Serum sex hormone-binding globulin levels are reduced and inversely associated with intrahepatic lipid content and saturated fatty acid fraction in adult patients with glycogen storage disease type 1a.

PURPOSE: De novo lipogenesis has been inversely associated with serum sex hormone-binding globulin (SHBG) levels. However, the directionality of this association has remained uncertain. We, therefore, studied individuals with glycogen storage disease type 1a (GSD1a), who are characterized by a genetic defect in glucose-6-phosphatase resulting in increased rates of de novo lipogenesis, to assess the downstream effect on serum SHBG levels. METHODS: A case-control study comparing serum SHBG levels in patients with GSD1a (n = 10) and controls matched for age, sex, and BMI (n = 10). Intrahepatic lipid content and saturated fatty acid fraction were quantified by proton magnetic resonance spectroscopy. RESULTS: Serum SHBG levels were statistically significantly lower in patients with GSD1a compared to the controls (p = 0.041), while intrahepatic lipid content and intrahepatic saturated fatty acid fraction-a marker of de novo lipogenesis-were significantly higher in patients with GSD1a (p = 0.001 and p = 0.019, respectively). In addition, there was a statistically significant, inverse association of intrahepatic lipid content and saturated fatty acid fraction with serum SHBG levels in patients and controls combined (ß: - 0.28, 95% CI: - 0.47;- 0.09 and ß: - 0.02, 95% CI: - 0.04;- 0.01, respectively). CONCLUSION: Patients with GSD1a, who are characterized by genetically determined higher rates of de novo lipogenesis, have lower serum SHBG levels than controls.

Impact of aging and exercise on skeletal muscle mitochondrial capacity, energy metabolism, and physical function.

The relationship between the age-associated decline in mitochondrial function and its effect on skeletal muscle physiology and function remain unclear. In the current study, we examined to what extent physical activity contributes to the decline in mitochondrial function and muscle health during aging and compared mitochondrial function in young and older adults, with similar habitual physical activity levels. We also studied exercise-trained older adults and physically impaired older adults. Aging was associated with a decline in mitochondrial capacity, exercise capacity and efficiency, gait stability, muscle function, and insulin sensitivity, even when maintaining an adequate daily physical activity level. Our data also suggest that a further increase in physical activity level, achieved through regular exercise training, can largely negate the effects of aging. Finally, mitochondrial capacity correlated with exercise efficiency and insulin sensitivity. Together, our data support a link between mitochondrial function and age-associated deterioration of skeletal muscle.

NAD+-Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults.

BACKGROUND: Boosting NAD+ via supplementation with niacin equivalents has been proposed as a potential modality capable of promoting healthy aging and negating age-dependent declines of skeletal muscle mass and function. OBJECTIVES: We investigated the efficacy of NAD+-precursor supplementation (tryptophan, nicotinic acid, and nicotinamide) on skeletal muscle mitochondrial function in physically compromised older adults. METHODS: A randomized, double-blind, controlled trial was conducted in 14 (female/male: 4/10) community-dwelling, older adults with impaired physical function [age, 72.9 ± 4.0 years; BMI, 25.2 ± 2.3 kg/m2]. Participants were supplemented with 207.5 mg niacin equivalents/day [intervention (INT)] and a control product (CON) that did not contain niacin equivalents, each for 32 days. The primary outcomes tested were mitochondrial oxidative capacity and exercise efficiency, analyzed by means of paired Student's t-tests. Secondary outcomes, such as NAD+ concentrations, were analyzed accordingly. RESULTS: Following supplementation, skeletal muscle NAD+ concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD+-precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD+ metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD+-precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. CONCLUSIONS: Our findings are consistent with previous findings on NAD+ efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD+-precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034.

Acute exercise does not decrease liver fat in men with overweight or NAFLD.

