Limits...
Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice.

Radović B, Vujić N, Leopold C, Schlager S, Goeritzer M, Patankar JV, Korbelius M, Kolb D, Reindl J, Wegscheider M, Tomin T, Birner-Gruenberger R, Schittmayer M, Groschner L, Magnes C, Diwoky C, Frank S, Steyrer E, Du H, Graier WF, Madl T, Kratky D - Diabetologia (2016)

Bottom Line: We observed 84% decreased plasma leptin levels and significantly reduced hepatic ATP, glucose, glycogen and glutamine concentrations in fed Lal (-/-) mice.Markedly reduced hepatic acyl-CoA concentrations decrease the expression of peroxisome proliferator-activated receptor α (PPARα) target genes.We conclude that decreased plasma VLDL production enhances glucose uptake into skeletal muscle to compensate for the lack of energy supply.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.

ABSTRACT

Aims/hypothesis: Lysosomal acid lipase (LAL) hydrolyses cholesteryl esters and triacylglycerols (TG) within lysosomes to mobilise NEFA and cholesterol. Since LAL-deficient (Lal (-/-) ) mice suffer from progressive loss of adipose tissue and severe accumulation of lipids in hepatic lysosomes, we hypothesised that LAL deficiency triggers alternative energy pathway(s).

Methods: We studied metabolic adaptations in Lal (-/-) mice.

Results: Despite loss of adipose tissue, Lal (-/-) mice show enhanced glucose clearance during insulin and glucose tolerance tests and have increased uptake of [(3)H]2-deoxy-D-glucose into skeletal muscle compared with wild-type mice. In agreement, fasted Lal (-/-) mice exhibit reduced glucose and glycogen levels in skeletal muscle. We observed 84% decreased plasma leptin levels and significantly reduced hepatic ATP, glucose, glycogen and glutamine concentrations in fed Lal (-/-) mice. Markedly reduced hepatic acyl-CoA concentrations decrease the expression of peroxisome proliferator-activated receptor α (PPARα) target genes. However, treatment of Lal (-/-) mice with the PPARα agonist fenofibrate further decreased plasma TG (and hepatic glucose and glycogen) concentrations in Lal (-/-) mice. Depletion of hepatic nuclear factor 4α and forkhead box protein a2 in fasted Lal (-/-) mice might be responsible for reduced expression of microsomal TG transfer protein, defective VLDL synthesis and drastically reduced plasma TG levels.

Conclusions/interpretation: Our findings indicate that neither activation nor inactivation of PPARα per se but rather the availability of hepatic acyl-CoA concentrations regulates VLDL synthesis and subsequent metabolic adaptations in Lal (-/-) mice. We conclude that decreased plasma VLDL production enhances glucose uptake into skeletal muscle to compensate for the lack of energy supply.

No MeSH data available.


Related in: MedlinePlus

Reduced scWAT and plasma leptin concentrations in Lal-/- mice. (a) H&E staining of inguinal scWAT sections. (b) scWAT mass normalised to BW (n = 6). (c) mRNA expression of leptin (Lep) and adiponectin (Adipoq) in scWAT (n = 4–5). Plasma concentrations of (d) leptin and (e) adiponectin (n = 6). mRNA expression of the receptors of hepatic leptin (Leptr) and adiponectin (Adipor) in (f) fed and (g) 12 h fasted WT and Lal-/- mice (n = 3–5). Data represent means ± SD; *p < 0.05, **p ≤ 0.01; ***p ≤ 0.001, Student’s unpaired t test. Mice were aged 12–16 weeks. Black bars, WT mice; white bars, Lal-/- mice
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4930475&req=5

Fig5: Reduced scWAT and plasma leptin concentrations in Lal-/- mice. (a) H&E staining of inguinal scWAT sections. (b) scWAT mass normalised to BW (n = 6). (c) mRNA expression of leptin (Lep) and adiponectin (Adipoq) in scWAT (n = 4–5). Plasma concentrations of (d) leptin and (e) adiponectin (n = 6). mRNA expression of the receptors of hepatic leptin (Leptr) and adiponectin (Adipor) in (f) fed and (g) 12 h fasted WT and Lal-/- mice (n = 3–5). Data represent means ± SD; *p < 0.05, **p ≤ 0.01; ***p ≤ 0.001, Student’s unpaired t test. Mice were aged 12–16 weeks. Black bars, WT mice; white bars, Lal-/- mice

