Abstract
We report here studies that integrate data of respiration rate from mouse skeletal muscle in response to leptin and pharmacological interference with intermediary metabolism, together with assays for phosphatidylinositol 3-kinase (PI3K) and AMP-activated protein kinase (AMPK). Our results suggest that the direct effect of leptin in stimulating thermogenesis in skeletal muscle is mediated by substrate cycling between de novo lipogenesis and lipid oxidation, and that this cycle requires both PI3K and AMPK signaling. This substrate cycling linking glucose and lipid metabolism to thermogenesis provides a novel thermogenic mechanism by which leptin protects skeletal muscle from excessive fat storage and lipotoxicity.
Highlights
Skeletal muscle, which accounts for 30–40% of body mass in mammals, is an important site for glucose disposal, lipid oxidation and thermogenesis whose impairments contribute to the pathogenesis of obesity and type 2 diabetes
Since leptin induces associations of phosphatidylinositol 3-kinase (PI3K) activity to PY residues and to insulin receptor substrate 1 (IRS1) and insulin receptor substrate 2 (IRS2) in muscle myotubes [12] and in skeletal muscle from mice injected with leptin [13], we investigate here whether an increase in PI3K association with these molecules correlates with the direct effect of leptin on muscle respiration rate (MO2)
Using in vitro kinase assays in ex vivo intact soleus muscles incubated with leptin, insulin or saline solution as control, we found that there is no induction of PY, IRS1, IRS2 and p85 associated PI3K activities in response to leptin, in contrast to what is observed in response to insulin (Fig. 1B)
Summary
Skeletal muscle, which accounts for 30–40% of body mass in mammals, is an important site for glucose disposal, lipid oxidation and thermogenesis whose impairments contribute to the pathogenesis of obesity and type 2 diabetes. The demonstrations that leptin can act directly on skeletal muscle, via the long form of the leptin receptor (ObRb), to stimulate glucose utilization [4], lipid oxidation through AMPactivated protein kinase (AMPK) [5,6] or thermogenesis in a phosphatidylinositol 3-kinase (PI3K)-dependent manner [7], have provided the impetus to investigate the mechanisms by which muscle substrate metabolism and thermogenesis are interdependent. The mechanism by which glucose and lipid metabolism are linked to thermogenesis in response to leptin’s direct effect on skeletal muscle is unknown. With the objective of elucidating the mechanisms by which leptin exerts its direct effect on skeletal muscle thermogenesis, we report here a study that integrates data of respiration rate from intact mouse skeletal muscle ex vivo in response to leptin and pharmacological interference with key control points of intermediary metabolism, together with biochemical measurements for PI3K and AMPK signaling
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