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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 the resting metabolic rates in Aymice. A-C: rates of oxygen consumption (A), locomotive activities (B) and respiratory exchange ratio (RER, VCO2/VO2) (C) in the light and dark cycles in young Ay mice at the end of 4 month treatment. D. Food intake per unit of fat-free body mass (FFM) during the indirect calorimetric analysis. * indicates p < 0.05, control vs. leucine-treated, n = 8.
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Figure 5: Leucine supplementation increases the resting metabolic rates in Aymice. A-C: rates of oxygen consumption (A), locomotive activities (B) and respiratory exchange ratio (RER, VCO2/VO2) (C) in the light and dark cycles in young Ay mice at the end of 4 month treatment. D. Food intake per unit of fat-free body mass (FFM) during the indirect calorimetric analysis. * indicates p < 0.05, control vs. leucine-treated, n = 8.

Mentions: In order to determine the effect of long term leucine supplementation on energy metabolism, indirect calorimetry was performed in the Ay mice at the end of 4 month leucine-treatment. Rates of oxygen consumption were ~10.7% and 8.9% higher, respectively, in the light and dark cycles in leucine-treated mice, relative to control mice (both p < 0.05) (Fig 5A). No increase in locomotive activity in leucine-treated mice was observed (Fig 5B). The respiratory exchange ratio (RER, VCO2/VO2) was slightly lower and food intake was slight higher in leucine-treated mice, compared to the control mice, although the differences were not statistically significant (Fig 5C-5D).


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 the resting metabolic rates in Aymice. A-C: rates of oxygen consumption (A), locomotive activities (B) and respiratory exchange ratio (RER, VCO2/VO2) (C) in the light and dark cycles in young Ay mice at the end of 4 month treatment. D. Food intake per unit of fat-free body mass (FFM) during the indirect calorimetric analysis. * indicates p < 0.05, 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 5: Leucine supplementation increases the resting metabolic rates in Aymice. A-C: rates of oxygen consumption (A), locomotive activities (B) and respiratory exchange ratio (RER, VCO2/VO2) (C) in the light and dark cycles in young Ay mice at the end of 4 month treatment. D. Food intake per unit of fat-free body mass (FFM) during the indirect calorimetric analysis. * indicates p < 0.05, control vs. leucine-treated, n = 8.
Mentions: In order to determine the effect of long term leucine supplementation on energy metabolism, indirect calorimetry was performed in the Ay mice at the end of 4 month leucine-treatment. Rates of oxygen consumption were ~10.7% and 8.9% higher, respectively, in the light and dark cycles in leucine-treated mice, relative to control mice (both p < 0.05) (Fig 5A). No increase in locomotive activity in leucine-treated mice was observed (Fig 5B). The respiratory exchange ratio (RER, VCO2/VO2) was slightly lower and food intake was slight higher in leucine-treated mice, compared to the control mice, although the differences were not statistically significant (Fig 5C-5D).

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