session of exercise completely reverses fatty acid-induced insulin resistance in humans. Reversal of insulin resistance accompanied enhanced lipogenic capacity within skeletal muscle, reduced accumulation of highly bioactive fatty acid metabolites, and suppressed activation of proinflammatory pathways known to impair insulin action.

Fatty acid mobilization from adipose tissue during exercise

By far the largest energy reserve in the human body is adipose tissue triglycerides, and these reserves are an important source of fuel during prolonged endurance exercise. To use this rich source of potential energy during exercise, adipose tissue triglycerides must first be hydrolyzed and the resultant fatty acids delivered to the working muscles. The aims of this review are to describe how exercise alters lipid mobilization from adipose tissue, to identify alternative sources of lipids and to discuss some of the key factors regulating fatty acid mobilization, uptake and oxidation during exercise. The impact of understanding factors involved in the coordinated regulation of lipid mobilization and oxidation during exercise goes far beyond its relevance for endurance exercise performance. A better understanding of the regulation of these processes will facilitate the development of more effective treatment modalities for obesity-related metabolic disorders.

Ceramides Contained in LDL Are Elevated in Type 2 Diabetes and Promote Inflammation and Skeletal Muscle Insulin Resistance

Dysregulated lipid metabolism and inflammation are linked to the development of insulin resistance in obesity, and the intracellular accumulation of the sphingolipid ceramide has been implicated in these processes. Here, we explored the role of circulating ceramide on the pathogenesis of insulin resistance. Ceramide transported in LDL is elevated in the plasma of obese patients with type 2 diabetes and correlated with insulin resistance but not with the degree of obesity. Treating cultured myotubes with LDL containing ceramide promoted ceramide accrual in cells and was accompanied by reduced insulin-stimulated glucose uptake, Akt phosphorylation, and GLUT4 translocation compared with LDL deficient in ceramide. LDL-ceramide induced a proinflammatory response in cultured macrophages via toll-like receptor–dependent and –independent mechanisms. Finally, infusing LDL-ceramide into lean mice reduced insulin-stimulated glucose uptake, and this was due to impaired insulin action specifically in skeletal muscle. These newly identified roles of LDL-ceramide suggest that strategies aimed at reducing hepatic ceramide production or reducing ceramide packaging into lipoproteins may improve skeletal muscle insulin action.

Effects of high- and low-velocity resistance training on the contractile properties of skeletal muscle fibers from young and older humans

A two-arm, prospective, randomized, controlled trial study was conducted to investigate the effects of movement velocity during progressive resistance training (PRT) on the size and contractile properties of individual fibers from human vastus lateralis muscles. The effects of age and sex were examined by a design that included 63 subjects organized into four groups: young (20-30 yr) men and women, and older (65-80 yr) men and women. In each group, one-half of the subjects underwent a traditional PRT protocol that involved shortening contractions at low velocities against high loads, while the other half performed a modified PRT protocol that involved contractions at 3.5 times higher velocity against reduced loads. Muscles were sampled by needle biopsy before and after the 14-wk PRT program, and functional tests were performed on permeabilized individual fiber segments isolated from the biopsies. We tested the hypothesis that, compared with low-velocity PRT, high-velocity PRT results in a greater increase in the cross-sectional area, force, and power of type 2 fibers. Both types of PRT increased the cross-sectional area, force, and power of type 2 fibers by 8-12%, independent of the sex or age of the subject. Contrary to our hypothesis, the velocity at which the PRT was performed did not affect the fiber-level outcomes substantially. We conclude that, compared with low-velocity PRT, resistance training performed at velocities up to 3.5 times higher against reduced loads is equally effective for eliciting an adaptive response in type 2 fibers from human skeletal muscle.

Recombinant Human Leptin Treatment Does not Improve Insulin Action in Obese Subjects With Type 2 Diabetes

