Associations of postprandial ghrelin, liver-expressed antimicrobial peptide 2 and leptin levels with body composition, disease progression and survival in patients with amyotrophic lateral sclerosis

Abstract

Background and purpose: Loss of appetite contributes to weight loss and faster disease progression in amyotrophic lateral sclerosis (ALS). Impairment of appetite control in ALS may include altered production or action of orexigenic (i.e., ghrelin) and anorexigenic (i.e., liver-expressed antimicrobial peptide 2 [LEAP2] and leptin) hormones. We aimed to determine if postprandial circulating ghrelin levels, LEAP2 levels, LEAP2:ghrelin molar ratio and leptin levels differ in ALS patients compared to non-neurodegenerative disease controls, and whether they are associated with disease progression and body composition.

Methods: In this prospective natural history study, we assessed postprandial plasma levels of ghrelin, LEAP2 and leptin in patients with ALS (cases; n = 46) and controls (controls; n = 43). For cases, measures were compared to changes in body weight, body composition and clinical outcomes.

Results: Postprandial ghrelin level was decreased by 52% in cases compared to controls (p = 0.013). LEAP2:ghrelin molar ratio was increased by 249% (p = 0.009), suggesting greater ghrelin resistance. Patients with lower LEAP2:ghrelin tended to have better functional capacity at assessment, as inferred by the ALS Functional Rating Scale-Revised (τ = -0.179, p = 0.086). Furthermore, ghrelin and LEAP2:ghrelin molar ratio correlated with diagnostic delay (ghrelin, τ = 0.223, p = 0.029; LEAP2:ghrelin, τ = -0.213, p = 0.037). Baseline ghrelin level, LEAP2 level, LEAP2:ghrelin ratio and leptin level were, however, not predictive of change in functional capacity during follow-up. Also, patients with higher postprandial ghrelin levels (hazard ratio [HR] 1.375, p = 0.048), and lower LEAP2:ghelin ratios (HR 0.828, p = 0.051) had an increased risk of earlier death.

Conclusions: Reduced postprandial ghrelin levels, coupled with increased LEAP2:ghrelin molar ratios, suggests a loss of ghrelin action in patients with ALS. Given ghrelin's actions on appetite, metabolism and neuroprotection, reduced ghrelin and greater ghrelin resistance could contribute to impaired capacity to tolerate the physiological impact of disease. Comprehensive studies are needed to explain how ghrelin and LEAP2 contribute to body weight regulation and disease progression in ALS.

Keywords: LEAP2; amyotrophic lateral sclerosis; disease progression; functional decline; ghrelin; leptin.

FIGURE 1

Peripherally produced and secreted ghrelin, liver‐expressed antimicrobial peptide‐2 (LEAP2) and leptin regulates appetite and body weight, acting within the hypothalamus to stimulate (ghrelin) or suppress (leptin) hunger. Binding to ghrelin's receptor (the growth hormone secretagogue receptor; GHSR), LEAP2 antagonizes the actions of ghrelin. LEPR, leptin receptor.

FIGURE 2

Patients were recruited from within ongoing studies on metabolism. Controls were recruited as a convenience sample of family and friends. ALS, amyotrophic lateral sclerosis; ALSFRS‐R, ALS Functional Rating Scale‐Revised; LEAP2, liver‐expressed antimicrobial peptide‐2; MND, motor neuron disease.

FIGURE 3

Correlation matrix illustrating associations between postprandial measures of ghrelin, leptin, liver‐expressed antimicrobial peptide‐2 (LEAP2) and LEAP2:ghrelin molar ratio, and measures of body composition in cases (grey shaded area) and controls (white area). Circles represent Kendall's t (where size and colour indicate the strength and direction of the correlation); only correlations with p values ≤ 0.05 are shown. BMI, body mass index; FMI, fat mass index.

FIGURE 4

Longitudinal anthropometric (top line) and clinical (bottom line) outcomes in patients with amyotrophic lateral sclerosis. Significance determined using the likelihood‐ratio test. m = slope of regression. ALSFRS‐R, Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised; BMI, body mass index; FMI, fat mass index.

FIGURE 5

Survival probability for patients with amyotrophic lateral sclerosis relative to postprandial ghrelin levels and the liver‐expressed antimicrobial peptide‐2 (LEAP2) (LEAP2):ghrelin molar ratio. Crude Kaplan–Meier curves for participants stratified by (a) ghrelin and (b) LEAP2:ghrelin molar ratio, where ‘lower’ values represent the first quartile, ‘intermediate’ values are the combined second and third quartiles, and ‘higher’ values are the fourth quartile. + indicate censors.