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Ghrelin Signaling in Immunometabolism and Inflamm-Aging.
Fang, C, Xu, H, Guo, S, Mertens-Talcott, SU, Sun, Y
Advances in experimental medicine and biology. 2018;:165-182
Abstract
Intracellular changes in immune cells lead to metabolic dysfunction, which is termed immunometabolism. Chronic inflammation is a hallmark of aging; this phenomenon is described as inflamm-aging. Immunometabolism and inflamm-aging are closely linked to obesity, insulin resistance, type 2 diabetes (T2D), cardiovascular diseases, and cancers, which consequently reduce life span and health span of the elderly. Ghrelin is an orexigenic hormone that regulates appetite and food intake. Ghrelin's functions are mediated through its receptor, growth hormone secretagogue receptor (GHS-R). Ghrelin and GHS-R have important roles in age-associated obesity, insulin resistance, and T2D. In this chapter, we have discussed the roles of ghrelin signaling in diet-induced obesity and normal aging as it relates to energy metabolism and inflammation in key metabolic tissues and organs. The new findings reveal that ghrelin signaling is an important regulatory mechanism for immunometabolism and inflamm-aging. Ghrelin signaling offers an exciting novel therapeutic strategy for treatment of obesity and insulin resistance of the elderly.
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2.
The Role of Ghrelin in Senescence: A Mini-Review.
Yin, Y, Zhang, W
Gerontology. 2016;(2):155-62
Abstract
Ghrelin, a 28-amino acid hormone produced mainly by the X/A-like endocrine cells in gastric mucosa, has a widespread tissue distribution and diverse physiological functions such as hormonal, orexigenic, metabolic, cardiovascular, neurological, and immunological activities. Considerable evidence has suggested that ghrelin plays an important role in organism senescence or aging. The present review provides a comprehensive picture of this new development. We first reviewed the aging (senescence)-dependent reduction of ghrelin signaling, and then highlighted its relationship with the aging-associated alteration in food intake, energy metabolism, cardiovascular function, neurological activity, and adaptive immunity. Our literature review suggests that ghrelin is an innovative and promising agent in the treatment of these pathophysiological conditions associated with senescence.
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3.
From endocrine to rheumatism: do gut hormones play roles in rheumatoid arthritis?
Chen, CY, Tsai, CY
Rheumatology (Oxford, England). 2014;(2):205-12
Abstract
RA is characterized by chronic inflammation in the musculoskeletal system, in which TNF-α is the key cytokine trigger. TNF-α, previously known as cachectin, is implicated in the modulation of body composition and energy expenditure. Gut hormones, including acyl ghrelin, des-acyl ghrelin, GIP, GLP-1 and PYY, have been known to be the major regulators of appetite, nutrition, energy expenditure and body mass formation. Emerging evidence indicates that blockade of TNF-α by biologics not only ameliorates rheumatoid inflammation, but can affect the secretion and action of gut hormones on appetite, body composition, energy expenditure, muscle catabolism and bone remodelling. A link between the gastrointestinal endocrine axis and the immune system may be established through the interaction of proinflammatory cytokines, including TNF-α and these gut hormones. With the ever-increasing understanding of rheumatoid inflammation and the invention of more biologics to modulate the cytokine network, more attention should be given to the possible immunomodulatory roles of gut hormones in autoimmune inflammatory reactions.
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4.
The growth hormone secretagogue receptor (Ghs-R).
Laviano, A, Molfino, A, Rianda, S, Rossi Fanelli, F
Current pharmaceutical design. 2012;(31):4749-54
Abstract
The growth hormone secretagogue receptor (GHS-R) is a component of the ghrelin signaling pathway and is involved in mediating the pleiotropic effects of ghrelin. Two isoforms have been identified, but only GHS-R1a binds with acyl ghrelin and transduces its message. However, the inactive variant of GHS-R, GHS-R1b, appears to play a critical role in modulating the activity of GHS-R1a by forming heterodimeric complexes which attenuates trafficking of the active variant to the cell surface. The molecular mechanisms of signal transduction are complex and are specific of the tissues where GHS-R1a is expressed. The potent induction of GH secretion and the stimulation of appetite are the most intensively studied functions of GHS-R1a. However, the tissue distribution of GHS-R1a extends beyond the pituitary and the hypothalamus, and reflects the different biological functions of the ghrelin/GHS-R system. GHS-R1a is also expressed in other brain areas, in the pancreas, adipose tissue, immune cells and cardiovascular system, and modulates learning and memory, glucose and lipid metabolism, inflammatory response and cardiac performance. The pleiotropic effects of the ghrelin/GHS-R system suggest their exploitation to prevent and treat a number of clinical conditions. Among many other syndromes and diseases, cancer cachexia, aging related cognitive decline, obesity and diabetes may significantly benefit from the use of GHS-R1a agonists or antagonists.