Elevated hepatic lipid content (IntraHepatic Lipid, IHL) increases the risk of metabolic complications. Although prolonged exercise training lowers IHL, it is unknown if acute exercise has the same effect. Furthermore, hepatic ATP content may be related to insulin resistance and IHL. We aimed to investigate if acute exercise leads to changes in IHL and whether this is accompanied by changes in hepatic ATP. Twenty-one men (age 54.8 ± 7.2 years, BMI 29.7 ± 2.2 kg/m(2)) performed a 2 h cycling protocol, once while staying fasted and once while ingesting glucose. IHL was determined at baseline, 30 min post-exercise and 4 h post-exercise. Additionally ATP/Total P ratio was measured at baseline and 4 h post-exercise. Compared with baseline values we did not observe any statistically significant changes in IHL within 30 min post-exercise in neither the fasted nor the glucose-supplemented condition. However, IHL was elevated 4 h post-exercise compared with baseline in the fasted condition (from 8.3 ± 1.8 to 8.7 ± 1.8%, p = 0.010), an effect that was blunted by glucose supplementation (from 8.3 ± 1.9 to 8.3 ± 1.9%, p = 0.789). Acute exercise does not decrease liver fat in overweight middle-aged men. Moreover, IHL increased 4 h post-exercise in the fasted condition, an increase that was absent in the glucose-supplemented condition. These data suggest that a single bout of exercise may not be able to lower IHL.

Lipotoxicity and the role of maternal nutrition.

Intrauterine malnutrition predisposes the offspring towards the development of type 2 diabetes and cardiovascular disease. To explain this association, the Developmental Origins of Health and Disease hypothesis was introduced, meaning that subtle environmental changes during embryonic and foetal development can influence post-natal physiological functions. Different mechanisms, including epigenetics, are thought to be involved in this foetal programming, but the link between epigenetics and disease is missing. There is increasing evidence that ectopic lipid accumulation and/or lipotoxicity is induced by foetal programming. The aim of this review is to provide insights into the mechanisms underlying lipotoxicity through programming, which contributes to the increase in hepatic and cardiac metabolic risk.

Exercise-induced modulation of cardiac lipid content in healthy lean young men.

Cardiac lipid accumulation is associated with decreased cardiac function and energy status (PCr/ATP). It has been suggested that elevated plasma fatty acid (FA) concentrations are responsible for the cardiac lipid accumulation. Therefore, the aim of the present study was to investigate if elevating plasma FA concentrations by exercise results in an increased cardiac lipid content, and if this influences cardiac function and energy status. Eleven male subjects (age 25.4 ± 1.1 years, BMI 23.6 ± 0.8 kg/m²) performed a 2-h cycling protocol, once while staying fasted and once while ingesting glucose, to create a state of high versus low plasma FA concentrations, respectively. Cardiac lipid content was measured by proton magnetic resonance spectroscopy (¹H-MRS) at baseline, directly after exercise and again 4 h post-exercise, together with systolic function (by multi-slice cine-MRI) and cardiac energy status (by ³¹P-MRS). Plasma FA concentrations were increased threefold during exercise and ninefold during recovery in the fasted state compared with the glucose-fed state (p < 0.01). Cardiac lipid content was elevated at the end of the fasted test day (from 0.26 ± 0.04 to 0.44 ± 0.04%, p = 0.003), while it did not change with glucose supplementation (from 0.32 ± 0.03 to 0.26 ± 0.05%, p = 0.272). Furthermore, PCr/ATP was decreased by 32% in the high plasma FA state compared with the low FA state (n = 6, p = 0.014). However, in the high FA state, the ejection fraction 4 h post-exercise was higher compared with the low FA state (63 ± 2 vs. 59 ± 2%, p = 0.018). Elevated plasma FA concentrations, induced by exercise in the fasted state, lead to increased cardiac lipid content, but do not acutely hamper systolic function. Although the lower cardiac energy status is in line with a lipotoxic action of cardiac lipid content, a causal relationship cannot be proven.

Lipid accumulation in non-adipose tissue and lipotoxicity.

