Intramuscular triglyceride synthesis: importance in muscle lipid partitioning in humans

Abstract

Intramuscular triglyceride (IMTG) concentration is elevated in insulin-resistant individuals and was once thought to promote insulin resistance. However, endurance-trained athletes have equivalent concentration of IMTG compared with individuals with type 2 diabetes, and have very low risk of diabetes, termed the "athlete's paradox." We now know that IMTG synthesis is positively related to insulin sensitivity, but the exact mechanisms for this are unclear. To understand the relationship between IMTG synthesis and insulin sensitivity, we measured IMTG synthesis in obese control subjects, endurance-trained athletes, and individuals with type 2 diabetes during rest, exercise, and recovery. IMTG synthesis rates were positively related to insulin sensitivity, cytosolic accumulation of DAG, and decreased accumulation of C18:0 ceramide and glucosylceramide. Greater rates of IMTG synthesis in athletes were not explained by alterations in FFA concentration, DGAT1 mRNA expression, or protein content. IMTG synthesis during exercise in Ob and T2D indicate utilization as a fuel despite unchanged content, whereas IMTG concentration decreased during exercise in athletes. mRNA expression for genes involved in lipid desaturation and IMTG synthesis were increased after exercise and recovery. Further, in a subset of individuals, exercise decreased cytosolic and membrane di-saturated DAG content, which may help explain insulin sensitization after acute exercise. These data suggest IMTG synthesis rates may influence insulin sensitivity by altering intracellular lipid localization, and decreasing specific ceramide species that promote insulin resistance.

Keywords: IMCL; intramyocellular triglyceride; sphingolipid.

Fig. 1.

Oxygen consumption (A), respiratory exchange ratio (B), carbohydrate oxidation (C), and fat oxidation (D) during rest, exercise, and recovery in obese volunteers, individuals with type 2 diabetes, and endurance-trained athletes. *Significantly different from T2D, P < 0.05; §significantly different from obese, P < 0.05; ¥significantly different from rest, P < 0.05. Values are means ± SE.

Fig. 2.

Plasma glucose enrichment (A), glucose rate of appearance (Ra) (B), palmitate enrichment (C), and palmitate rate of appearance (Ra) (D) during rest, exercise, and recovery in obese volunteers, individuals with type 2 diabetes, and endurance-trained athletes. *Significantly different from T2D, P < 0.05; §significantly different from obese, P < 0.05; ¥significantly different from rest, P < 0.05. Values are means ± SE.

Fig. 3.

IMTG concentration (A), fractional synthesis rate (B), relationship between IMTG FSR and insulin sensitivity (C), and percentage of whole body palmitate turnover trafficked into IMTG (D) during rest, exercise, and recovery in obese volunteers, individuals with type 2 diabetes, and endurance-trained athletes. The relationship between IMTG synthesis rate and C18:0 ceramide content (E), C18:0 glucosylceramide content (F), and cytosolic DAG content (G) are also shown. #Significantly different from athletes, P < 0.05; *significantly different from T2D, P < 0.05; §significantly different from obese, P < 0.05; ¥significantly different from rest, P < 0.05. Values are means ± SE.

Fig. 3.

IMTG concentration (A), fractional synthesis rate (B), relationship between IMTG FSR and insulin sensitivity (C), and percentage of whole body palmitate turnover trafficked into IMTG (D) during rest, exercise, and recovery in obese volunteers, individuals with type 2 diabetes, and endurance-trained athletes. The relationship between IMTG synthesis rate and C18:0 ceramide content (E), C18:0 glucosylceramide content (F), and cytosolic DAG content (G) are also shown. #Significantly different from athletes, P < 0.05; *significantly different from T2D, P < 0.05; §significantly different from obese, P < 0.05; ¥significantly different from rest, P < 0.05. Values are means ± SE.

Fig. 4.

