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    • The effect of exercise on plasma ghrelin has

    2022-02-14

    The effect of exercise on plasma ghrelin has previously been investigated mostly in humans using exercise regimens such as treadmill running, cycling, and rowing, and also in a few rodent studies and in some other animal models. While many of these clinical studies and some preclinical studies demonstrated lower plasma ghrelin following exercise [36], [38], [39], [40], [41], [42], [43], [69], [70], higher plasma ghrelin also has been observed [37], [44], [45], [46], [71], [72], [73], as has unchanged plasma ghrelin [47], [48], [74]. The wide range of changes to plasma ghrelin could be due to the differences in the type, intensity, and duration of exercise, the metabolic and age profiles of the study subjects, the blood sample processing (which optimally is performed using a specific regimen to preserve bioactive acyl-ghrelin), and the types of ghrelin (e.g. acyl-ghrelin vs. total ghrelin) measured. In our studies, we consistently observed exercise-induced plasma acyl-ghrelin elevations, which positively correlated with the extent of exercise, although it is as yet unclear how much duration of exercise vs. distance run vs. intensity of exercise factored in to this finding. Importantly, these plasma ghrelin elevations were noted immediately at the end of the exercise bouts but were not sustained, instead falling to baseline levels by 2 h post-exercise, and thus highlighting differences in timing of the blood draw as another factor to explain some of the variability in plasma ghrelin level measurements in published human clinical trials. Since ghrelin has the capacity to raise blood glucose [56] and as GHSR-null mice [21] along with ghrelin-knockout mice and several related models [15], [16], [19], [20] exhibit lower blood glucose levels upon caloric restriction, we had expected GHSR-null mice to exhibit lower blood glucose levels upon exercise. However, this was not observed. The lack of genotypic differences in blood glucose between Wt and GHSR-null littermates and the different trajectories of acyl-ghrelin and blood glucose (acyl-ghrelin remains elevated slightly longer than the blood glucose; Supplementary Figure 1) in the exercised mice suggest that the transient rise in blood glucose induced by the HIIE protocol is not dependent on ghrelin. Also of note, we found that somatostatin receptor of GHSR markedly reduced food intake following exercise. While there has been no consensus from clinical studies regarding the overall impact of exercise on food intake, our finding in exercised Wt mice agrees with a majority of clinical studies, which suggest that exercise either does not impact food intake or decreases short-term food intake and/or appetite [35], [75]. Some studies even have suggested that vigorous exercise reduces hunger sensations, a phenomenon referred to as “exercise-induced anorexia” [35], [76], [77]. As genetic deletion of GHSR previously has been shown to have no to only modest effects on food intake in mice with ad lib exposure to regular chow despite the highly potent orexigenic effects of administered ghrelin [2], [3], [4], [5], [14], [18], [78], [79], it was perhaps unexpected for the post-exercise food intake curves of GHSR-null mice to so clearly diverge from those of Wt littermates. Nonetheless, our data suggest that an intact ghrelin system is required for the usual food intake response to exercise, may last several hours post-exercise, and when blocked, may potentially amplify the efficacy of exercise to reduce post-exercise food intake. A noteworthy topic of discussion relates to the potential processes mediating the ghrelin system's overall effect to boost exercise endurance capacity and, in particular, the decreased exercise endurance of GHSR-null mice. Differences in lactate levels and glycogen utilization were observed in GHSR-null mice as compared to Wt littermates and may be relevant to the differential exercise endurance phenotypes. Indeed, exercise endurance is thought by some to rely in part on the amount of blood lactate, which accumulates during exercise as a byproduct of the higher rate of glycolysis needed to meet skeletal muscle energy demand [80]. Importantly, GHSR-null mice coaxed to run past their natural exhaustion time to match the exhaustion time of exercised Wt mice had lower blood lactate concentrations than the Wt mice. Although GHSR deletion did not affect skeletal muscle glycogen utilization, activation of hepatic gluconeogenic genes, or skeletal muscle pAMPK, our data suggest that GHSR deletion was possibly associated with a greater rate of hepatic glycogen depletion during exercise. Furthermore, reduced levels of hepatic glycogen phosphorylase and pyruvate carboxylase mRNA were observed in GHSR-nulls forced to run as long as exhausted Wt mice. Thus, overutilization of hepatic glycogen stores and/or inefficiencies in the ability to generate sufficient amounts of gluconeogenic intermediates could reduce exercise endurance in GHSR-null mice. In fact, the inability to generate those gluconeogenic substrates has been proposed to be a key deficit that leads to severe hypoglycemia in ghrelin-knockout mice challenged with a week-long 60% caloric restriction protocol [19], [20].