High-fat diets rich in medium- versus long-chain fatty acids induce distinct patterns of tissue specific insulin resistance

Excess dietary long-chain fatty acid (LCFA) intake results in ectopic lipid accumulation and insulin resistance. Since medium-chain fatty acids (MCFA) are preferentially oxidized over LCFA, we hypothesized that diets rich in MCFA result in a lower ectopic lipid accumulation and insulin resistance compared to diets rich in LCFA. Feeding mice high-fat (HF) (45% kcal fat) diets for 8 weeks rich in triacylglycerols composed of MCFA (HFMCT) or LCFA (HFLCT) revealed a lower body weight gain in the HFMCT-fed mice. Indirect calorimetry revealed higher fat oxidation on HFMCT compared to HFLCT (0.011.0±0.0007 vs. 0.0096±0.0015 kcal/g body weight per hour, P<.05). In line with this, neutral lipid immunohistochemistry revealed significantly lower lipid storage in skeletal muscle (0.05±0.08 vs. 0.30±0.23 area%, P <.05) and in liver (0.9±0.4 vs. 6.4±0.8 area%, P<.05) after HFMCT vs. HFLCT, while ectopic fat storage in low fat (LF) was very low. Hyperinsulinemic euglycemic clamps revealed that the HFMCT and HFLCT resulted in severe whole body insulin resistance (glucose infusion rate: 53.1±6.8, 50.8±15.3 vs. 124.6±25.4 μmol min⁻¹ kg⁻¹, P<.001 in HFMCT, HFLCT and LF-fed mice, respectively). However, under hyperinsulinemic conditions, HFMCT revealed a lower endogenous glucose output (22.6±8.0 vs. 34.7±8.5 μmol min⁻¹ kg⁻¹, P<.05) and a lower peripheral glucose disappearance (75.7±7.8 vs. 93.4±12.4 μmol min⁻¹ kg⁻¹, P<.03) compared to HFLCT-fed mice. In conclusion, both HF diets induced whole body insulin resistance compared to LF. However, the HFMCT gained less weight, had less ectopic lipid accumulation, while peripheral insulin resistance was more pronounced compared to HFLCT. This suggests that HF-diets rich in medium- versus long-chain triacylglycerols induce insulin resistance via distinct mechanisms.     

Peroxisomes contribute to the acylcarnitine production when the carnitine shuttle is deficient

Fatty acid β-oxidation may occur in both mitochondria and peroxisomes. While peroxisomes oxidize specific carboxylic acids such as very long-chain fatty acids, branched-chain fatty acids, bile acids, and fatty dicarboxylic acids, mitochondria oxidize long-, medium-, and short-chain fatty acids. Oxidation of long-chain substrates requires the carnitine shuttle for mitochondrial access but medium-chain fatty acid oxidation is generally considered carnitine-independent. Using control and carnitine palmitoyltransferase 2 (CPT2)- and carnitine/acylcarnitine translocase (CACT)-deficient human fibroblasts, we investigated the oxidation of lauric acid (C12:0). Measurement of the acylcarnitine profile in the extracellular medium revealed significantly elevated levels of extracellular C10- and C12-carnitine in CPT2- and CACT-deficient fibroblasts. The accumulation of C12-carnitine indicates that lauric acid also uses the carnitine shuttle to access mitochondria. Moreover, the accumulation of extracellular C10-carnitine in CPT2- and CACT-deficient cells suggests an extramitochondrial pathway for the oxidation of lauric acid. Indeed, in the absence of peroxisomes C10-carnitine is not produced, proving that this intermediate is a product of peroxisomal β-oxidation. In conclusion, when the carnitine shuttle is impaired lauric acid is partly oxidized in peroxisomes. This peroxisomal oxidation could be a compensatory mechanism to metabolize straight medium- and long-chain fatty acids, especially in cases of mitochondrial fatty acid β-oxidation deficiency or overload.     

Changes in carnitine octanoyltransferase activity induce alteration in fatty acid metabolism

The peroxisomal beta oxidation of very long chain fatty acids (VLCFA) leads to the formation of medium chain acyl-CoAs such as octanoyl-CoA. Today, it seems clear that the exit of shortened fatty acids produced by the peroxisomal beta oxidation requires their conversion into acyl-carnitine and the presence of the carnitine octanoyltransferase (CROT). Here, we describe the consequences of an overexpression and a knock down of the CROT gene in terms of mitochondrial and peroxisomal fatty acids metabolism in a model of hepatic cells. Our experiments showed that an increase in CROT activity induced a decrease in MCFA and VLCFA levels in the cell. These changes are accompanied by an increase in the level of mRNA encoding enzymes of the peroxisomal beta oxidation. In the same time, we did not observe any change in mitochondrial function. Conversely, a decrease in CROT activity had the opposite effect. These results suggest that CROT activity, by controlling the peroxisomal amount of medium chain acyls, may control the peroxisomal oxidative pathway.     

不同链长脂肪酸对斑马鱼的性腺脂肪酸组成、繁殖力与仔鱼成活率的影响

将体质健壮的4月龄斑马鱼(Danio rerio)亲鱼[雄鱼(0.36±0.05) g/尾, 雌鱼(0.59±0.06) g/尾]雌雄各180尾, 随机平均分配在室内斑马鱼循环系统的18个养殖缸中。在斑马鱼基础饲料(对照组)中分别添加7 g/kg n-3HUFA (高不饱和脂肪酸, Highly unsaturated fatty acid)(HUFA组)及10 g/kg MCFA (中链脂肪酸, Medium chain fatty acid)(MCFA组), 制成3组等氮等脂饲料, 饲养90d后, 探究不同链长脂肪酸对斑马鱼的性腺脂肪酸组成、繁殖力和仔鱼成活率的影响。结果表明: (1)3组雌鱼性腺的脂肪酸组成均受到所饲喂饲料脂肪酸组成的影响, 其相关系数均在0.8以上。HUFA组雌鱼性腺中EPA和DHA的相对含量显著高于MCFA组及对照组(P<0.05), 而MCFA组与对照组之间无显著差异; HUFA组油酸的相对含量显著低于MCFA组及对照组(P<0.05), 而MCFA组与对照组之间无显著差异; HUFA组及MCFA组亚麻酸的相对含量与对照组之间均无显著差异, 但MCFA组显著高于HUFA组(P<0.05)。(2)HUFA组及MCFA组雌鱼的成熟系数、绝对繁殖力、体重与体长的相对繁殖力均显著高于对照组(P<0.05), 同时在雌鱼绝对繁殖力、相对繁殖力上, HUFA组显著高于MCFA组(P<0.05)。(3)将对照组雄鱼与各组雌鱼配对繁殖的结果显示, 分别与HUFA组及MCFA组雌鱼配对繁殖后的雌鱼的绝对产卵量、相对产卵量和仔鱼成活率均显著高于与对照组雌鱼的配对, 同时以上指标HUFA组雌鱼均显著高于MCFA组雌鱼(P<0.05)。将对照组雌鱼与各组雄鱼配对繁殖的结果表明, 与HUFA组雄鱼配对后其受精率均显著高于与MCFA组及对照组雄鱼的配对(P<0.05)。综上所述, 试验饲料显著影响斑马鱼雌鱼性腺的脂肪酸组成, HUFA及MCFA均可以促进斑马鱼雌鱼的繁殖性能和仔鱼成活率的提高, 在试验条件下, HUFA的效果更好。