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Skeletal muscle-specific deletion of lipoprotein lipase enhances insulin signaling in skeletal muscle but causes insulin resistance in liver and other tissues.

Wang H, Knaub LA, Jensen DR, Young Jung D, Hong EG, Ko HJ, Coates AM, Goldberg IJ, de la Houssaye BA, Janssen RC, McCurdy CE, Rahman SM, Soo Choi C, Shulman GI, Kim JK, Friedman JE, Eckel RH - Diabetes (2008)

Bottom Line: High-fat diet feeding accelerated the development of obesity.LPL deletion in skeletal muscle reduces lipid storage and increases insulin signaling in skeletal muscle without changes in body composition.Moreover, lack of LPL in skeletal muscle results in insulin resistance in other key metabolic tissues and ultimately leads to obesity and systemic insulin resistance.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA.

ABSTRACT

Objective: Skeletal muscle-specific LPL knockout mouse (SMLPL(-/-)) were created to study the systemic impact of reduced lipoprotein lipid delivery in skeletal muscle on insulin sensitivity, body weight, and composition.

Research design and methods: Tissue-specific insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp and 2-deoxyglucose uptake. Gene expression and insulin-signaling molecules were compared in skeletal muscle and liver of SMLPL(-/-) and control mice.

Results: Nine-week-old SMLPL(-/-) mice showed no differences in body weight, fat mass, or whole-body insulin sensitivity, but older SMLPL(-/-) mice had greater weight gain and whole-body insulin resistance. High-fat diet feeding accelerated the development of obesity. In young SMLPL(-/-) mice, insulin-stimulated glucose uptake was increased 58% in the skeletal muscle, but was reduced in white adipose tissue (WAT) and heart. Insulin action was also diminished in liver: 40% suppression of hepatic glucose production in SMLPL(-/-) vs. 90% in control mice. Skeletal muscle triglyceride was 38% lower, and insulin-stimulated phosphorylated Akt (Ser473) was twofold greater in SMLPL(-/-) mice without changes in IRS-1 tyrosine phosphorylation and phosphatidylinositol 3-kinase activity. Hepatic triglyceride and liver X receptor, carbohydrate response element-binding protein, and PEPCK mRNAs were unaffected in SMLPL(-/-) mice, but peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1alpha and interleukin-1beta mRNAs were higher, and stearoyl-coenzyme A desaturase-1 and PPARgamma mRNAs were reduced.

Conclusions: LPL deletion in skeletal muscle reduces lipid storage and increases insulin signaling in skeletal muscle without changes in body composition. Moreover, lack of LPL in skeletal muscle results in insulin resistance in other key metabolic tissues and ultimately leads to obesity and systemic insulin resistance.

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Related in: MedlinePlus

Intracellular TG and lipid metabolite concentrations in skeletal muscle, liver, and heart. A: Intracellular TG concentrations in skeletal muscle, liver, and heart. n = 8 for SMLPL−/− and n = 10 for control mice for skeletal muscle, n = 4 for liver, and n = 6 for heart. B: Intracelluar LC acyl-CoA, DAG, and ceramides levels in skeletal muscle. n = 8 for both groups of mice.
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f4: Intracellular TG and lipid metabolite concentrations in skeletal muscle, liver, and heart. A: Intracellular TG concentrations in skeletal muscle, liver, and heart. n = 8 for SMLPL−/− and n = 10 for control mice for skeletal muscle, n = 4 for liver, and n = 6 for heart. B: Intracelluar LC acyl-CoA, DAG, and ceramides levels in skeletal muscle. n = 8 for both groups of mice.

Mentions: To understand whether changes in cellular and circulating lipids might underlie the changes in insulin sensitivity in SMLPL−/− mice, we measured TG content in skeletal muscle, liver, and heart (Fig. 4A). SMLPL−/− mice showed a 40% reduction (P = 0.045) in skeletal muscle TG, with no difference in liver TG. Yet there were no differences in intramuscular total LC acyl-CoA, total DAG, or total ceramide levels in SMLPL−/− and control mice (Fig. 4B). Heart TG was not different (P = 0.126) in SMLPL−/− mice (Fig. 4A).


