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Chronic leucine supplementation improves glycemic control in etiologically distinct mouse models of obesity and diabetes mellitus.

Guo K, Yu YH, Hou J, Zhang Y - Nutr Metab (Lond) (2010)

Bottom Line: However, the treatment had no long term effect on body weight or adiposity.The expression levels of UCP3, CrAT, PPAR-alpha, and NRF-1, which are known to regulate mitochondrial oxidative function, were significantly increased in the soleus muscle of leucine-treated Ay mice whereas the expression levels of MCP-1 and TNF-alpha and macrophage infiltration in adipose tissue were significantly reduced.The metabolic benefits of leucine supplementation are likely mediated via multiple mechanisms in different tissues, but are not necessarily dependent of weight reduction.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics, Division of Molecular Genetics, Columbia University, New York, USA. yz84@columbia.edu.

ABSTRACT

Background: Leucine may function as a signaling molecule to regulate metabolism. We have previously shown that dietary leucine supplementation significantly improves glucose and energy metabolism in diet-induced obese mice, suggesting that leucine supplementation could potentially be a useful adjuvant therapy for obesity and type 2 diabetes. Since the underlying cause for obesity and type 2 diabetes is multifold, we further investigated metabolic effects of leucine supplementation in obese/diabetes mouse models with different etiologies, and explored the underlying molecular mechanisms.

Methods: Leucine supplementation was carried out in NONcNZO10/LtJ (RCS10) - a polygenic model predisposed to beta cell failure and type 2 diabetes, and in B6.Cg-Ay/J (Ay) - a monogenic model for impaired central melanocortin receptor signaling, obesity, and severe insulin resistance. Mice in the treatment group received the drinking water containing 1.5% leucine for up to 8 months; control mice received the tap water. Body weight, body composition, blood HbA1c levels, and plasma glucose and insulin levels were monitored throughout and/or at the end of the study period. Indirect calorimetry, skeletal muscle gene expression, and adipose tissue inflammation were also assessed in Ay mice.

Results: Leucine supplementation significantly reduced HbA1c levels throughout the study period in both RCS10 and Ay mice. However, the treatment had no long term effect on body weight or adiposity. The improvement in glycemic control was associated with an increased insulin response to food challenge in RCS10 mice and decreased plasma insulin levels in Ay mice. In leucine-treated Ay mice, energy expenditure was increased by ~10% (p < 0.05) in both dark and light cycles while the physical activity level was unchanged. The expression levels of UCP3, CrAT, PPAR-alpha, and NRF-1, which are known to regulate mitochondrial oxidative function, were significantly increased in the soleus muscle of leucine-treated Ay mice whereas the expression levels of MCP-1 and TNF-alpha and macrophage infiltration in adipose tissue were significantly reduced.

Conclusions: Chronic leucine supplementation significantly improves glycemic control in multiple mouse models of obesity and diabetes with distinct etiologies. The metabolic benefits of leucine supplementation are likely mediated via multiple mechanisms in different tissues, but are not necessarily dependent of weight reduction.

No MeSH data available.


Related in: MedlinePlus

Leucine supplementation increases skeletal muscle expression of genes involved in regulating energy metabolism in Aymice. Messenger RNA levels of uncoupling protein 3 (UCP3), carnitine acetyltransferase (CrAT), carnitine palmitoyltransferase 1B (CPT-1B), peroxisome proliferator-activated receptor alpha (PPAR-alpha), nuclear respiratory factor 1 (NRF-1), nuclear respiratory factor 2 (NRF-2), and TATA-binding protein (TBP) were determined in the soleus muscle of young Ay mice after 4 months of treatment. The expression levels in leucine-treated mice are expressed relatively to the levels of the control mice. * and ** indicate p < 0.05 and 0.01, respectively, control vs. leucine-treated, n = 8.
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Figure 6: Leucine supplementation increases skeletal muscle expression of genes involved in regulating energy metabolism in Aymice. Messenger RNA levels of uncoupling protein 3 (UCP3), carnitine acetyltransferase (CrAT), carnitine palmitoyltransferase 1B (CPT-1B), peroxisome proliferator-activated receptor alpha (PPAR-alpha), nuclear respiratory factor 1 (NRF-1), nuclear respiratory factor 2 (NRF-2), and TATA-binding protein (TBP) were determined in the soleus muscle of young Ay mice after 4 months of treatment. The expression levels in leucine-treated mice are expressed relatively to the levels of the control mice. * and ** indicate p < 0.05 and 0.01, respectively, control vs. leucine-treated, n = 8.

Mentions: In order to further understand the effect of leucine supplementation on energy metabolism at the molecular level, we next examined the expression level of key genes involved in fatty acid metabolism and mitochondrial function in the skeletal muscle of Ay mice. The mRNA levels for uncoupling protein 3 (UCP3), carnitine acetyltransferase (CrAT), peroxisome proliferators-activated receptor alpha (PPAR-alpha), and nuclear respiratory factor 1 (NRF-1) were significantly higher in the soleus muscle of leucine-treated mice than in control mice (Fig 6). The mRNA levels for carnitine palmitoyltransferase-1B (CPT-1B) and nuclear respiratory factor 2 (NRF-2) were also increased although the differences were not statistically significant. The expression level of TATA-binding protein (TBP) was unaltered. These results suggest that long term leucine treatment may increase energy expenditure by selectively stimulating the expression of a set of key genes involved in fatty acid metabolism and mitochondrial biogenesis in the skeletal muscle.