OBJECTIVE Leptin therapy improves insulin sensitivity in people with leptin deficiency, but it is not known whether it improves insulin action in people who are not leptin deficient. The purpose of the current study was to determine whether leptin treatment has weight loss–independent effects on insulin action in obese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS We conducted a randomized, placebo-controlled trial in obese subjects (BMI: 35.4 ± 0.6 kg/m2; mean ± SE) with newly diagnosed type 2 diabetes. Subjects were randomized to treatment with placebo (saline), low-dose (30 mg/day), or high-dose (80 mg/day) recombinant methionyl human (r-Met hu) leptin for 14 days. Multiorgan insulin sensitivity before and after treatment was evaluated by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled tracer infusions to measure glucose, glycerol, and fatty acid kinetics. RESULTS Low-dose and high-dose leptin treatment resulted in a threefold (P < 0.01) and 150-fold (P < 0.001) increase in basal plasma leptin concentrations, respectively. However, neither low-dose nor high-dose therapy had an effect on insulin-mediated suppression of glucose, glycerol, or palmitate rates of appearance into plasma compared with placebo. In addition, leptin treatment did not increase insulin-mediated stimulation of glucose disposal compared with placebo (14.3 ± 3.1, 18.4 ± 3.6, 16.7 ± 2.4 vs. 17.5 ± 2.5, 20.7 ± 3.0, 19.1 ± 3.3 μmol/kg body wt/min before vs. after treatment in the placebo, low-dose, and high-dose leptin groups, respectively). CONCLUSIONS r-Met hu leptin does not have weight loss–independent, clinically important effects on insulin sensitivity in obese people with type 2 diabetes.

Improved insulin sensitivity after weight loss and exercise training is mediated by a reduction in plasma fatty acid mobilization, not enhanced oxidative capacity

Obesity is characterized by excessive rates of plasma fatty acid mobilization and uptake, which play a key role in mediating insulin resistance. While weight loss via diet‐only or a diet + exercise program clearly improves insulin sensitivity, the precise mechanisms modulating this improvement are not completely understood. The purpose of the present study was to determine the role of the reduced fatty acid mobilization and uptake after weight loss in obese women who were randomly assigned to lifestyle interventions of either weight loss without exercise (WL) (n= 7) or a weight loss + exercise program (WL + EX) (n= 10). Before and after losing 12% of their body weight, we measured insulin sensitivity (SI), systemic fatty acid rate of appearance (Ra) and disappearance (Rd), oxidative capacity, and markers for pro‐inflammatory pathways in skeletal muscle. Fatty acid Ra and Rd were reduced by ∼30% after both interventions (P < 0.05). While oxidative capacity increased 25% in WL + EX (compared with no increase after WL), the improvement in SI was identical in both groups (∼60%; P < 0.05), and skeletal muscle pro‐inflammatory pathways were reduced (P < 0.05) similarly in both groups. When we artificially increased fatty acid mobilization after weight loss to pre‐weight‐loss levels via an overnight lipid infusion, the improvement in SI was almost completely reversed. Importantly, WL + EX did not protect against this lipid‐induced reversal in SI despite a significant increase in resting whole‐body fat oxidation and a marked increase in skeletal muscle oxidative capacity. In conclusion, reduced fatty acid mobilization and uptake appears to be a primary mediator of improved insulin sensitivity after weight loss. Moreover, enhancing fatty acid oxidative capacity via exercise training is not sufficient to prevent the insulin resistance caused by high fatty acid mobilization, such as that found in obesity.

Role of Growth Hormone in Regulating Lipolysis, Proteolysis, and Hepatic Glucose Production during Fasting

CONTEXT Fasting is associated with suppressed insulin and augmented GH secretion. The involvement of each mechanism in the regulation of fuel mobilization during fasting is unknown. OBJECTIVE To ascertain the role of GH in the regulation of the rates of lipolysis, proteolysis, and hepatic glucose production (HGP) during the physiological daily feed/fast cycle and after 2 d of complete fasting, we used a model of selective GH suppression by the administration of GHRH receptor antagonist (GHRH-A). DESIGN AND SETTING We conducted an open label in-patient study in the General Clinical Research Center at the University of Michigan. PARTICIPANTS Six healthy, nonobese volunteers participated. MAIN OUTCOME MEASURES We assessed 24-h plasma GH concentration and rates of lipolysis, proteolysis, and HGP using stable isotope techniques after an overnight fast and after 2 d of fasting. RESULTS GHRH-A suppressed plasma GH by about 65% during the fed state (P = 0.015) but did not alter the rates of lipolysis, proteolysis, or HGP. Fasting for 2 d suppressed plasma insulin concentration by about 80% and elevated plasma GH about 4-fold (both P < 0.01). This was accompanied by a doubling in the rate of lipolysis, an approximately 40% increase in proteolysis, and an approximately 30% decline in HGP (all P < 0.05). Preventing the fasting-induced increase in GH with GHRH-A largely abolished the increase in the rate of lipolysis. GHRH-A also augmented the fasting-induced reduction in HGP but did not alter proteolysis. CONCLUSIONS Endogenous GH plays a very limited metabolic role during the daily feed/fast cycle but is essential for the increased lipolytic rate found with more prolonged fasting.