Obesity is a well-known risk factor for the development of type 2 diabetes mellitus and cardiovascular disease. Importantly, obesity is not only associated with lipid accumulation in adipose tissue, but also in non-adipose tissues. The latter is also known as ectopic lipid accumulation and may be a possible link between obesity and its comorbidities such as insulin resistance, type 2 diabetes mellitus and cardiovascular disease. In skeletal muscle and liver, lipid accumulation has been associated with the development of insulin resistance, an early hallmark of developing type 2 diabetes mellitus. More specifically, accumulation of intermediates of lipid metabolism, such as diacylglycerol (DAG) and Acyl-CoA have been shown to interfere with insulin signaling in these tissues. Initially, muscular and hepatic insulin resistance can be overcome by an increased insulin production by the pancreas, resulting in hyperinsulinemia. However, during the progression towards overt type 2 diabetes, pancreatic failure occurs resulting in reduced insulin production. Interestingly, also in the pancreas lipid accumulation has been shown to precede dysfunction. Finally, accumulation of fat in the heart has been associated with cardiac dysfunction and heart failure, which may be an explanation for diabetic cardiomyopathy. Taken together, we conclude that evidence for deleterious effects of lipid accumulation in non-adipose tissue (lipotoxicity) is strong. However, while ample human data is available for skeletal muscle and the liver, future research should focus on lipid accumulation in the pancreas and the heart.

Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients with type 2 diabetes mellitus and BMI-matched control subjects.

AIMS/HYPOTHESIS: Mitochondrial dysfunction and increased intramyocellular lipid (IMCL) content have both been implicated in the development of insulin resistance and type 2 diabetes mellitus, but the relative contributions of these two factors in the aetiology of diabetes are unknown. As obesity is an independent determinant of IMCL content, we examined mitochondrial function and IMCL content in overweight type 2 diabetes patients and BMI-matched normoglycaemic controls. METHODS: In 12 overweight type 2 diabetes patients and nine controls with similar BMI (29.4 +/- 1 and 29.3 +/- 0.9 kg/m(2) respectively) in vivo mitochondrial function was determined by measuring phosphocreatine recovery half-time (PCr half-time) immediately after exercise, using phosphorus-31 magnetic resonance spectroscopy. IMCL content was determined by proton magnetic resonance spectroscopic imaging and insulin sensitivity was measured with a hyperinsulinaemic-euglycaemic clamp. RESULTS: The PCr half-time was 45% longer in diabetic patients compared with controls (27.3 +/- 3.5 vs 18.7 +/- 0.9 s, p < 0.05), whereas IMCL content was similar (1.37 +/- 0.30 vs 1.25 +/- 0.22% of the water resonance), and insulin sensitivity was reduced in type 2 diabetes patients (26.0 +/- 2.2 vs 18.9 +/- 2.3 mumol min(-1) kg(-1), p < 0.05 [all mean +/- SEM]). PCr half-time correlated positively with fasting plasma glucose (r (2) = 0.42, p < 0.01) and HbA(1c) (r (2) = 0.48, p < 0.05) in diabetic patients. CONCLUSIONS/INTERPRETATION: The finding that in vivo mitochondrial function is decreased in type 2 diabetes patients compared with controls whereas IMCL content is similar suggests that low mitochondrial function is more strongly associated with insulin resistance and type 2 diabetes than a high IMCL content per se. Whether low mitochondrial function is a cause or consequence of the disease remains to be investigated.

Short-term training is accompanied by a down regulation of ACC2 mRNA in skeletal muscle.

