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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

A: mRNA expression of LPL in muscle tissues. LPL mRNA expression was measured in red skeletal muscle (SM-Red), white skeletal muscle (SM-White), and heart using RT-PCR. n = 3 for both SMLPL−/− and control mice. B: Tissue-specific LPL activities in young SMLPL−/− mice. Heparin-releasable LPL activities were measured for skeletal red muscle (SM-Red), skeletal white muscle (SM-White), WAT, and heart from both the 9- to 11-week-old SMLPL−/− and control mice. LPL activities were expressed as nanomoles of FFA per minute per gram of tissue. n = 8 for SMLPL−/− and n = 10 for control mice. C: Weight, lean mass, and fat mass comparisons between young and old SMLPL−/− mice. The body weights of young (8–9 weeks) and old (8–10 months) SMLPL−/− mice were compared. Body compositions were determined by dual-energy X-ray absorptiometry. n = 5 for both SMLPL−/− and control mice at different ages. D: Weight gain in HF-fed SMLPL−/− mice. The body weights of 6-week-old SMLPL−/− and control mice that are subjected to either HF or LF diet were monitored every 2 weeks for 6 weeks. n = 6 for each group of mice.
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f1: A: mRNA expression of LPL in muscle tissues. LPL mRNA expression was measured in red skeletal muscle (SM-Red), white skeletal muscle (SM-White), and heart using RT-PCR. n = 3 for both SMLPL−/− and control mice. B: Tissue-specific LPL activities in young SMLPL−/− mice. Heparin-releasable LPL activities were measured for skeletal red muscle (SM-Red), skeletal white muscle (SM-White), WAT, and heart from both the 9- to 11-week-old SMLPL−/− and control mice. LPL activities were expressed as nanomoles of FFA per minute per gram of tissue. n = 8 for SMLPL−/− and n = 10 for control mice. C: Weight, lean mass, and fat mass comparisons between young and old SMLPL−/− mice. The body weights of young (8–9 weeks) and old (8–10 months) SMLPL−/− mice were compared. Body compositions were determined by dual-energy X-ray absorptiometry. n = 5 for both SMLPL−/− and control mice at different ages. D: Weight gain in HF-fed SMLPL−/− mice. The body weights of 6-week-old SMLPL−/− and control mice that are subjected to either HF or LF diet were monitored every 2 weeks for 6 weeks. n = 6 for each group of mice.

Mentions: In 9- to 11-week-old SMLPL−/− mice, RT-PCR showed a 83% reduction (P < 0.001) in LPL mRNA expression in the red skeletal muscle, with only 50% reduction in white skeletal muscle and no change in the heart (Fig. 1A). Skeletal muscle LPL activity was decreased by 72% (P < 0.001) in the predominantly red muscle fibers of the soleus and red gastrocnemius muscles (Fig. 1B). White muscle LPL activity was 22% lower in SMLPL−/− mice and was not statistically significant (P = 0.131). LPL activities in heart and WAT were not affected.


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)

A: mRNA expression of LPL in muscle tissues. LPL mRNA expression was measured in red skeletal muscle (SM-Red), white skeletal muscle (SM-White), and heart using RT-PCR. n = 3 for both SMLPL−/− and control mice. B: Tissue-specific LPL activities in young SMLPL−/− mice. Heparin-releasable LPL activities were measured for skeletal red muscle (SM-Red), skeletal white muscle (SM-White), WAT, and heart from both the 9- to 11-week-old SMLPL−/− and control mice. LPL activities were expressed as nanomoles of FFA per minute per gram of tissue. n = 8 for SMLPL−/− and n = 10 for control mice. C: Weight, lean mass, and fat mass comparisons between young and old SMLPL−/− mice. The body weights of young (8–9 weeks) and old (8–10 months) SMLPL−/− mice were compared. Body compositions were determined by dual-energy X-ray absorptiometry. n = 5 for both SMLPL−/− and control mice at different ages. D: Weight gain in HF-fed SMLPL−/− mice. The body weights of 6-week-old SMLPL−/− and control mice that are subjected to either HF or LF diet were monitored every 2 weeks for 6 weeks. n = 6 for each group of mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: A: mRNA expression of LPL in muscle tissues. LPL mRNA expression was measured in red skeletal muscle (SM-Red), white skeletal muscle (SM-White), and heart using RT-PCR. n = 3 for both SMLPL−/− and control mice. B: Tissue-specific LPL activities in young SMLPL−/− mice. Heparin-releasable LPL activities were measured for skeletal red muscle (SM-Red), skeletal white muscle (SM-White), WAT, and heart from both the 9- to 11-week-old SMLPL−/− and control mice. LPL activities were expressed as nanomoles of FFA per minute per gram of tissue. n = 8 for SMLPL−/− and n = 10 for control mice. C: Weight, lean mass, and fat mass comparisons between young and old SMLPL−/− mice. The body weights of young (8–9 weeks) and old (8–10 months) SMLPL−/− mice were compared. Body compositions were determined by dual-energy X-ray absorptiometry. n = 5 for both SMLPL−/− and control mice at different ages. D: Weight gain in HF-fed SMLPL−/− mice. The body weights of 6-week-old SMLPL−/− and control mice that are subjected to either HF or LF diet were monitored every 2 weeks for 6 weeks. n = 6 for each group of mice.
Mentions: In 9- to 11-week-old SMLPL−/− mice, RT-PCR showed a 83% reduction (P < 0.001) in LPL mRNA expression in the red skeletal muscle, with only 50% reduction in white skeletal muscle and no change in the heart (Fig. 1A). Skeletal muscle LPL activity was decreased by 72% (P < 0.001) in the predominantly red muscle fibers of the soleus and red gastrocnemius muscles (Fig. 1B). White muscle LPL activity was 22% lower in SMLPL−/− mice and was not statistically significant (P = 0.131). LPL activities in heart and WAT were not affected.

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