Dietary effects on body composition, glucose metabolism, and longevity are modulated by skeletal muscle mitochondrial uncoupling in mice

Nov 13, 2010Aging cell

Muscle energy use changes how diet affects body fat, blood sugar, and lifespan in mice

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Abstract

HCHF feeding decreased median lifespan of wild-type mice by 33% compared to a control diet.

High-carbohydrate/high-fat (HCHF) diets rapidly increased body fat content in wild-type mice.
Median lifespan of wild-type mice decreased by 33% with HCHF and 7% with low-carbohydrate/high-fat (LCHF) diets compared to control.
Insulin resistance in wild-type mice significantly increased after 24 weeks of HCHF feeding.
Transgenic (TG) mice exhibited lower lean body mass but higher energy expenditure and insulin sensitivity, leading to a maximum lifespan increase of 10% compared to wild-type mice.
TG mice developed obesity more slowly on HCHF but reached similar maximum fat levels as wild-type mice.
Decreased longevity was more closely linked to rapid fat gain rather than total body fat, with insulin resistance negatively correlating and energy expenditure positively correlating with lifespan.

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Little is known about how diet and energy metabolism interact in determination of lifespan under ad libitum feeding. From 12 weeks of age until death, male and female wild-type (WT) and transgenic (TG) mice with increased skeletal muscle mitochondrial uncoupling (HSA-mUCP1 mice) were fed one of three different semisynthetic diets differing in macronutrient ratio: control (high-carbohydrate/low-fat-HCLF) and two high-fat diets: high-carbohydrate/high-fat (HCHF), and low-carbohydrate/high-fat (LCHF). Compared to control and LCHF, HCHF feeding rapidly and significantly increased body fat content in WT. Median lifespan of WT was decreased by 33% (HCHF) and 7% (LCHF) compared to HCLF. HCHF significantly increased insulin resistance (HOMA) of WT from 24 weeks on compared to control. TG mice had lower lean body mass and increased energy expenditure, insulin sensitivity, and maximum lifespan (+10%) compared to WT. They showed a delayed development of obesity on HCHF but reached similar maximum adiposity as WT. TG median lifespan was only slightly reduced by HCHF (-7%) and unaffected by LCHF compared to control. Correlation analyses showed that decreased longevity was more strongly linked to a high rate of fat gain than to adiposity itself. Furthermore, insulin resistance was negatively and weight-specific energy expenditure was positively correlated with longevity. We conclude that (i) dietary macronutrient ratios strongly affected obesity development, glucose homeostasis, and longevity, (ii) that skeletal muscle mitochondrial uncoupling alleviated the detrimental effects of high-fat diets, and (iii) that early imbalances in energy homeostasis leading to increased insulin resistance are predictive for a decreased lifespan.

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Dietary effects on body composition, glucose metabolism, and longevity are modulated by skeletal muscle mitochondrial uncoupling in mice

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