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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 decreases adipose tissue inflammation in Ay mice. A: messenger RNA levels of aP2, leptin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-alpha), and F4/80, a macrophage-specific marker, in the epididymal adipose tissue of leucine-treated and control young Ay mice at the end of 4 month study period. 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. B. Immunohistochemical staining of F4/80 of epididymal adipose tissue of leucine-treated and control young Ay mice. The arrows indicate the nuclei positive for F4/80 staining.
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Figure 7: Leucine supplementation decreases adipose tissue inflammation in Ay mice. A: messenger RNA levels of aP2, leptin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-alpha), and F4/80, a macrophage-specific marker, in the epididymal adipose tissue of leucine-treated and control young Ay mice at the end of 4 month study period. 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. B. Immunohistochemical staining of F4/80 of epididymal adipose tissue of leucine-treated and control young Ay mice. The arrows indicate the nuclei positive for F4/80 staining.

Mentions: Obesity and insulin resistance have been associated with adipose tissue inflammation in both humans and rodents [18-22]. In order to assess the effect of leucine supplementation on adipose tissue inflammation, we examined the expression of several proinflammatory markers and macrophage infiltration in leucine-treated and control Ay mice. Messenger RNA levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha), and F4/80, a specific marker of macrophage, were significantly decreased in the epididymal adipose tissue of leucine-treated Ay mice, relative to the control mice (Fig 7A). In contrast, mRNA levels of two adipocyte-specific genes, aP2 and leptin, were not significantly different between the two groups (Fig 7A). Consistent with the decreased mRNA expression of F4/80 gene, immunostaining of the epididymal adipose tissue with anti-mouse F4/80 antibody confirmed that the degree of macrophage infiltration in the epididymal adipose tissue was also decreased in leucine-treated Ay mice, relative to the control mice (Fig 7B). These results suggest that long term leucine supplementation may attenuate adipose tissue inflammation associated with obesity.


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 decreases adipose tissue inflammation in Ay mice. A: messenger RNA levels of aP2, leptin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-alpha), and F4/80, a macrophage-specific marker, in the epididymal adipose tissue of leucine-treated and control young Ay mice at the end of 4 month study period. 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. B. Immunohistochemical staining of F4/80 of epididymal adipose tissue of leucine-treated and control young Ay mice. The arrows indicate the nuclei positive for F4/80 staining.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Leucine supplementation decreases adipose tissue inflammation in Ay mice. A: messenger RNA levels of aP2, leptin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-alpha), and F4/80, a macrophage-specific marker, in the epididymal adipose tissue of leucine-treated and control young Ay mice at the end of 4 month study period. 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. B. Immunohistochemical staining of F4/80 of epididymal adipose tissue of leucine-treated and control young Ay mice. The arrows indicate the nuclei positive for F4/80 staining.
Mentions: Obesity and insulin resistance have been associated with adipose tissue inflammation in both humans and rodents [18-22]. In order to assess the effect of leucine supplementation on adipose tissue inflammation, we examined the expression of several proinflammatory markers and macrophage infiltration in leucine-treated and control Ay mice. Messenger RNA levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha), and F4/80, a specific marker of macrophage, were significantly decreased in the epididymal adipose tissue of leucine-treated Ay mice, relative to the control mice (Fig 7A). In contrast, mRNA levels of two adipocyte-specific genes, aP2 and leptin, were not significantly different between the two groups (Fig 7A). Consistent with the decreased mRNA expression of F4/80 gene, immunostaining of the epididymal adipose tissue with anti-mouse F4/80 antibody confirmed that the degree of macrophage infiltration in the epididymal adipose tissue was also decreased in leucine-treated Ay mice, relative to the control mice (Fig 7B). These results suggest that long term leucine supplementation may attenuate adipose tissue inflammation associated with obesity.

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