Contraction-induced skeletal muscle FAT/CD36 trafficking and FA uptake is AMPK independent

Jeppesen, Jacob; Albers, Peter H.; Rose, Adam J.; Birk, Jesper B.; Schjerling, Peter; Dzamko, Nicolas; Steinberg, Gregory R.; Kiens, Bente

doi:10.1194/jlr.m007138

Cited by 68 publications

(76 citation statements)

References 46 publications

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“…Prolonged light exposure decreased phosphorylation of CREB and AMPK, two main targets of β3-adrenergic signaling in the brown adipocyte. AMPK not only modulates intracellular lipolysis by phosphorylation of HSL, but also regulates uptake of lipids and glucose by inducing translocation of CD36, LPL, and GLUT4 to the plasma membrane (22,23), which may explain the reduced nutrient uptake by BAT. Moreover, we showed that in the absence of sympathetic input, BAT activity is equal among the various light-exposure groups.…”

Section: Discussionmentioning

confidence: 99%

Prolonged daily light exposure increases body fat mass through attenuation of brown adipose tissue activity

Kooijman¹,

Berg²,

Ramkisoensing

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

121

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Disruption of circadian rhythmicity is associated with obesity and related disorders, including type 2 diabetes and cardiovascular disease. Specifically, prolonged artificial light exposure associates with obesity in humans, although the underlying mechanism is unclear. Here, we report that increasing the daily hours of light exposure increases body adiposity through attenuation of brown adipose tissue (BAT) activity, a major contributor of energy expenditure. Mice exposed to a prolonged day length of 16-and 24-h light, compared with regular 12-h light, showed increased adiposity without affecting food intake or locomotor activity. Mechanistically, we demonstrated that prolonged day length decreases sympathetic input into BAT and reduces β3-adrenergic intracellular signaling. Concomitantly, prolonging day length decreased the uptake of fatty acids from triglyceride-rich lipoproteins, as well as of glucose from plasma selectively by BAT. We conclude that impaired BAT activity is an important mediator in the association between disturbed circadian rhythm and adiposity, and anticipate that activation of BAT may overcome the adverse metabolic consequences of disturbed circadian rhythmicity. M odern world society is subjected to disturbances of circadian rhythms by shift work, sleep deprivation, and environmental light pollution. Importantly, the increasing prevalence of obesity is associated with a disrupted sleep-wake pattern in humans (1) and coincides with the availability of artificial light (2, 3). Additionally, a recent study revealed a relationship between exposure to light at night and obesity in a cross-sectional analysis of over 100,000 women (4). Light input is the most important cue for generation of circadian (∼24 h) rhythms by the master clock. Both in rodents and humans the master clock is situated in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN is responsible for synchronization of peripheral clocks throughout the body, which is mediated by endocrine and neuronal signals (5). A causal role for a disturbed circadian rhythm in the development of obesity has been demonstrated by animal studies. Mice with genetically dysfunctional clock genes develop obesity and insulin resistance (6-9). Moreover, specific ablation of the SCN induces acute weight gain (10). These results indicate a crucial role for the SCN in the regulation of adiposity.Interestingly, we previously showed that prolonged light exposure only is sufficient to enhance weight gain in mice. Constant light disrupts the central circadian clock, evidenced by an immediate reduction in the circadian amplitude of SCN electrical activity. Moreover, constant light induces body weight gain and insulin resistance, even faster than high-fat diet, which was not caused by increased food intake or reduced locomotor activity (11). Therefore, disruption of the central biological clock likely induces weight gain by decreasing energy expenditure.Recently, it has been recognized that brown adipose tissue (BAT) importantly contributes to energy ...

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Section: Discussionmentioning

confidence: 99%

Prolonged daily light exposure increases body fat mass through attenuation of brown adipose tissue activity

Kooijman¹,

Berg²,

Ramkisoensing

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

121

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“…Lipid spots were visualized with iodine vapor, and incorporated radioactivity was measured by liquid scintillation counting. FA uptake was determined as the sum of FA oxidation and incorporation, similar to methods described previously (17,20,30).…”

Section: Methodsmentioning

confidence: 99%

Myocardial ATGL Overexpression Decreases the Reliance on Fatty Acid Oxidation and Protects against Pressure Overload-Induced Cardiac Dysfunction

