One of the many interesting but unresolved questions relating to calorie restriction and its beneficial effects on health and longevity is the role played by ghrelin. This hormone regulates appetite, but also has a range of other effects on metabolism. For example, it appears to be involved in immune function and inflammation. This sort of observation raises the question of the degree to which the full physiological experience of hunger is a necessary part of the benefits produced by calorie restriction. Researchers here take a first step in the exploration of this topic with a study of mice genetically engineered to lack ghrelin. The interesting portion of the data is that mice without ghrelin eat less, at least while young, but did not live longer, as is reliably the case in normal mice with a reduced calorie intake. I think that the authors head off in the wrong direction with a focus on AMPK, rather than exploring calorie restriction as an explanation for much of what they observed. There is no real discussion of why it might be that life span was not increased in ghrelin knockout mice, which seems to me the real question here.
In line with what is seen in humans during aging, here we show that old wild-type (WT) mice show an increase in body weight and fat mass, along with a significant decrease in muscle strength and endurance. Although ghrelin deletion (KO) in young animals on regular diet was previously shown not to have a significant effect on food intake, energy expenditure, or body weight, we show for the first time that ghrelin deletion significantly prevented body weight and fat mass gain in older mice while maintaining lean mass and muscle function when compared to wild-type age-matched animals.
As body weight gain develops as a result of energy imbalance, food intake and energy expenditure were studied in detail. Aging was associated with a decline in food intake, but also in spontaneous locomotor activity and total energy expenditure. Ghrelin deletion decreased food intake in young animals and partially prevented the decrease in energy expenditure seen with aging in WT mice. Given that the decrease in locomotor activity seen with aging was similar in WT and KO mice, we postulate that the difference in total energy expenditure between genotypes was primarily due to changes in resting energy expenditure. The data also suggest that a decrease in energy expenditure due to decrease locomotor activity and, perhaps also in resting energy expenditure, is the main variable driving the energy imbalance during aging in mice.
We found no differences in muscle mass or whole body lean mass between genotypes. Nevertheless, the decline in endurance and grip strength seen with aging in WT mice was also partially prevented by ghrelin deletion. In this study, we also show a significant increase in type IIa (fatigue resistant, more oxidative) fiber content with aging in KO compared to WT mice that is likely to be responsible for the increased endurance seen in KO aged animals. We postulate that this increase in type IIa, fatigue-resistant, oxidative fibers could have contributed to the increased energy expenditure and subsequently decreased fat mass seen in aged KO mice as skeletal muscle fibers are major contributors to resting energy expenditure.
At the molecular level, the age-related decreases in endurance and muscle strength were associated with downregulation of phospho-AMPK and its downstream mediators. These changes were partially prevented by ghrelin deletion. Previous studies have shown the importance of the AMPK pathway on improving endurance, and this finding suggests that AMPK modulation by ghrelin could contribute to the phenotype seen in our model of increased endurance and muscle strength. The interplay between ghrelin and AMPK is not well-understood, however. There are no previous reports of chronic effects of ghrelin or ghrelin blockade on AMPK activation; however, it is known that AMPK target genes are key to mitochondrial biogenesis, fatty acid oxidation, and energy expenditure. Taken together, the data are consistent with the hypothesis that AMPK modulation by ghrelin may contribute to ghrelin's effects on muscle function, fat accumulation, and energy expenditure.