Acipimox Administration With Exercise Induces a Co-feedback Action of the GH, PP, and PYY on Ghrelin Associated With a Reduction of Peripheral Lipolysis in Bulimic and Healthy-Weight Czech Women: A Randomized Study

Kvido Smitka, Jara Nedvidkova, Karel Vondra, Martin Hill, Hana Papezova, Vojtech Hainer, Kvido Smitka, Jara Nedvidkova, Karel Vondra, Martin Hill, Hana Papezova, Vojtech Hainer

Abstract

Objective: Anti-lipolytic drugs and exercise are enhancers of growth hormone (GH) secretion. Decreased circulating free fatty acids (FFA) have been proposed to exert ghrelin-GH feedback loop after administration of an anti-lipolytic longer-acting analog of nicotinic acid, Acipimox (OLB, 5-Methylpyrazine-2-carboxylic acid 4-oxide, molecular weight of 154.1 Da). OLB administration strongly suppresses plasma FFA during exercise. Neuroendocrine perturbations of the adipose tissue (AT), gut, and brain peptides may be involved in the etiopathogenesis of eating disorders including bulimia nervosa (BN) and anorexia nervosa. BN is characterized by binge eating, self-induced vomiting or excessive exercise. Approach: To test the hypothesis that treatment with OLB together with exercise vs. exercise alone would induce feedback action of GH, pancreatic polypeptide (PP), peptide tyrosine tyrosine (PYY), and leptin on ghrelin in Czech women with BN and in healthy-weight Czech women (HW). The lipolysis rate (as glycerol release) in subcutaneous abdominal AT was assessed with microdialysis. At an academic medical center, 12 BN and 12 HW (the control group) were randomized to OLB 500 mg 1 h before a single exercise bout (45 min, 2 W/kg of lean body mass [LBM]) once a week vs. identical placebo over a total of 2 weeks. Blood plasma concentrations of GH, PP, PYY, leptin, ghrelin, FFA, glycerol, and concentrations of AT interstitial glycerol were estimated during the test by RIA utilizing 125I-labeled tracer, the electrochemiluminescence technique (ECLIA) or colorimetric kits. Results: OLB administration together with short-term exercise significantly increased plasma GH (P < 0.0001), PP (P < 0.0001), PYY, and leptin concentrations and significantly decreased plasma ghrelin (P < 0.01) concentrations in both groups, whereas short-term exercise with placebo resulted in plasma ghrelin (P < 0.05) decrease exclusively in BN. OLB administration together with short-term exercise significantly lowered local subcutaneous abdominal AT interstitial glycerol (P < 0.0001) to a greater extent in BN. Conclusion: OLB-induced suppression of plasma ghrelin concentrations together with short-term exercise and after the post-exercise recovering phase suggests a potential negative co-feedback of GH, PP, PYY, and leptin on ghrelin secretion to a greater extent in BN. Simultaneously, the exercise-induced elevation in AT interstitial glycerol leading to a higher inhibition of peripheral lipolysis by OLB in BN. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03338387.

Keywords: eating disorders; exercise; ghrelin; growth hormone; human adipose tissue; microdialysis; olbetam; pancreatic polypeptide family.