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5.
Serum ghrelin levels in inflammatory bowel disease with relation to disease activity and nutritional status.
Ates, Y, Degertekin, B, Erdil, A, Yaman, H, Dagalp, K
Digestive diseases and sciences. 2008;(8):2215-21
Abstract
Ghrelin possesses various biological activities -- it stimulates growth hormone (GH) release, plays a major role in energy metabolism, and is one of the hormones that affects body composition. It also plays a role in modulating immune response and inflammatory processes. In this study we aimed to determine whether serum ghrelin levels had correlation with markers associated with disease activation. We also investigated any probable relationship between serum ghrelin level and nutritional status. Serum levels of ghrelin and its relationship with disease activity and nutritional status were evaluated in 34 patients with ulcerative colitis (UC), 25 patients with Crohn's disease (CD), and 30 healthy controls. Serum ghrelin levels, serum IGF-1 and GH levels, and markers of disease activity (sedimentation, C-reactive protein, and fibrinogen) were measured in all subjects. Body composition and nutritional status was assessed by both direct (by anthropometry) and indirect (by bioimpedance) methods. Serum ghrelin levels were significantly higher in patients with active UC and CD than in those in remission (108 +/- 11 pg/ml vs. 71 +/- 13 pg/ml for UC patients, P < 0.001; 110 +/- 10 pg/ml vs. 75 +/- 15 pg/ml for CD patients, P < 0.001). Circulating ghrelin levels in UC and CD patients were positively correlated with sedimentation, fibrinogen and CRP and was negatively correlated with IGF-1, BMI, TSFT, MAC, fat mass (%), and fat free mass (%). This study demonstrates that patients with active IBD have higher serum ghrelin levels than patients in remission and high levels of circulating ghrelin correlate with the severity of disease and the activity markers. Ghrelin levels in inflammatory bowel disease (IBD) patients show an appositive correlation with IGF-1 and bioelectrical impedance analysis, body composition, and anthropometric assessments. Finally, we arrived at the conclusion that ghrelin level may be important in determination of the activity in IBD patients and evaluation of nutritional status.
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6.
Gut hormones and the treatment of disease cachexia.
Ashby, D, Choi, P, Bloom, S
The Proceedings of the Nutrition Society. 2008;(3):263-9
Abstract
Advances in the understanding of appetite are leading to a refined concept of disease cachexia and point to novel therapeutic strategies based on the manipulation of appetite. The complex social and psychological short-term influences on appetite obscure the fact that over the longer term appetite is tightly regulated by physiological considerations; the homeostatic control of energy balance. Like obesity, which is now viewed as a disorder of homeostasis, cachexia can be seen as an adaptive response to the disease state that becomes harmful when prolonged. Several lines of evidence implicate a disorder of appetite regulation in the pathogenesis of cachexia. As the only known circulating mediator of increased appetite the peptide hormone ghrelin has attracted attention as a potential therapy. Trials in patients with various chronic illnesses, including cancer and kidney failure, have demonstrated short-term increases in energy intake. Trials in patients with emphysema and heart failure have also shown benefits in clinical outcomes such as lean body mass and exercise capacity, and longer-term trials using oral analogues are being undertaken. As well as improving nutrition, ghrelin has a number of other actions that may be useful, including an anti-inflammatory effect; of interest since many cachexias are associated with inappropriate immune activation. The manipulation of appetite, in particular by ghrelin agonism, is emerging as an exciting potential therapy for disease cachexia. Future research should focus on the ascertainment of clinically-relevant outcomes, and further characterisation of the non-nutritional effects of this pathway.