Skeletal muscle-specific deletion of lipoprotein lipase enhances insulin signaling in skeletal muscle but causes insulin resistance in liver and other tissues.

Wang H, Knaub LA, Jensen DR, Young Jung D, Hong EG, Ko HJ, Coates AM, Goldberg IJ, de la Houssaye BA, Janssen RC, McCurdy CE, Rahman SM, Soo Choi C, Shulman GI, Kim JK, Friedman JE, Eckel RH - Diabetes (2008)

Intracellular TG and lipid metabolite concentrations in skeletal muscle, liver, and heart. A: Intracellular TG concentrations in skeletal muscle, liver, and heart. n = 8 for SMLPL−/− and n = 10 for control mice for skeletal muscle, n = 4 for liver, and n = 6 for heart. B: Intracelluar LC acyl-CoA, DAG, and ceramides levels in skeletal muscle. n = 8 for both groups of mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2606858&req=5

f4: Intracellular TG and lipid metabolite concentrations in skeletal muscle, liver, and heart. A: Intracellular TG concentrations in skeletal muscle, liver, and heart. n = 8 for SMLPL−/− and n = 10 for control mice for skeletal muscle, n = 4 for liver, and n = 6 for heart. B: Intracelluar LC acyl-CoA, DAG, and ceramides levels in skeletal muscle. n = 8 for both groups of mice.
Mentions: To understand whether changes in cellular and circulating lipids might underlie the changes in insulin sensitivity in SMLPL−/− mice, we measured TG content in skeletal muscle, liver, and heart (Fig. 4A). SMLPL−/− mice showed a 40% reduction (P = 0.045) in skeletal muscle TG, with no difference in liver TG. Yet there were no differences in intramuscular total LC acyl-CoA, total DAG, or total ceramide levels in SMLPL−/− and control mice (Fig. 4B). Heart TG was not different (P = 0.126) in SMLPL−/− mice (Fig. 4A).

Bottom Line: High-fat diet feeding accelerated the development of obesity.LPL deletion in skeletal muscle reduces lipid storage and increases insulin signaling in skeletal muscle without changes in body composition.Moreover, lack of LPL in skeletal muscle results in insulin resistance in other key metabolic tissues and ultimately leads to obesity and systemic insulin resistance.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA.

ABSTRACT

Objective: Skeletal muscle-specific LPL knockout mouse (SMLPL(-/-)) were created to study the systemic impact of reduced lipoprotein lipid delivery in skeletal muscle on insulin sensitivity, body weight, and composition.

Research design and methods: Tissue-specific insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp and 2-deoxyglucose uptake. Gene expression and insulin-signaling molecules were compared in skeletal muscle and liver of SMLPL(-/-) and control mice.

Results: Nine-week-old SMLPL(-/-) mice showed no differences in body weight, fat mass, or whole-body insulin sensitivity, but older SMLPL(-/-) mice had greater weight gain and whole-body insulin resistance. High-fat diet feeding accelerated the development of obesity. In young SMLPL(-/-) mice, insulin-stimulated glucose uptake was increased 58% in the skeletal muscle, but was reduced in white adipose tissue (WAT) and heart. Insulin action was also diminished in liver: 40% suppression of hepatic glucose production in SMLPL(-/-) vs. 90% in control mice. Skeletal muscle triglyceride was 38% lower, and insulin-stimulated phosphorylated Akt (Ser473) was twofold greater in SMLPL(-/-) mice without changes in IRS-1 tyrosine phosphorylation and phosphatidylinositol 3-kinase activity. Hepatic triglyceride and liver X receptor, carbohydrate response element-binding protein, and PEPCK mRNAs were unaffected in SMLPL(-/-) mice, but peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1alpha and interleukin-1beta mRNAs were higher, and stearoyl-coenzyme A desaturase-1 and PPARgamma mRNAs were reduced.

Conclusions: LPL deletion in skeletal muscle reduces lipid storage and increases insulin signaling in skeletal muscle without changes in body composition. Moreover, lack of LPL in skeletal muscle results in insulin resistance in other key metabolic tissues and ultimately leads to obesity and systemic insulin resistance.

Show MeSH
Related in: MedlinePlus