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Alterations in skeletal muscle fatty acid handling predisposes middle-aged mice to diet-induced insulin resistance.

Koonen DP, Sung MM, Kao CK, Dolinsky VW, Koves TR, Ilkayeva O, Jacobs RL, Vance DE, Light PE, Muoio DM, Febbraio M, Dyck JR - Diabetes (2010)

Bottom Line: Although advanced age is a risk factor for type 2 diabetes, a clear understanding of the changes that occur during middle age that contribute to the development of skeletal muscle insulin resistance is currently lacking.Therefore, we sought to investigate how middle age impacts skeletal muscle fatty acid handling and to determine how this contributes to the development of diet-induced insulin resistance.Our data also demonstrate that limiting skeletal muscle fatty acid transport is an effective approach for delaying the development of age-associated insulin resistance and metabolic disease during exposure to a high-fat diet.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada.

ABSTRACT

Objective: Although advanced age is a risk factor for type 2 diabetes, a clear understanding of the changes that occur during middle age that contribute to the development of skeletal muscle insulin resistance is currently lacking. Therefore, we sought to investigate how middle age impacts skeletal muscle fatty acid handling and to determine how this contributes to the development of diet-induced insulin resistance.

Research design and methods: Whole-body and skeletal muscle insulin resistance were studied in young and middle-aged wild-type and CD36 knockout (KO) mice fed either a standard or a high-fat diet for 12 weeks. Molecular signaling pathways, intramuscular triglycerides accumulation, and targeted metabolomics of in vivo mitochondrial substrate flux were also analyzed in the skeletal muscle of mice of all ages.

Results: Middle-aged mice fed a standard diet demonstrated an increase in intramuscular triglycerides without a concomitant increase in insulin resistance. However, middle-aged mice fed a high-fat diet were more susceptible to the development of insulin resistance-a condition that could be prevented by limiting skeletal muscle fatty acid transport and excessive lipid accumulation in middle-aged CD36 KO mice.

Conclusion: Our data provide insight into the mechanisms by which aging becomes a risk factor for the development of insulin resistance. Our data also demonstrate that limiting skeletal muscle fatty acid transport is an effective approach for delaying the development of age-associated insulin resistance and metabolic disease during exposure to a high-fat diet.

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Protection of diet-induced obesity in middle-aged CD36 KO mice fed a high-fat (HF) diet for 12 weeks. Representative image of middle-aged (48–52 weeks of age) wild-type (□) and CD36 KO (■) mice fed a high-fat diet for 12 weeks (A). Weight gain (B) and food intake adjusted for body weight (BW) (C) in wild-type and KO mice fed a high-fat diet. Respiratory exchange ratio (RER) (D), oxygen consumption (VO2) (E), and carbon dioxide production (VCO2) (F) in both the dark (active) and light (inactive) phase following 12 weeks of high-fat feeding in wild-type and KO mice. Total activity for a complete dark/light cycle (G), heat production (H), and heat production adjusted for body weight (I) in wild-type and KO mice following 12 weeks of high-fat feeding. Values are the means ± SEM of n = 6–10 mice in each group. *P < 0.05 indicates comparisons performed between the low-fat (LF)-fed mice and between high-fat–fed mice (Mann-Whitney U test [B and G] or ANOVA with Bonferroni post hoc test for pairwise comparison). (A high-quality digital representation of this figure is available in the online issue.)
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Figure 4: Protection of diet-induced obesity in middle-aged CD36 KO mice fed a high-fat (HF) diet for 12 weeks. Representative image of middle-aged (48–52 weeks of age) wild-type (□) and CD36 KO (■) mice fed a high-fat diet for 12 weeks (A). Weight gain (B) and food intake adjusted for body weight (BW) (C) in wild-type and KO mice fed a high-fat diet. Respiratory exchange ratio (RER) (D), oxygen consumption (VO2) (E), and carbon dioxide production (VCO2) (F) in both the dark (active) and light (inactive) phase following 12 weeks of high-fat feeding in wild-type and KO mice. Total activity for a complete dark/light cycle (G), heat production (H), and heat production adjusted for body weight (I) in wild-type and KO mice following 12 weeks of high-fat feeding. Values are the means ± SEM of n = 6–10 mice in each group. *P < 0.05 indicates comparisons performed between the low-fat (LF)-fed mice and between high-fat–fed mice (Mann-Whitney U test [B and G] or ANOVA with Bonferroni post hoc test for pairwise comparison). (A high-quality digital representation of this figure is available in the online issue.)