Exercise-induced alterations in muscle lipid metabolism improve insulin sensitivity.

Exercise is a key component for the successful management of many obesity-related metabolic complications, including insulin resistance. This review addresses the effect of chronic and acute endurance exercise on insulin action in obesity and the role of exercise-induced alterations in fatty acid partitioning within the muscle cell on insulin sensitivity.

Regulation of plasma ceramide levels with fatty acid oversupply : evidence that the liver detects and secretes de novo synthesised ceramide

Aims/hypothesisPlasma ceramide concentrations correlate with insulin sensitivity, inflammation and atherosclerotic risk. We hypothesised that plasma ceramide concentrations are increased in the presence of elevated fatty acid levels and are regulated by increased liver serine C-palmitoyltransferase (SPT) activity.MethodsLean humans and rats underwent an acute lipid infusion and plasma ceramide levels were determined. One group of lipid-infused rats was administered myriocin to inhibit SPT activity. Liver SPT activity was determined in lipid-infused rats, and obese, insulin resistant mice. The time and palmitate dose-dependent synthesis of intracellular and secreted ceramide was determined in HepG2 liver cells.ResultsPlasma ceramide levels were increased during lipid infusion in humans and rats, and in obese, insulin-resistant mice. The increase in plasma ceramide was not associated with changes in liver SPT activity, and inhibiting SPT activity by ∼50% did not alter plasma ceramide levels in lipid-infused rats. In HepG2 liver cells, palmitate incorporation into extracellular ceramide was both dose- and time-dependent, suggesting the liver cells rapidly secreted the newly synthesised ceramide.Conclusions/interpretationElevated systemic fatty acid availability increased plasma ceramide but this was not associated with changes in hepatic SPT activity, suggesting that liver ceramide synthesis is driven by substrate availability rather than increased SPT activity. This report also provides evidence that the liver is sensitive to the intracellular ceramide concentration, and an increase in liver ceramide secretion may help protect the liver from the deleterious effects of intracellular ceramide accumulation.

Energy deficit after exercise augments lipid mobilization but does not contribute to the exercise-induced increase in insulin sensitivity

The content of meals consumed after exercise can impact metabolic responses for hours and even days after the exercise session. The purpose of this study was to compare the effect of low dietary carbohydrate (CHO) vs. low energy intake in meals after exercise on insulin sensitivity and lipid metabolism the next day. Nine healthy men participated in four randomized trials. During the control trial (CON) subjects remained sedentary. During the other three trials, subjects exercised [65% peak oxygen consumption (Vo(2 peak)); cycle ergometer and treadmill exercise] until they expended approximately 800 kcal. Dietary intake during CON and one exercise trial (BAL) was designed to provide sufficient energy and carbohydrate to maintain nutrient balance. In contrast, the diets after the other two exercise trials were low in either CHO (LOW-CHO) or energy (LOW-EN). The morning after exercise we obtained a muscle biopsy, assessed insulin sensitivity (S(i); intravenous glucose tolerance test) and measured lipid kinetics (isotope tracers). Although subjects were in energy balance during both LOW-CHO and CON, the lower muscle glycogen concentration during LOW-CHO vs. CON (402 +/- 29 vs. 540 +/- 33 mmol/kg dry wt, P < 0.01) coincided with a significant increase in S(i) [5.2 +/- 0.7 vs. 3.8 +/- 0.7 (mU/l)(-1) x min(-1); P < 0.05]. Conversely, despite ingesting several hundred fewer kilocalories after exercise during LOW-EN compared with BAL, this energy deficit did not affect S(i) the next day [4.9 +/- 0.9, and 5.0 +/- 0.8 (mU/l)(-1) x min(-1)]. Maintaining an energy deficit after exercise had the most potent effect on lipid metabolism, as measured by a higher plasma triacylglycerol concentration, and increased plasma fatty acid mobilization and oxidation compared with when in nutrient balance. Carbohydrate deficit after exercise, but not energy deficit, contributed to the insulin-sensitizing effects of acute aerobic exercise, whereas maintaining an energy deficit after exercise augmented lipid mobilization.