Chronic leucine supplementation improves glycemic control in etiologically distinct mouse models of obesity and diabetes mellitus.

Guo K, Yu YH, Hou J, Zhang Y - Nutr Metab (Lond) (2010)

Leucine supplementation increases skeletal muscle expression of genes involved in regulating energy metabolism in Aymice. Messenger RNA levels of uncoupling protein 3 (UCP3), carnitine acetyltransferase (CrAT), carnitine palmitoyltransferase 1B (CPT-1B), peroxisome proliferator-activated receptor alpha (PPAR-alpha), nuclear respiratory factor 1 (NRF-1), nuclear respiratory factor 2 (NRF-2), and TATA-binding protein (TBP) were determined in the soleus muscle of young Ay mice after 4 months of treatment. The expression levels in leucine-treated mice are expressed relatively to the levels of the control mice. * and ** indicate p < 0.05 and 0.01, respectively, control vs. leucine-treated, n = 8.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2914079&req=5

Figure 6: Leucine supplementation increases skeletal muscle expression of genes involved in regulating energy metabolism in Aymice. Messenger RNA levels of uncoupling protein 3 (UCP3), carnitine acetyltransferase (CrAT), carnitine palmitoyltransferase 1B (CPT-1B), peroxisome proliferator-activated receptor alpha (PPAR-alpha), nuclear respiratory factor 1 (NRF-1), nuclear respiratory factor 2 (NRF-2), and TATA-binding protein (TBP) were determined in the soleus muscle of young Ay mice after 4 months of treatment. The expression levels in leucine-treated mice are expressed relatively to the levels of the control mice. * and ** indicate p < 0.05 and 0.01, respectively, control vs. leucine-treated, n = 8.
Mentions: In order to further understand the effect of leucine supplementation on energy metabolism at the molecular level, we next examined the expression level of key genes involved in fatty acid metabolism and mitochondrial function in the skeletal muscle of Ay mice. The mRNA levels for uncoupling protein 3 (UCP3), carnitine acetyltransferase (CrAT), peroxisome proliferators-activated receptor alpha (PPAR-alpha), and nuclear respiratory factor 1 (NRF-1) were significantly higher in the soleus muscle of leucine-treated mice than in control mice (Fig 6). The mRNA levels for carnitine palmitoyltransferase-1B (CPT-1B) and nuclear respiratory factor 2 (NRF-2) were also increased although the differences were not statistically significant. The expression level of TATA-binding protein (TBP) was unaltered. These results suggest that long term leucine treatment may increase energy expenditure by selectively stimulating the expression of a set of key genes involved in fatty acid metabolism and mitochondrial biogenesis in the skeletal muscle.

Bottom Line: However, the treatment had no long term effect on body weight or adiposity.The expression levels of UCP3, CrAT, PPAR-alpha, and NRF-1, which are known to regulate mitochondrial oxidative function, were significantly increased in the soleus muscle of leucine-treated Ay mice whereas the expression levels of MCP-1 and TNF-alpha and macrophage infiltration in adipose tissue were significantly reduced.The metabolic benefits of leucine supplementation are likely mediated via multiple mechanisms in different tissues, but are not necessarily dependent of weight reduction.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics, Division of Molecular Genetics, Columbia University, New York, USA. yz84@columbia.edu.

ABSTRACT

Background: Leucine may function as a signaling molecule to regulate metabolism. We have previously shown that dietary leucine supplementation significantly improves glucose and energy metabolism in diet-induced obese mice, suggesting that leucine supplementation could potentially be a useful adjuvant therapy for obesity and type 2 diabetes. Since the underlying cause for obesity and type 2 diabetes is multifold, we further investigated metabolic effects of leucine supplementation in obese/diabetes mouse models with different etiologies, and explored the underlying molecular mechanisms.

Methods: Leucine supplementation was carried out in NONcNZO10/LtJ (RCS10) - a polygenic model predisposed to beta cell failure and type 2 diabetes, and in B6.Cg-Ay/J (Ay) - a monogenic model for impaired central melanocortin receptor signaling, obesity, and severe insulin resistance. Mice in the treatment group received the drinking water containing 1.5% leucine for up to 8 months; control mice received the tap water. Body weight, body composition, blood HbA1c levels, and plasma glucose and insulin levels were monitored throughout and/or at the end of the study period. Indirect calorimetry, skeletal muscle gene expression, and adipose tissue inflammation were also assessed in Ay mice.

Results: Leucine supplementation significantly reduced HbA1c levels throughout the study period in both RCS10 and Ay mice. However, the treatment had no long term effect on body weight or adiposity. The improvement in glycemic control was associated with an increased insulin response to food challenge in RCS10 mice and decreased plasma insulin levels in Ay mice. In leucine-treated Ay mice, energy expenditure was increased by ~10% (p < 0.05) in both dark and light cycles while the physical activity level was unchanged. The expression levels of UCP3, CrAT, PPAR-alpha, and NRF-1, which are known to regulate mitochondrial oxidative function, were significantly increased in the soleus muscle of leucine-treated Ay mice whereas the expression levels of MCP-1 and TNF-alpha and macrophage infiltration in adipose tissue were significantly reduced.

Conclusions: Chronic leucine supplementation significantly improves glycemic control in multiple mouse models of obesity and diabetes with distinct etiologies. The metabolic benefits of leucine supplementation are likely mediated via multiple mechanisms in different tissues, but are not necessarily dependent of weight reduction.

No MeSH data available.


Related in: MedlinePlus