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Insulin and Brain Reward Systems
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Brian C. Liu, Qingchen Zhang, Emmanuel N. Pothos
Ghrelin is often known as the “hunger hormone” and is secreted from the stomach (59). The growth hormone secretagogue receptor (GHSR), the receptor for ghrelin, is found in the hypothalamus as well (60, 61). Mice with a GHSR knockout fed with a high-fat diet store fewer calories and have lower body weight and adipose tissue compared to control mice. These mice also demonstrate improved glucose homeostasis. The site of action by which ghrelin increases food intake and adipose tissue appears to be the hypothalamus (62). Indeed, it has been hypothesized that the effects of ghrelin may oppose and regulate the effects of leptin and insulin in the hypothalamus (61). There is additional evidence that ghrelin, like leptin, not only impacts on homeostatic processing of energy balance but also on hedonic properties of food intake and underlying neurotransmission (62–65) so much so that it plays a significant role in the neurochemical ‘signatures” of obesity and eating disorders. Although the synergistic or additive role of central insulin to ghrelin effects on food reward has not been adequately investigated, one can only assume that such interaction is at play and likely constitutes a significant part of the neurochemical phenotype of disorders that impact both metabolism and hedonic/compulsive food intake.
Central and Peripheral Modulators of Appetite and Satiety
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
Gabrielle Page-Wilson, Sam Dagogo-Jack
The polypeptide ghrelin was initially described and characterized as the endogenous ligand for the growth hormone secretagogue receptor in 1999 (Kojima et al. 1999). The ghrelin molecule contains 28 amino acids and an acyl radical, the latter being essential for biologic effect. The post-translational acylation of ghrelin is mediated by the enzyme gastric O-acyl transferase (GOAT) (Yang et al. 2008). Ghrelin is synthesized and secreted by the stomach, reaches the anterior pituitary via the circulation, and stimulates growth hormone secretion by the somatotrophs. The nutritional effects of ghrelin became evident when it was shown that central (ICV) administration potently increased food intake in rodents (Wren et al. 2000). A similar effect on food intake was observed following peripheral (IV) injection of ghrelin in rats (Wren et al. 2000). In humans, intravenous administration of ghrelin stimulates food intake by approximately 30% (Wren et al. 2001). Interestingly, ghrelin is the only metabotropic peptide thus far identified that stimulates food intake directly when administered peripherally.
Adipose Tissue as an Important Body Organ
Published in Roy J. Shephard, Obesity: A Kinesiologist’s Perspective, 2018
Low levels of energy reserves lead (probably through the leptin/ghrelin feedback mechanism) to a disruption in normal functioning of the hypothalamic/pituitary/ovarian axis [15]. Amenorrhoea and infertility are associated with a low fat mass, low leptin levels, and increased ghrelin levels [15]. Ghrelin is the endogenous ligand of the growth hormone secretagogue receptor, eliciting the secretion of growth hormone and regulating food intake. Leptin receptors have also been located in those areas of the hypothalamus associated with the pulsatility of gonadotropin-releasing hormone (GRH). Ghrelin levels influence the function of various tissues involved in reproduction, including the placenta, endometrium, ovary, and Leydig cells of the testis (where testosterone secretion is inhibited) [47, 80]. Impaired GRH pulsatility leads to a disruption of luteinizing hormone pulses that would normally trigger ovulation, formation of the corpus luteum, and gonadal steroid release from the ovaries [59]. A lack of fat also leads to low levels of oestrogen formation from androgens in adipose tissue, with loss of libido and an absence of normal endometrial thickening over the menstrual cycle.
Effect of feeding regimen on circadian activity rhythms of food anticipatory by ghrelin hormone in a pig model
Published in Nutritional Neuroscience, 2023
He Zhang, Xiaoxi Yan, Ailian Lin, Pengke Xia, Menglan Jia, Yong Su
Total protein was extracted from the hypothalamus tissue of pigs in animal experiment 1 and animal experiment 2, and N38 cells using the RIPA lysis buffer (Thermo Scientific, Waltham, MA, USA) containing protease inhibitors. The protein concentrations were determined using the BCA protein assay kit (Nanjing Jiancheng Institute of Bioengineering, Nanjing, China). A total of 20 μg extracted protein were separated by 10% SDS-PAGE gel electrophoresis and then transferred onto the polyvinylidene fluoride (PVDF) membrane (Millipore, Bedford, MA, USA). Primary antibodies against growth hormone secretagogue receptor (GHS-R1a) (Bioss, China), phospho-CREB (p-CREB) (Bioss, China), and phospho-CaMKII (p-CaMKII) (Bioss, China) were used, and β-Actin was used as an internal control for normalization. HRP conjugated Goat Anti-mouse or Anti-rabbit IgG (Santa Cruz, USA) was used as the secondary antibody.
New approved and emerging pharmacological approaches to alcohol use disorder: a review of clinical studies
Published in Expert Opinion on Pharmacotherapy, 2021
Kirsten C Morley, Christina J Perry, Joshua Watt, Tristan Hurzeler, Lorenzo Leggio, Andrew J Lawrence, Paul Haber
The novel ghrelin receptor inverse agonist PF-5,190,457, which blocks the growth hormone secretagogue receptor 1a (GHS-R1a), has recently been examined in heavy drinking individuals [119,120]. In a crossover design, 12 heavy drinking individuals were randomized to placebo/0 mg b.i.d. or PF-519,045 (50 mg b.i.d. or 100 mg b.i.d.) and completed an alcohol and food cue-reactivity procedure and an alcohol challenge administration session. All adverse events were mild or moderate and dose did not change alcohol concentration or alcohol-induced sitmulation or sedation. The highest dose of PF-5,190,457 reduced alcohol craving during the cue-reactivity procedure. This study provides the first translational evidence of safety and tolerability of the ghrelin receptor inverse agonist PF-5,190,457 when coadministered with alcohol [120]. The same group also reported on the effects of PF-5,190,457 on blood neuroendocrine hormone concentrations, whereby blood hormone levels were largely unaffected both during dosing and during an alcohol challenge [119].
An overview of ghrelin O-acyltransferase inhibitors: a literature and patent review for 2010-2019
Published in Expert Opinion on Therapeutic Patents, 2020
Jacob E. Moose, Katelyn A. Leets, Nilamber A. Mate, John D. Chisholm, James L. Hougland
Ghrelin is a 28-amino acid peptide hormone that is notable as the only known hunger-stimulating hormone in humans. Originally discovered in 1999 during the search for the endogenous ligand of the growth hormone secretagogue receptor (GHS-R1a), ghrelin stimulates the release of growth hormone (GH) upon receptor activation [1]. When compared to ghrelin isolated from rat stomach extracts by reverse-phase HPLC, a synthetic ghrelin peptide exhibited a shift in retention time indicating the presence of a hydrophobic modification on the naturally occurring hormone [1]. This modification was identified as octanoylation of the hydroxyl sidechain of serine-3, with this acylation found to be essential for ghrelin to activate GH secretion [1]. While originally identified in the stomach, ghrelin expression has also been reported in a wide range of other tissues, consistent with the variety of physiological effects attributed to ghrelin signaling [1–4].