Gene transcription of transcription factors, proteins associated with the lipid droplet, and enzymes involved in lipid desaturation, oxidation, transport, and IMTG degradation and synthesis. mRNA expression is reported relative to the obese control group, which was set to a value of 1. Data are shown for each group at rest (A), and in all groups combined during the change from rest to exercise (B), and rest to recovery (C). #Significantly different from athletes, P < 0.05; *significantly different from T2D, P < 0.05; §significantly different from obese, P < 0.05; ¥significantly different from rest, P < 0.05. Values are means ± SE. PPARD, peroxisome proliferator-activated receptor delta; PPARA, peroxisome proliferator-activated receptor alpha; NRF1, nuclear respiratory receptor 1; PGC1A, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PLIN5, perilipin 5; PLIN2, perilipin 2; ELOVL5, ELOVL Fatty Acid Elongase 5; SCD5, stearoyl-CoA desaturase 5; SCD, stearoyl-CoA desaturase; CPT2, carnitine palmitoyl transferase 2, CPT1A, carnitine palmitoyl transferase 1a, CS, citrate synthase, SLC27A1, fatty acid transport protein 1, CD36, cluster of differentiation 36, FABP4, fatty acid binding protein 4, LIPE, hormone-sensitive lipase, PNPLA2, Patatin-like phospholipase domain containing 2, a.k.a. adipose triglyceride lipase; DGAT2, diacylglycerol acyltransferase 2; DGAT1, diacylglycerol acyltransferase 1; PPAP2A, phosphatidic acid phosphatase type 2A; Lipin 2; Lipin 1; AGPAT, 1-acylglycerol-3-phosphate O-acyltransferase; GPAT, glycerol-3-phosphate acyltransferase.

Fig. 4.

Gene transcription of transcription factors, proteins associated with the lipid droplet, and enzymes involved in lipid desaturation, oxidation, transport, and IMTG degradation and synthesis. mRNA expression is reported relative to the obese control group, which was set to a value of 1. Data are shown for each group at rest (A), and in all groups combined during the change from rest to exercise (B), and rest to recovery (C). #Significantly different from athletes, P < 0.05; *significantly different from T2D, P < 0.05; §significantly different from obese, P < 0.05; ¥significantly different from rest, P < 0.05. Values are means ± SE. PPARD, peroxisome proliferator-activated receptor delta; PPARA, peroxisome proliferator-activated receptor alpha; NRF1, nuclear respiratory receptor 1; PGC1A, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PLIN5, perilipin 5; PLIN2, perilipin 2; ELOVL5, ELOVL Fatty Acid Elongase 5; SCD5, stearoyl-CoA desaturase 5; SCD, stearoyl-CoA desaturase; CPT2, carnitine palmitoyl transferase 2, CPT1A, carnitine palmitoyl transferase 1a, CS, citrate synthase, SLC27A1, fatty acid transport protein 1, CD36, cluster of differentiation 36, FABP4, fatty acid binding protein 4, LIPE, hormone-sensitive lipase, PNPLA2, Patatin-like phospholipase domain containing 2, a.k.a. adipose triglyceride lipase; DGAT2, diacylglycerol acyltransferase 2; DGAT1, diacylglycerol acyltransferase 1; PPAP2A, phosphatidic acid phosphatase type 2A; Lipin 2; Lipin 1; AGPAT, 1-acylglycerol-3-phosphate O-acyltransferase; GPAT, glycerol-3-phosphate acyltransferase.

Fig. 5.

Skeletal muscle protein content and phosphorylation for SCD1 (A), HSL^ser660 phosphorylation (B), ATGL (C), and ATGL/HSL^ser660 phosphorylation (D) during rest, exercise, and recovery in obese volunteers, individuals with type 2 diabetes, and endurance-trained athletes. *Significantly different from T2D, P < 0.05, §significantly different from obese, P < 0.05, ¥significantly different from rest, P < 0.05. Values are means ± SE.