Mentions: To investigate whether inhibition of fatty acid transport into the skeletal muscle could alter the observed responses of a middle-aged mouse to a high-fat diet, we utilized the CD36 KO mouse, which has skeletal muscle fatty acid uptake rates ∼40–70% of those in wild-type mice (31,32). Interestingly, there was a striking difference in weight gain between middle-aged wild-type and CD36 KO mice following 12 weeks of high-fat feeding (Fig. 4A), with middle-aged CD36 KO mice accumulating 51% less weight than the wild-type mice over the same period of time (Fig. 4B). Though differences in caloric intake (Fig. 4C) or substrate preference (Fig. 4D) between groups could not account for this dramatic change in weight gain, indirect calorimetry indicated that energy expenditure (Fig. 4E and F) and overall activity (Fig. 4G) were significantly increased in middle-aged CD36 KO mice fed a high-fat diet compared with those in high-fat–fed middle-aged wild-type mice. Although this increased activity in the middle-aged CD36 KO mouse fed a high-fat diet could be attributed to the absence of obesity, heat production was also increased in middle-aged CD36 KO mice fed a low-fat diet compared with that in low-fat–fed middle-aged wild-type mice (Fig. 4H) and in high-fat–fed middle-aged KO mice when normalized for body weight (Fig. 4I).


Alterations in skeletal muscle fatty acid handling predisposes middle-aged mice to diet-induced insulin resistance.

Koonen DP, Sung MM, Kao CK, Dolinsky VW, Koves TR, Ilkayeva O, Jacobs RL, Vance DE, Light PE, Muoio DM, Febbraio M, Dyck JR - Diabetes (2010)

Protection of diet-induced obesity in middle-aged CD36 KO mice fed a high-fat (HF) diet for 12 weeks. Representative image of middle-aged (48–52 weeks of age) wild-type (□) and CD36 KO (■) mice fed a high-fat diet for 12 weeks (A). Weight gain (B) and food intake adjusted for body weight (BW) (C) in wild-type and KO mice fed a high-fat diet. Respiratory exchange ratio (RER) (D), oxygen consumption (VO2) (E), and carbon dioxide production (VCO2) (F) in both the dark (active) and light (inactive) phase following 12 weeks of high-fat feeding in wild-type and KO mice. Total activity for a complete dark/light cycle (G), heat production (H), and heat production adjusted for body weight (I) in wild-type and KO mice following 12 weeks of high-fat feeding. Values are the means ± SEM of n = 6–10 mice in each group. *P < 0.05 indicates comparisons performed between the low-fat (LF)-fed mice and between high-fat–fed mice (Mann-Whitney U test [B and G] or ANOVA with Bonferroni post hoc test for pairwise comparison). (A high-quality digital representation of this figure is available in the online issue.)
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Related In: Results  -  Collection