Figures

Figure 1
Figure 1
Scheme demonstrating the various pathways of food intake regulations. Ghrelin is produced by stomach and stimulates GH release by acting GHS-R1a in the anterior pituitary and on GHRH neurons in the ARC of hypothalamus. Further, ghrelin stimulates the NPY/AGRP neurons via GHS-R1a in the ARC. GHS-R1a in the hypothalamus is also expressed in PVN and VMH. Moreover, ghrelin via GHS-R1a increases food intake by releasing of GABA inhibitory input from NPY/AGRP neurons to POMC/CART neurons in the ARC. PYY and PP are secreted from distal ileum, colon and pancreas to produce an inhibitory effect on NPY/AGRP neurons via Y2R and Y4R in the ARC. Leptin is secreted from AT to inhibit the NPY/AGRP neurons and stimulate the POMC/CART neurons via LEPR in the ARC. Elevated activity of POMC neurons increases alpha-MSH release in the PVN, which acts on MC4R to inhibit food intake. Orexigenic signals from the NPY neurons act on Y1R and Y5R in the PVN, whereas AGRP antagonizes MC4R. NPY, neuropeptide tyrosine; GH, growth hormone; ARC, arcuate nucleus; PVN, paraventricular nucleus; VMH, ventromedial nucleus; AT, adipose tissue; LEPR, leptin receptor; GHS-R1a, growth hormone secretagogue receptor type 1a; GHRH, growth hormone releasing hormone; POMC, pro-opiomelanocortin; CART, cocaine and amphetamine related transcript; GABA, gamma-aminobutyric acid; AGRP, agouti-related protein; MC4R, melanocortin 4 receptor; alpha-MSH, alpha-melanocyte-stimulating hormone; Y1, 2, 4, 5R, Y receptors; PP, pancreatic polypeptide; PYY, peptide tyrosine tyrosine; (+) = the stimulatory effect; (-) = the inhibitory effect.
Figure 2
Figure 2
Flow chart depicting the experimental timeline when drugs and exercise were administered. Microdialysis and venous catheters were inserted at least 60 min before microdialysate and blood sampling. After 60 min of equilibration, basal microdialysate samples were collected in 45 min interval. OLB or placebo were administered orally 60 min before a single exercise bout. Then the subjects performed 45 min a single exercise bout (2 W/kg of LBM) followed by 90 min of recovery period. Microdialysate samples were collected 45 min during exercise and at last 45 min interval before ending the 90 min post-exercise recovering period. Blood samples were collected at 45 min of the investigation (basal) and at 165 min of the investigation (immediately after exercise) and at 255 min of the investigation (90 min after post-exercise recovering period). OLB, Olbetam; LBM, lean body mass.
Figure 3
Figure 3
Effect of Acipimox or placebo administration together with exercise on plasma growth hormone (A), ghrelin (B), and leptin (C) levels. Values are means ± S.E.M. HW = healthy-weight Czech women, BN = Czech women with bulimia nervosa, n = the numbers of subjects are in brackets. Effect of 45 min exercise (at 165 min after the start of the experiment, 2 W/kg of lean body mass [LBM]) and effect of 90 min post-exercise recovery phase (at 255 min after the start of the experiment) alone or together with Acipimox (OLB) administration on plasma growth hormone (GH), ghrelin and leptin levels in healthy-weight Czech women (HW) (n = 12) and in Czech women with bulimia nervosa (BN) (n = 12). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 vs. resting (basal) values.
Figure 4
Figure 4
Effect of Acipimox or placebo administration together with exercise on plasma pancreatic polypeptide (A), neuropeptide Y (B), and peptide YY (C) levels. Values are means ± S.E.M. HW = healthy-weight Czech women, BN = Czech women with bulimia nervosa, n = the numbers of subjects are in brackets. Effect of 45 min exercise (at 165 min after the start of the experiment, 2 W/kg of lean body mass [LBM]) and effect of 90 min post-exercise recovery phase (at 255 min after the start of the experiment) alone or together with Acipimox (OLB) administration on plasma pancreatic polypeptide (PP), neuropeptide tyrosine (NPY), and peptide tyrosine tyrosine (PYY) levels in healthy-weight Czech women (HW) (n = 12) and in Czech women with bulimia nervosa (BN) (n = 12). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 vs. resting (basal) values.
Figure 5
Figure 5
Effect of Acipimox or placebo administration together with exercise on adipose tissue (AT) glycerol (A), and plasma glycerol (B), and plasma free fatty acids (C) levels. Values are means ± S.E.M. HW = healthy-weight Czech women, BN = Czech women with bulimia nervosa, n = the numbers of subjects are in brackets. Effect of 45 min exercise (at 165 min after the start of the experiment, 2 W/kg of lean body mass [LBM]) and effect of 90 min post-exercise recovery phase (at 255 min after the start of the experiment) alone or together with Acipimox (OLB) administration on adipose tissue (AT) glycerol levels and plasma glycerol and plasma free fatty acids (FFA) levels in healthy-weight Czech women (HW) (n = 12) and in Czech women with bulimia nervosa (BN) (n = 12). *P < 0.05, **P < 0.01, ****P < 0.0001 vs. resting (basal) values.

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