Metformin promotes induction of lipoprotein lipase in skeletal muscle through activation of adenosine monophosphate–activated protein kinase

Ohira, Masahiro; Miyashita, Yoh; Murano, Takeyoshi; Watanabe, Fusako; Shirai, Kohji

doi:10.1016/j.metabol.2009.04.024

Cited by 24 publications

(20 citation statements)

References 22 publications

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“…To date, a few reports have shown that AMPK regulated LPL expression in cultured skeletal muscle cell lines (17,18). These findings were consistent with the observation that exercise training induced increased muscle LPL expression (23).…”

supporting

confidence: 83%

Role of AMPK and PPARγ1 in exercise-induced lipoprotein lipase in skeletal muscle

Sasaki

Nakata

Inoue

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Exercise can effectively ameliorate type 2 diabetes and insulin resistance. Here we show that the mRNA levels of one of peroxisome proliferatoractivated receptor (PPAR) family members, PPAR␥1, and genes related to energy metabolism, including PPAR␥ coactivator-1 protein-1␣ (PGC-1␣) and lipoprotein lipase (LPL), increased in the gastrocnemius muscle of habitual exercise-trained mice. When mice were intraperitoneally administered an AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), the mRNA levels of the aforementioned three genes increased in gastrocnemius muscle. AICAR treatment to C2C12 differentiated myotubes also increased PPAR␥1 mRNA levels, but not PPAR␣ and -␦ mRNA levels, concomitant with increased PGC-1␣ mRNA levels. An AMPK inhibitor, compound C, blocked these AICAR effects. AICAR treatment increased the half-life of PPAR␥1 mRNA nearly threefold (4 -12 h) by activating AMPK. When C 2C12 myoblast cells infected with a PPAR␥1 expression lentivirus were differentiated into myotubes, PPAR␥1 overexpression dramatically increased LPL mRNA levels more than 40-fold. In contrast, when PPAR␥1 expression was suppressed in C2C12 myotubes, LPL mRNA levels were significantly reduced, and the effect of AICAR on increased LPL gene expression was almost completely blocked. These results indicated that PPAR␥1 was intimately involved in LPL gene expression in skeletal muscle and the AMPK-PPAR␥1 pathway may play a role in exercise-induced LPL expression. Thus, we identified a novel critical role for PPAR␥1 in response to AMPK activation for controlling the expression of a subset of genes associated with metabolic regulation in skeletal muscle.AMP-activated protein kinase; peroxisome proliferator-activated receptor-␥1; lipoprotein lipase; C2C12 cells; exercise PHYSICAL EXERCISE HAS BENEFICIAL EFFECTS on general health and results in increased catabolism of glucose and fatty acids as energy sources in skeletal muscle. AMPK and its related cellular signaling pathways are thought to play a critical role in exercise-mediated adaptations in the muscle (19). AMPK is an evolutionarily conserved heterotrimer that consists of ␣-catalytic and ␤-and ␥-regulatory subunits and is a regulator of energy homeostasis. AMPK is activated by an increased AMP: ATP ratio associated with ATP consumption during exercise (3, 30). Activated AMPK drives several energy production systems, including glucose uptake, fatty acid oxidation, and mitochondria biogenesis, to maintain energy balance. Because of these beneficial activities, AMPK is considered to be a target for preventing type 2 diabetes.The capacity of muscle to catabolize fatty acids is determined at the transcriptional level for genes involved in fatty acid uptake and catabolism. PPAR␣ and -␦, members of the nuclear receptor superfamily, control the transcription of these genes in the muscle (32). PPAR␣ induces the expression of genes involved in the numerous steps of fatty acid uptake and oxidation in muscle; these genes are shared with PPA...

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supporting

confidence: 83%

Role of AMPK and PPARγ1 in exercise-induced lipoprotein lipase in skeletal muscle

Sasaki

Nakata

Inoue

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Moreover, AMPK activation by AICAR and metformin increased intralipid clearance and increased heparin-releasable LPL activity in rat hearts without causing any change in LPL mRNA (31,32). Furthermore, AICAR and metformin enhanced LPL activity in rat L6 muscle cells (33). These findings suggest a role of LPL in the lowering of plasma TG by AMPK.…”

Section: Discussionmentioning

confidence: 74%

Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise

Catoire

Alex

Paraskevopulos

et al. 2014

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

123

165

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Physical activity increases energy metabolism in exercising muscle. Whether acute exercise elicits metabolic changes in nonexercising muscles remains unclear. We show that one of the few genes that is more highly induced in nonexercising muscle than in exercising human muscle during acute exercise encodes angiopoietin-like 4 (ANGPTL4), an inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. Using a combination of human, animal, and in vitro data, we show that induction of ANGPTL4 in nonexercising muscle is mediated by elevated plasma free fatty acids via peroxisome proliferator-activated receptor-δ, presumably leading to reduced local uptake of plasma triglyceride-derived fatty acids and their sparing for use by exercising muscle. In contrast, the induction of ANGPTL4 in exercising muscle likely is counteracted via AMP-activated protein kinase (AMPK)-mediated down-regulation, promoting the use of plasma triglycerides as fuel for active muscles. Our data suggest that nonexercising muscle and the local regulation of ANGPTL4 via AMPK and free fatty acids have key roles in governing lipid homeostasis during exercise.

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“…At the beginning of tracer infusion, plasma free palmitate was the only source of tracer entering the IM precursor pool. Thereafter, plasma TG-bound palmitate enrichment increased gradually, which also contributed labeled palmitate to the IM precursor pool through the action of lipoprotein lipase ( 22,23 ). Thus, it was proper to calculate the mean precursor enrichment over the 3 h infusion period.…”

Section: Discussionmentioning

confidence: 99%

Measurement of precursor enrichment for calculating intramuscular triglyceride fractional synthetic rate

Zhang

Rodriguez

Wang

et al. 2012

Journal of Lipid Research

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Metformin promotes induction of lipoprotein lipase in skeletal muscle through activation of adenosine monophosphate–activated protein kinase

Cited by 24 publications

References 22 publications

Role of AMPK and PPARγ1 in exercise-induced lipoprotein lipase in skeletal muscle

Role of AMPK and PPARγ1 in exercise-induced lipoprotein lipase in skeletal muscle

Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise

Measurement of precursor enrichment for calculating intramuscular triglyceride fractional synthetic rate

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