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    • Previously we have shown that ghrelin and

    2022-09-30

    Previously, we have shown that ghrelin and cannabinoids stimulate hypothalamic AMPK activity (Kola et al., 2005). In contrast, both the orexigenic compounds have inhibitory effects on AMPK activity in the liver and visceral fat (Kola et al., 2005). In this study, we were able to reproduce our previous results. Both ghrelin and HU210 administration had a stimulatory effect on WT hypothalamic AMPK activity. Similarly, both led to a significant reduction of AMPK activity in WT liver and visceral fat. Previous studies have shown that ghrelin and cannabinoids have no effect on AMPK activity of subcutaneous fat (Kola et al., 2005). Here, we show that the effect of ghrelin on WT IF (equivalent to subcutaneous fat) AMPK activity was comparable to controls (p=0.2132). However, treatment with HU210 at 20ng/g significantly inhibited WT IF AMPK activity (p=0.0252). The high potency of HU210 might explain the lack of a significant effect in previous studies using the less potent THC, AEA, and 2-AG (Kola et al., 2005). Consistent with a previous report (Andrews et al., 2008), the stimulatory effect of ghrelin on hypothalamic AMPK activity was diminished in GHS-R KO mice. Here, we show that ghrelin administration reduces AMPK activity in peripheral tissues such as liver and visceral fat AMPK, an effect that also requires the BS-181 HCl australia of GHS-R. This is in line with previous data which have shown that GHS-R mediates the orexigenic effects of ghrelin, and a GHS-R antagonist was able to reduce food intake and to block the effects of ghrelin on adipose tissue (Asakawa et al., 2003). Previous studies have shown that the liver only expresses the non-functional GHS-R1b, and GHS-R1a is known to be absent at this site (Gnanapavan et al., 2002). We confirmed that GHS-R1a expression is absent in the liver of WT mice (Fig. 2). Thus, the loss of inhibitory effect of ghrelin on the liver AMPK activity in GHS-R KO mice suggests that this effect is mediated by GHS-R1a activity in other tissues. Studies involving the use of mouse models with tissue-specific expression of GHS-R may be useful in exploring the mechanisms whereby ghrelin inhibits liver AMPK activity. We show here that the stimulatory effect of HU210 on hypothalamic AMPK activity, as well as its inhibitory effect on AMPK activity on liver and subcutaneous and visceral fat, requires the expression of GHS-R. Considering the key role of AMPK activity in the control of energy metabolism, this result suggests that ghrelin signalling is an essential component of the pathways by which cannabinoids control energy balance. Interestingly, there is evidence that the orexigenic effect of ghrelin requires a functional endogenous cannabinoid system. Hence, administration of the CB1 receptor antagonist rimonabant blunted the orexigenic effect of ghrelin (Tucci et al., 2004). Furthermore, ghrelin failed to increase feeding in CB1-KO mice (Kola et al., 2008), suggesting that at least CB1 receptor is mandatory for the orexigenic effects of ghrelin and cannabinoids and their influence on AMPK activity. In addition, ghrelin increased the cannabinoid content of the hypothalamus, and this effect was CB1-dependent (Kola et al., 2008). Rimonabant also blocked the stimulatory effects of ghrelin on 2-AG content (Kola et al., 2008) and abolished the inhibitory effects of ghrelin on the excitatory synaptic input in the PVN (Kola et al., 2008). These studies have substantiated the involvement of cannabinoids system in the effects of ghrelin. In this study, we propose that an intact ghrelin pathway is also required for the tissue-specific AMPK effects of cannabinoids. The effects of HU210 on AMPK activity were totally abolished in the hypothalamus, liver, subcutaneous and visceral fat of GHS-R KO mice. Our data indicate:
    Acknowledgements
    Introduction The peptide hormone, ghrelin, has major roles in the control of appetite, growth hormone release and metabolic functions (Kojima and Kangawa, 2005, Kojima and Kangawa, 2010, Delhanty and van der Lely, 2011). It reduces blood pressure in human and animals when administered intravenously (Nagaya et al., 2001, Okumura et al., 2002) and reduces sympathetic nerve activity when administered into the lower brain stem of rats and rabbits (Matsumura et al., 2002, Lin et al., 2004). Ghrelin has no direct vasodilator action on vessels from rat and the ghrelin receptor, growth hormone secretagogue receptor 1a (GHSR1a), is not expressed in rat vessels (Callaghan et al., 2012).