Kienesberger

Pulinilkunnil

Sung

et al. 2012

Molecular and Cellular Biology

100

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Alterations in myocardial triacylglycerol content have been associated with poor left ventricular function, suggesting that enzymes involved in myocardial triacylglycerol metabolism play an important role in regulating contractile function. Myocardial triacylglycerol catabolism is mediated by adipose triglyceride lipase (ATGL), which is rate limiting for triacylglycerol hydrolysis. To address the influence of triacylglycerol hydrolysis on myocardial energy metabolism and function, we utilized mice with cardiomyocyte-specific ATGL overexpression (MHC-ATGL). Biochemical examination of MHC-ATGL hearts revealed chronically reduced myocardial triacylglycerol content but unchanged levels of long-chain acyl coenzyme A esters, ceramides, and diacylglycerols. Surprisingly, fatty acid oxidation rates were decreased in ex vivo perfused working hearts from MHC-ATGL mice, which was compensated by increased rates of glucose oxidation. Interestingly, reduced myocardial triacylglycerol content was associated with moderately enhanced in vivo systolic function in MHC-ATGL mice and increased isoproterenol-induced cell shortening of isolated primary cardiomyocytes. Most importantly, MHC-ATGL mice were protected from pressure overloadinduced systolic dysfunction and detrimental structural remodeling following transverse aortic constriction. Overall, this study shows that ATGL overexpression is sufficient to alter myocardial energy metabolism and improve cardiac function. Myocardial triacylglycerol (TG) is stored in cytosolic lipid droplets within cardiomyocytes and constitutes a critical fatty acid (FA) and energy reserve for the heart. Metabolism of cardiac TG is highly dynamic (2, 29), which likely evolved as a means to ensure continuous FA supply for mitochondrial oxidation independent of short-term fluctuations in plasma FA availability. Previous studies have shown that FAs released by intracellular TG hydrolysis contribute significantly to the generation of ATP necessary for contractile function (2, 34, 39), suggesting that TG hydrolysis plays a critical role in regulating cardiac function. In agreement with this finding, dysregulation of myocardial TG metabolism and either increased or reduced TG content have been associated with cardiac dysfunction and/or heart failure induced by obesity, diabetes, aging, ischemia, and hemodynamic pressure overload (3,5,8,22,26,(31)(32)(33)(34). Moreover, a clear correlation between increased myocardial TG content and decreased cardiac function has been established in rodents and humans (7,12,22,24), supporting the concept that excessive TG accumulation in the heart is detrimental. On the other hand, it has also been postulated that increasing TG content and sequestration of potentially lipotoxic FA metabolites in the myocardial TG pool can be beneficial for heart function (28, 42). As such, the physiological consequences of preventing myocardial TG accumulation with regard to normal physiology and disease remain to be elucidated.As the enzymes that control TG lipolysis may have an as yet und...

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“…Isolated SOL muscles were incubated at 30°C in Krebs-Henseleit-Ringer buffer, pH 7.4, containing 2 mmol/L pyruvate, 2% FA-free BSA, and 0.5 mmol/L palmitic acid. After incubation at resting tension (4-5 mN) for 20 min, the incubation buffer was refreshed and supplemented with 0.5 mCi/mL [1- C] palmitate, as previously described (31). The incorporation of exogenous FAs into DAG and intracellular TAG was measured by thin-layer chromatography (TLC), as described below.…”

Section: Fa Oxidationmentioning

confidence: 99%

Partial Disruption of Lipolysis Increases Postexercise Insulin Sensitivity in Skeletal Muscle Despite Accumulation of DAG

et al. 2016

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Type 2 diabetes and skeletal muscle insulin resistance have been linked to accumulation of the intramyocellular lipid-intermediate diacylglycerol (DAG). However, recent animal and human studies have questioned such an association. Given that DAG appears in different stereoisomers and has different reactivity in vitro, we investigated whether the described function of DAGs as mediators of lipid-induced insulin resistance was dependent on the different DAG isomers. We measured insulin-stimulated glucose uptake in hormone-sensitive lipase (HSL) knockout (KO) mice after treadmill exercise to stimulate the accumulation of DAGs in skeletal muscle. We found that, despite an increased DAG content in muscle after exercise in HSL KO mice, the HSL KO mice showed a higher insulin-stimulated glucose uptake postexercise compared with wild-type mice. Further analysis of the chemical structure and cellular localization of DAG in skeletal muscle revealed that HSL KO mice accumulated sn-1,3 DAG and not sn-1,2 DAG. Accordingly, these results highlight the importance of taking the chemical structure and cellular localization of DAG into account when evaluating the role of DAG in lipid-induced insulin resistance in skeletal muscle and that the accumulation of sn-1,3 DAG originating from lipolysis does not inhibit insulin-stimulated glucose uptake.

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Contraction-induced skeletal muscle FAT/CD36 trafficking and FA uptake is AMPK independent

Cited by 68 publications

References 46 publications

Prolonged daily light exposure increases body fat mass through attenuation of brown adipose tissue activity

Prolonged daily light exposure increases body fat mass through attenuation of brown adipose tissue activity

Myocardial ATGL Overexpression Decreases the Reliance on Fatty Acid Oxidation and Protects against Pressure Overload-Induced Cardiac Dysfunction

Partial Disruption of Lipolysis Increases Postexercise Insulin Sensitivity in Skeletal Muscle Despite Accumulation of DAG

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