Publishing in Aging, researchers from the Chengdu Jinjiang Hospital in China have discovered that caloric restriction is less effective on mice previously fed a high-calorie diet.
In their introduction, the researchers discuss what caloric restriction is known to do, citing papers that show its effects on autophagy , inflammation , nutrient sensing , and mitochondrial handling of oxidative stress , all of which are related to aging. The researchers also cite papers showing the well-known effects of obesity, focusing on its related cardiac issues .
One of the critical points of cardiac function, and a focus of this paper, is how mitochondria use fatty acids as fuel through oxidative phosphorlyzation (OXPHOS), which generates 95% of the energy used by the heart  and is regulated through nutrient sensing pathways that involve AMPK, SIRT1, and mTOR.
The researchers also focused on adiponectin, a hormone that is downregulated in obesity and upregulated after weight loss. This hormone is known to have multiple positive effects, including reducing inflammation and oxidation .
With this in mind, the researchers sought to investigate another question: how does caloric restriction affect obesity?
Transitioning between different types of food
For this study, the researchers used four different groups of mice: mice fed nothing but a standard food diet of 3.1 kcal/kg (3.1CG), mice fed standard food for 17 weeks and then a diet of 60% of their previous calories for 13 weeks (3.1CR), mice fed nothing but a 5.5 kcal/kg diet (5.5CG) for the duration of the study, and mice fed a 5.5 kcal/kg diet for 17 weeks and then a 3.1 kcal/kg diet (5.5CR). All of these mice had spent the first 12 weeks of their lives eating a 3.1 kcal/kg diet.
Most of the results of this study were no surprise. The 5.5CG group initially ingested less food than the 3.1CG group, although its food intake approximated the 3.1CG group after 17 weeks. The 5.5CG group had more fat content and was significantly heavier than the other groups, and it had more of the protein Fabp4, a measurement of fat infiltration into other tissues.
Interestingly, the 3.1CR group did not have significantly less fat than the 3.1CG group, although it did have notably lower glucose. The blood glucose of the 5.5CR group closely approximated that of the 3.1CG group after 9 to 13 weeks.
Some surprising effects on the heart
Probably the most surprising finding of this study is how much the caloric restriction groups’ hearts resembled each other in multiple respects. Their sizes during both expansion and contraction were significantly smaller than the control groups, which had similar heart sizes.
However, the ejection fraction of the 3.1CR group was much higher than the 5.5CR group, suggesting permanent damage to the heart in the latter group. Accordingly, and in line with expectations, the 5.5CG group suffered from heart hypertrophy.
Effects on mitochondria
While some metabolic measurements were similar between the two control groups, others were not. The NADH of the 5.5CR group was similar to that of the 3.1CG group, and only the 3.1CR group enjoyed substantial improvements there. Cytochrome numbers were much higher in the 3.1CR group.
While the mtDNA copy numbers were higher in both caloric restriction groups, the researchers examined the biomarker eNOS, using it to conclude that this proliferation only represented significant biogenesis in the 3.1CR group.
Many other biomarkers related to nutrient sensing showed similar effects. AMPK-related biomarkers that were upregulated in the 3.1CR group were significantly downregulated in both 5.5 groups. PGC-1a, a biomarker of metabolic fitness, behaved similarly. Interestingly, SIRT1 was most upregulated in the 5.5CR group, even more than the 3.1CR group; the 5.5CG group had the least SIRT1.
Perhaps this study’s main issue is that it measured the effects of caloric restriction as a percentage of what the mice were used to rather than an absolute value. If the 5.5CR group had received the same amount of calories as the 3.1CR group, the results, and the researchers’ conclusion, might have been significantly different.
Still, this is illustrative of a very real-world scenario: people engaging in weight loss strategies might choose to eat significantly less than they did previously, which might still not be enough of a reduction to confer a measurable benefit in all areas. Such people may wish to seek personalized medical advice in order to engage in healthy weight loss without malnutrition.
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