Mentions: Despite comparable food intake, Lal-/- mice were lighter and gained less weight (ESM Fig. 3a, b). They lacked visceral fat and exhibited markedly reduced subcutaneous (sc) WAT at the age of 4 and 12 weeks (ESM Fig. 3c). H&E staining of scWAT sections revealed smaller adipocytes with reduced fat content (Fig. 5a) and we observed reduced inguinal scWAT mass (Fig. 5b) in Lal-/- mice. Adipose tissue fundamentally influences systemic insulin sensitivity and glucose metabolism via the adipokines leptin and adiponectin [23]. Leptin mRNA expression was significantly decreased in scWAT of Lal-/- compared with WT mice, whereas adiponectin mRNA expression was unchanged (Fig. 5c). Since fasting significantly decreases basal leptin levels [24], decreased plasma leptin concentrations (84%) in fed Lal-/- mice but comparable levels as WT mice after fasting (Fig. 5d) indicate that feeding is ineffective to increase the satiety hormone leptin in Lal-/- mice. Plasma adiponectin levels were comparable between both genotypes (Fig. 5e). mRNA expression of the leptin receptors (Leptr)1 and 2 were markedly increased in livers of fed (Fig. 5f) and fasted (Fig. 5g) Lal-/- mice. Expression of adiponectin receptor (Adipor)1 mRNA was higher and expression of Adipor2 mRNA was lower in livers of fed Lal-/- mice than WT fed mice (Fig. 5f). While Adipor1 mRNA levels were similar in fasted livers of both genotypes, transcript levels of Adipor2 were reduced in livers of Lal-/- mice compared with WT livers (Fig. 5g).Fig. 5


Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice.

Radović B, Vujić N, Leopold C, Schlager S, Goeritzer M, Patankar JV, Korbelius M, Kolb D, Reindl J, Wegscheider M, Tomin T, Birner-Gruenberger R, Schittmayer M, Groschner L, Magnes C, Diwoky C, Frank S, Steyrer E, Du H, Graier WF, Madl T, Kratky D - Diabetologia (2016)

Reduced scWAT and plasma leptin concentrations in Lal-/- mice. (a) H&E staining of inguinal scWAT sections. (b) scWAT mass normalised to BW (n = 6). (c) mRNA expression of leptin (Lep) and adiponectin (Adipoq) in scWAT (n = 4–5). Plasma concentrations of (d) leptin and (e) adiponectin (n = 6). mRNA expression of the receptors of hepatic leptin (Leptr) and adiponectin (Adipor) in (f) fed and (g) 12 h fasted WT and Lal-/- mice (n = 3–5). Data represent means ± SD; *p < 0.05, **p ≤ 0.01; ***p ≤ 0.001, Student’s unpaired t test. Mice were aged 12–16 weeks. Black bars, WT mice; white bars, Lal-/- mice
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4930475&req=5