Recently, we showed that short-term training induced a rapid increase in IMCL whilst insulin sensitivity tended to improve. Here we investigate molecular adaptations accompanying this physiological training-induced accumulation of IMCL. Nine untrained men (age: 23.3 +/- 3.2 y; maximal power output: 3.8 +/- 0.6 W/kg body weight) trained for two weeks. Before and after training, subjects cycled for three hours and biopsies were taken before and after exercise. mRNA concentrations of ACC2, HSL, LPL, Glut4 and HKII were quantified by RT-PCR and association of Glut4 with the membrane was quantified by immunohistochemical method. Endurance training resulted in a decrease of 29.1 % in ACC2 mRNA (p = 0.02). After training, ACC2 mRNA tended to decrease with acute exercise (- 24.4 % [p = 0.06]). HSL mRNA decreased with acute exercise after training (- 37.3 % [p = 0.002]). LPL mRNA concentrations increased with acute exercise before training (+ 42.4 % [p = 0.05]) and HKII mRNA increased with acute exercise before (+ 72.5 % [p = 0.025]) and after training (+ 99.3 % [p = 0.05]). After acute exercise, more Glut4 was associated with the membrane than before exercise, but it was not affected by training. We conclude that the training-induced increase in IMCL was accompanied by molecular adaptations in muscle to improve fat oxidative capacity, while markers of glucose metabolism were not yet changed. The present data are in line with the hypothesis that the fat oxidative capacity might be more important than the IMCL content in determining insulin sensitivity.

Intramyocellular lipid content is increased after exercise in nonexercising human skeletal muscle.

Intramyocellular lipid (IMCL) content has been reported to decrease after prolonged submaximal exercise in active muscle and, therefore, seems to form an important local substrate source. Because exercise leads to a substantial increase in plasma free fatty acid (FFA) availability with a concomitant increase in FFA uptake by muscle tissue, we aimed to investigate potential differences in the net changes in IMCL content between contracting and noncontracting skeletal muscle after prolonged endurance exercise. IMCL content was quantified by magnetic resonance spectroscopy in eight trained cyclists before and after a 3-h cycling protocol (55% maximal energy output) in the exercising vastus lateralis and the nonexercising biceps brachii muscle. Blood samples were taken before and after exercise to determine plasma FFA, glycerol, and triglyceride concentrations, and substrate oxidation was measured with indirect calorimetry. Prolonged endurance exercise resulted in a 20.4 +/- 2.8% (P < 0.001) decrease in IMCL content in the vastus lateralis muscle. In contrast, we observed a substantial (37.9 +/- 9.7%; P < 0.01) increase in IMCL content in the less active biceps brachii muscle. Plasma FFA and glycerol concentrations were substantially increased after exercise (from 85 +/- 6 to 1450 +/- 55 and 57 +/- 11 to 474 +/- 54 microM, respectively; P < 0.001), whereas plasma triglyceride concentrations were decreased (from 1498 +/- 39 to 703 +/- 7 microM; P < 0.001). IMCL is an important substrate source during prolonged moderate-intensity exercise and is substantially decreased in the active vastus lateralis muscle. However, prolonged endurance exercise with its concomitant increase in plasma FFA concentration results in a net increase in IMCL content in less active muscle.

The increase in intramyocellular lipid content is a very early response to training.

The present study investigated the influences of a 2-wk training program on intramyocellular lipid (IMCL) content, IMCL decrease during exercise, fat oxidation, and insulin sensitivity. Nine untrained men (age, 23.3 +/- 3.2 yr; body mass index, 22.6 +/- 2.6 kg/m(2); maximal power output, 3.8 +/- 0.6 W/kg body weight) trained for 2 wk. Before and after training, subjects cycled for 3 h while substrate oxidation was measured. IMCL content in the vastus lateralis muscle was determined before and after cycling by proton magnetic resonance spectroscopy. Before and after training, insulin sensitivity was assessed by an insulin tolerance test. The training period resulted in a significant increase in IMCL content by 42 +/- 14%. IMCL content decreased significantly during cycling. However, 2 wk of training were not sufficient to achieve increases in fat oxidation and/or use of IMCL during exercise. All markers used to test insulin sensitivity point toward improved insulin sensitivity, albeit not significant. We conclude that the increase in IMCL content is a very early response to training, preceding significant changes in insulin sensitivity. The results suggest that the presence of triglycerides alone does not necessarily have detrimental effects on insulin sensitivity. We confirm earlier reports that IMCL contributes to the energy used during prolonged submaximal exercise.