Capítulo 2. Los estudios de comunicación móvil desde un
2.2. Discursos y sentidos
2.3.2. Llenado de tiempos vacíos y tele-encapullamiento
Knocking out the activity of a gene provides powerful information for studying the biological function of gene products. Table 4 shows a summary of the results from studies investigating transgenic and knockout models for ghrelin and GHSR. The global deletion of the GHRL gene in mice results in a normal energy balance, food intake and adiposity on a standard diet [176, 320-322]. These findings were surprising and lead to the interpretation that endogenous ghrelin may not be of crucial relevance for physiological energy homeostasis. Others have attributed the lack of a metabolic phenotype to compensatory processes during early developmental phases or the presumably redundant multiplicity of pathways controlling energy balance. Furthermore, some studies have suggested that the GHSR 1a exhibits basal constitutive activity [152, 323] and thus could still provide possible residual signalling in ghrelin target cells, even in the absence of the primary ligand in mice with targeted disruption of the GHRL gene [153]. However, chronic exposure of ghrelin-deficient mice to a high-fat diet resulted in a reduction in weight gain and increased use of fat as fuel [176, 321]. When ghrelin deficiency was induced in adult animals, reduced food intake, reduced fat storage and weight loss were observed [324, 325]. This suggests that ghrelin is an important player in the field of energy homeostasis and appetite regulation, as part of a bigger network of regulatory
Table 4. Animal models for ghrelin and GHSR (modified from Higgins et al, 2007 [173])
Ghrelin Embryonic/Adult Finding/phenotype compared to WT littermates Reference
Embryonic ghrelin KO No detected difference as compared to WT [320]
Embryonic ghrelin KO KO animals on a high-fat diet showed preferential
use of fat as a metabolic substrate
[176]
Embryonic ghrelin KO Males on high-fat diet showed less weight gain and
higher locomotor activity
[321]
Embryonic ghrelin KO Young animals showed lower RQ and higher heat
production
[326]
Embryonic ghrelin KO Normal body weight and feeding pattern [327]
Embryonic ghrelin KO Normal feeding behaviour; increase in locomotor
activity
[328] Transgenic mice overexpressing
des-acyl ghrelin
Lower body weight and fat mass with decreased food intake and gastric emptying rate
[177] Transgenic mice overexpressing
des-acyl ghrelin
Small phenotype, lower IGF-1 levels [329]
Transgenic mice overexpressing ghrelin
Normal size animal (no difference in food intake, body growth, body weights, and fat depots compared to WT). No desensitisation of the orexigenic effect of exogenous ghrelin. Desensitization of epididymal fat pads.
[330]
Embryonic ghrelin/leptin double KO Obesity and hyperphagia shown, but with
improved insulin sensitivity
[331]
Congenic adult ghrelin KO Lower glucose and insulin levels [332]
Adult (given synthetic
oligonucleotides to neutralise effects of ghrelin)
Weight loss occurred in diet-induced obese mice [324]
Adult (immunisation against ghrelin) Weight loss and reduced food intake in pigs [325]
GHSR Embryonic/Adult Finding/phenotype compared to WT littermates Reference
Embryonic GHSR KO Lower body weight and IGF-1 levels [148]
Embryonic GHSR KO Reduced food intake and weight gain on high-fat
diet, increased fat burning
[322]
Embryonic GHSR KO Normal feeding behaviour [328]
Embryonic (given antisense GHSR mRNA, which selectively attenuates GHSR protein expression in the ARC)
Lower body weight and less adipose tissue, reduced food intake, abolition of the stimulatory effect of GHS on feeding
[333]
Adult (given GHSR antagonist (D-Lys-3)-GHRP-6)
Reduced food intake and weight gain on high-fat diet, increased fat burning
[334]
Congenic adult GHSR KO Lower body, increased insulin sensitivity [332]
Ghrelin and GHSR
Embryonic/Adult Finding/phenotype compared to WT littermates Reference
Embryonic ghrelin/GHSR double KO Lower body weight, decreased fat mass; normal feeding behaviour; increased energy expenditure
[328] WT, wild type; KO, knockout; RQ, respiratory quotient; IGF-1, insulin-like growth factor 1; ARC, arcuate nucleus of the hypothalamus; GHS, growth hormone secretagogue
Similar to ghrelin-deficient mice, the appearance of GHSR-deficient mice is not dramatically different from that of their wild-type littermates [148]. However, the body weights of mature GHSR-null mice are modestly reduced compared to wild-type littermates, which is consistent with ghrelin’s property as an amplifier of GH pulsatility [148]. In a model
selectively attenuating GHSR protein expression in the ARC, transgenic rats had lower body weight and less adipose tissue than did control rats [333], which is in agreement with the role of ghrelin and its receptor in the regulation of GH secretion, food intake, and adiposity. On a high-fat diet, GHSR-deficient mice showed reduced food intake and weight gain and utilized fat in preference to other metabolic fuels [322, 334]. When a high-fat diet was induced in adult ghrelin- or GHSR-deficient mice, they were not protected from weight gain, suggesting that as animals reach adulthood, they develop compensatory pathways to adjust for the loss of a ghrelin/GHSR signal [332].
Simultaneous knockout of the GHRL and the GHSR genes leads to changes in energy balance, which are not observed in mice deficient for either the ligand or the receptor alone on normal standard chow [328]. It was therefore speculated that either ghrelin may also act through an additional, as yet unknown, receptor, or that there exists another ghrelin-like ligand [328].