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    • br Ghrelin and energy balance To characterize the

    2021-12-10


    Ghrelin and bromophenol blue sale balance To characterize the physiological role of ghrelin in energy homeostasis, ghsr−/− and ghrelin−/− mice were generated [33], [36], [41], [47]. Although ghrelin regulates the amplitude of episodic GH release, ghsr−/− mice were not dwarfs, and in fact appear identical to their wild type (WT) littermates [36]. However, in these animals, ghrelin and MK-677 failed to induce GH release, whereas GH stimulated by growth hormone releasing hormone (GHRH) remained unaffected. These studies thus highlight selective ablation of ghrelin-induced GH release in ghsr−/− mice, with the main GH regulatory pathway remaining intact. Importantly, these studies also provided the first evidence that ghrelin acts through the GHS-R1a in vivo [36]. In the ghsr−/− mice created by our group, ghrelin treatment failed to induce increases in food intake, as was observed in WT littermates [36]. Insulin and leptin levels are reduced with fasting, and this response remained intact in mice lacking the GHS-R1a. In mice fed a normal chow diet, the body weights of congenic adult ghsr−/− mice (C57BL6J) were modestly lower than WT controls. IGF-1 levels were also slightly lower, but food intake was unchanged [36]. In a second ghsr−/− mouse line created by Zigman et al., ghsr−/− mice of mixed genetic background (C57BL6J:129sv) fed a normal chow diet had similar body weights to WT mice, but were relatively resistant to diet induced obesity, at least when the high fat diet (HFD) was started immediately after weaning [47]. However, a caveat in this study was that the influence of the 129Sv genetic background in the knockout mice make them inherently more resistant to diet-induced obesity compared to congenic C57BL6J knockout mice. By the end of 19 weeks on a HFD, ghsr−/− mice had consumed less food overall compared to WT, and had significant lower fat mass, as shown by a whole body dual X-ray absorptiometry (DEXA) [47]. These, ghsr−/− mice also exhibited lower release of CO2 over O2 consumption ratio or respiratory quotient (RQ) and decreased total locomotor activity [47], suggesting ghrelin's role in energy metabolism may be more extensive and complex than merely increasing appetite. The first ghrelin−/− mice were characterized in 2003 by Sun et al. [33]. This knockout was crucial in demonstrating ghrelin's role in energy balance. Originally it was thought that ablation of ghrelin would decrease food intake, mice weight/size and growth. However, these animals did not exhibit dwarfism or differences in their body composition (fat content), bone density, body weight or cumulative food intake over an 8-week period, when compared to WT littermates. These results were confirmed in ghrelin−/− mice generated independently by Wortley et al. [41]. This group also showed that ghrelin−/− mice had a normal circadian pattern of food intake, and that hypothalamic basal expression levels of AGRP, melanin-concentrating hormone (MCH), proopiomelanocortin, VGF peptide, and NPY were not distinct between ghrelin−/− and WT mice [41]. Leptin and insulin levels responded as expected upon fasting, and both WT and ghrelin−/− showed similar weight changes and food intake after a 24-h fast and re-feed [33], [36], [41]. Together, these results indicate that hypothalamic regulatory feeding centers are intact in ghrelin−/− mice. Both male and female ghrelin−/− mice are susceptible to a HFD over a 10-week period, resulting in increased fat deposition [33]. Wortley and co-workers confirmed these results, showing that ghrelin−/− mice increased in body weight but this result did not correlated with an increase in food intake in response to a HFD [41]. Interestingly, in this study, RQ was also significantly reduced in ghrelin−/− mice, as was reported in ghsr−/− mice [35], [41]. The results suggest that in ghrelin−/− mice most of the energy utilization comes from fat rather than carbohydrate, since the higher the RQ ratio the higher utilization of carbohydrates as the main source of energy. Interestingly, when animals were started on a HFD just 3 weeks post weaning, ghrelin−/− mice showed increased energy expenditure, lower body weight, lower percentage of fat, but similar food intake, when compared to WT mice [42]. These results suggest that ghrelin−/− mice on HFD have less efficient food utilization compared with WT mice [42], as shown in the ghsr−/− mice.