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Figure 4: Protection of diet-induced obesity in middle-aged CD36 KO mice fed a high-fat (HF) diet for 12 weeks. Representative image of middle-aged (48–52 weeks of age) wild-type (□) and CD36 KO (■) mice fed a high-fat diet for 12 weeks (A). Weight gain (B) and food intake adjusted for body weight (BW) (C) in wild-type and KO mice fed a high-fat diet. Respiratory exchange ratio (RER) (D), oxygen consumption (VO2) (E), and carbon dioxide production (VCO2) (F) in both the dark (active) and light (inactive) phase following 12 weeks of high-fat feeding in wild-type and KO mice. Total activity for a complete dark/light cycle (G), heat production (H), and heat production adjusted for body weight (I) in wild-type and KO mice following 12 weeks of high-fat feeding. Values are the means ± SEM of n = 6–10 mice in each group. *P < 0.05 indicates comparisons performed between the low-fat (LF)-fed mice and between high-fat–fed mice (Mann-Whitney U test [B and G] or ANOVA with Bonferroni post hoc test for pairwise comparison). (A high-quality digital representation of this figure is available in the online issue.)
Mentions: To investigate whether inhibition of fatty acid transport into the skeletal muscle could alter the observed responses of a middle-aged mouse to a high-fat diet, we utilized the CD36 KO mouse, which has skeletal muscle fatty acid uptake rates ∼40–70% of those in wild-type mice (31,32). Interestingly, there was a striking difference in weight gain between middle-aged wild-type and CD36 KO mice following 12 weeks of high-fat feeding (Fig. 4A), with middle-aged CD36 KO mice accumulating 51% less weight than the wild-type mice over the same period of time (Fig. 4B). Though differences in caloric intake (Fig. 4C) or substrate preference (Fig. 4D) between groups could not account for this dramatic change in weight gain, indirect calorimetry indicated that energy expenditure (Fig. 4E and F) and overall activity (Fig. 4G) were significantly increased in middle-aged CD36 KO mice fed a high-fat diet compared with those in high-fat–fed middle-aged wild-type mice. Although this increased activity in the middle-aged CD36 KO mouse fed a high-fat diet could be attributed to the absence of obesity, heat production was also increased in middle-aged CD36 KO mice fed a low-fat diet compared with that in low-fat–fed middle-aged wild-type mice (Fig. 4H) and in high-fat–fed middle-aged KO mice when normalized for body weight (Fig. 4I).

Bottom Line: Although advanced age is a risk factor for type 2 diabetes, a clear understanding of the changes that occur during middle age that contribute to the development of skeletal muscle insulin resistance is currently lacking.Therefore, we sought to investigate how middle age impacts skeletal muscle fatty acid handling and to determine how this contributes to the development of diet-induced insulin resistance.Our data also demonstrate that limiting skeletal muscle fatty acid transport is an effective approach for delaying the development of age-associated insulin resistance and metabolic disease during exposure to a high-fat diet.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada.

ABSTRACT

Objective: Although advanced age is a risk factor for type 2 diabetes, a clear understanding of the changes that occur during middle age that contribute to the development of skeletal muscle insulin resistance is currently lacking. Therefore, we sought to investigate how middle age impacts skeletal muscle fatty acid handling and to determine how this contributes to the development of diet-induced insulin resistance.

Research design and methods: Whole-body and skeletal muscle insulin resistance were studied in young and middle-aged wild-type and CD36 knockout (KO) mice fed either a standard or a high-fat diet for 12 weeks. Molecular signaling pathways, intramuscular triglycerides accumulation, and targeted metabolomics of in vivo mitochondrial substrate flux were also analyzed in the skeletal muscle of mice of all ages.

Results: Middle-aged mice fed a standard diet demonstrated an increase in intramuscular triglycerides without a concomitant increase in insulin resistance. However, middle-aged mice fed a high-fat diet were more susceptible to the development of insulin resistance-a condition that could be prevented by limiting skeletal muscle fatty acid transport and excessive lipid accumulation in middle-aged CD36 KO mice.

Conclusion: Our data provide insight into the mechanisms by which aging becomes a risk factor for the development of insulin resistance. Our data also demonstrate that limiting skeletal muscle fatty acid transport is an effective approach for delaying the development of age-associated insulin resistance and metabolic disease during exposure to a high-fat diet.

Show MeSH
Related in: MedlinePlus