Fig5: Reduced scWAT and plasma leptin concentrations in Lal-/- mice. (a) H&E staining of inguinal scWAT sections. (b) scWAT mass normalised to BW (n = 6). (c) mRNA expression of leptin (Lep) and adiponectin (Adipoq) in scWAT (n = 4–5). Plasma concentrations of (d) leptin and (e) adiponectin (n = 6). mRNA expression of the receptors of hepatic leptin (Leptr) and adiponectin (Adipor) in (f) fed and (g) 12 h fasted WT and Lal-/- mice (n = 3–5). Data represent means ± SD; *p < 0.05, **p ≤ 0.01; ***p ≤ 0.001, Student’s unpaired t test. Mice were aged 12–16 weeks. Black bars, WT mice; white bars, Lal-/- mice
Mentions: Despite comparable food intake, Lal-/- mice were lighter and gained less weight (ESM Fig. 3a, b). They lacked visceral fat and exhibited markedly reduced subcutaneous (sc) WAT at the age of 4 and 12 weeks (ESM Fig. 3c). H&E staining of scWAT sections revealed smaller adipocytes with reduced fat content (Fig. 5a) and we observed reduced inguinal scWAT mass (Fig. 5b) in Lal-/- mice. Adipose tissue fundamentally influences systemic insulin sensitivity and glucose metabolism via the adipokines leptin and adiponectin [23]. Leptin mRNA expression was significantly decreased in scWAT of Lal-/- compared with WT mice, whereas adiponectin mRNA expression was unchanged (Fig. 5c). Since fasting significantly decreases basal leptin levels [24], decreased plasma leptin concentrations (84%) in fed Lal-/- mice but comparable levels as WT mice after fasting (Fig. 5d) indicate that feeding is ineffective to increase the satiety hormone leptin in Lal-/- mice. Plasma adiponectin levels were comparable between both genotypes (Fig. 5e). mRNA expression of the leptin receptors (Leptr)1 and 2 were markedly increased in livers of fed (Fig. 5f) and fasted (Fig. 5g) Lal-/- mice. Expression of adiponectin receptor (Adipor)1 mRNA was higher and expression of Adipor2 mRNA was lower in livers of fed Lal-/- mice than WT fed mice (Fig. 5f). While Adipor1 mRNA levels were similar in fasted livers of both genotypes, transcript levels of Adipor2 were reduced in livers of Lal-/- mice compared with WT livers (Fig. 5g).Fig. 5

Bottom Line: We observed 84% decreased plasma leptin levels and significantly reduced hepatic ATP, glucose, glycogen and glutamine concentrations in fed Lal (-/-) mice.Markedly reduced hepatic acyl-CoA concentrations decrease the expression of peroxisome proliferator-activated receptor α (PPARα) target genes.We conclude that decreased plasma VLDL production enhances glucose uptake into skeletal muscle to compensate for the lack of energy supply.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.

ABSTRACT

Aims/hypothesis: Lysosomal acid lipase (LAL) hydrolyses cholesteryl esters and triacylglycerols (TG) within lysosomes to mobilise NEFA and cholesterol. Since LAL-deficient (Lal (-/-) ) mice suffer from progressive loss of adipose tissue and severe accumulation of lipids in hepatic lysosomes, we hypothesised that LAL deficiency triggers alternative energy pathway(s).

Methods: We studied metabolic adaptations in Lal (-/-) mice.

Results: Despite loss of adipose tissue, Lal (-/-) mice show enhanced glucose clearance during insulin and glucose tolerance tests and have increased uptake of [(3)H]2-deoxy-D-glucose into skeletal muscle compared with wild-type mice. In agreement, fasted Lal (-/-) mice exhibit reduced glucose and glycogen levels in skeletal muscle. We observed 84% decreased plasma leptin levels and significantly reduced hepatic ATP, glucose, glycogen and glutamine concentrations in fed Lal (-/-) mice. Markedly reduced hepatic acyl-CoA concentrations decrease the expression of peroxisome proliferator-activated receptor α (PPARα) target genes. However, treatment of Lal (-/-) mice with the PPARα agonist fenofibrate further decreased plasma TG (and hepatic glucose and glycogen) concentrations in Lal (-/-) mice. Depletion of hepatic nuclear factor 4α and forkhead box protein a2 in fasted Lal (-/-) mice might be responsible for reduced expression of microsomal TG transfer protein, defective VLDL synthesis and drastically reduced plasma TG levels.

Conclusions/interpretation: Our findings indicate that neither activation nor inactivation of PPARα per se but rather the availability of hepatic acyl-CoA concentrations regulates VLDL synthesis and subsequent metabolic adaptations in Lal (-/-) mice. We conclude that decreased plasma VLDL production enhances glucose uptake into skeletal muscle to compensate for the lack of energy supply.

No MeSH data available.


Related in: MedlinePlus