Acylated Ghrelin Response to Acute Exercise in Obesity

• Ghrelin is the natural ligand of the hypothalamic GH-secretagogue receptor (GHS-R)-1a (1). Over the time, it has been documented that ghrelin predominantly functions as a central modulator of energy homeostasis via NP-Y and AgRP-containing neurons located in the arcuate nucleus of the hypothalamus (2). It thus promotes the drive to eat and governs long-term energy accumulation; clearly, circulating ghrelin concentrations are related to energy balance based on the following evidences (3):

• ghrelin levels are acutely modulated by food intake and glucose administration
• long-term ghrelin homeostasis reflects adiposity, insulin resistance and chronic exercise
• in fasting and postabsorptive conditions, a negative correlation exists between ghrelin and resting energy expenditure independent of variations in insulin levels, energy intake, body composition or body weight.

In summary, circulating ghrelin levels are approximately 30% lower than normal; are inversely related to increasing body fat, leptin and insulin levels; and are far less responsive to post-meal inhibition than in controls (3).

• In the circulation, ghrelin is found as acylated and desacylated peptide. Ser(3)-octanoylation is a prerequisite for ghrelin biological activity (3). Des-octanoyl ghrelin variants have been additionally identified (4,5) and found to exert novel antiapoptotic effects in primary adult and cultured rat cardiomyocytes (6). Using specific immunoassays recognizing active (N-terminus) and total (N- plus C-terminus) ghrelin levels, assessment of circulating ghrelin concentrations helped to further discriminate specific functions of each at the hypothalamic level (7), on insulin sensitivity (8) or after bariatric surgery (9). Also, an association has been documented between obesity and total and acylated ghrelin concentrations, being respectively 30% and 56% lower than normal (10). Our laboratory showed previously that stratification of obese patients by the ratio of measured/predicted resting energy expenditure, allowed to detect a positive relationship between acylated ghrelin levels and the efficiency of energy expenditure (10). Speculatively, this could be interpreted as an obesity-related compensatory mechanism acting to contain the orexigenic signals afferent to the brain.
• Studies on ghrelin responsiveness to cycloergometer exercise, treadmill exercise or long-distance marathons, originally showed no variation of ghrelin secretion (11-13). More recently, significant decrements of ghrelin levels following acute exercise bouts has been observed in elite athletes and their healthy controls, as well as in lean individuals (14, 15). While these findings suggested a link of ghrelin suppression with GH rise on one side and appetite regulation upon exercise on the other, little is known on the metabolic mechanisms regulating ghrelin response to acute exercise in the lean and obese state.

Based on these observations, our comparative study aims at exploring the response of ghrelin components to a standardized maximal exercise test in the lean and obese state, to identify the neuroendocrine and metabolic predictors of ghrelin response in these groups and document if ghrelin components change as a function of fat accumulation, insulin homeostasis, growth hormone secretion, non-esterified fatty acid availability and exercise performance.

Inclusion criteria

• healthy status
• lean (BMI < 25 kg/m2) and obese subjects (BMI>30 kg/m2)

Exclusion criteria

• cardiovascular disease
• gastrointestinal disease
• diabetes mellitus
• alcohol consumption (wine or equivalents) > 125 ml Day
• physical inability