PP 2 In the liver ghrelin has opposite effects
In the liver, ghrelin has opposite effects to insulin on the expression of the enzyme PEPCK, thereby promoting gluconeogenesis and also causing a decrease in glucose uptake and fatty PP 2 oxidation (Rigault et al., 2007). Ghrelin also stimulates hepatic lipogenesis de novo in a GH-independent fashion (Sangiao-Alvarellos et al., 2009). Ghrelin promotes adipose tissue deposition by reducing the use of fat as metabolic fuel (Tschop et al., 2000). Intracerebroventricular infusion of ghrelin into neuropeptide-Y (NPY) neurons promotes adiposity, thereby suggesting that the effects of ghrelin on adiposity could be driven through central NPY pathways (Baran et al., 2002). Ghrelin has also recently been shown to play a crucial role in blood glucose maintenance during prolonged extreme hypocaloric conditions via an increase in growth hormone release, and possibly via a direct action (Zhao et al., 2010). All these central and peripheral effects of ghrelin are suggested to be via an effect on the GHS-R.
We have previously shown that ghrelin increases AMP-activated protein kinase (AMPK) activity in the hypothalamus and inhibits it in the liver and adipose tissue (Kola et al., 2005), suggesting that AMPK mediates at least some of the central and peripheral metabolic effects of ghrelin. AMPK is a key enzyme regulator in energy homeostasis both at cellular and whole body energy levels (Kola et al., 2006, Xue and Kahn, 2006). Activated AMPK inhibits anabolic pathways as well as stimulating catabolic pathways and appetite, thus conserving the ATP levels (Xue and Kahn, 2006).
Cannabinoids are also orexigenic compounds that have been shown to increase food intake (Williams et al., 1998) via the cannabinoid (CB)-1 receptor (Jamshidi and Taylor, 2001, Williams and Kirkham, 1999). Peripherally, cannabinoids promote lipogenesis in the liver (Osei-Hyiaman et al., 2005). We have also shown that cannabinoids increase AMPK activity in the hypothalamus and inhibit it in the liver and adipose tissue (Kola et al., 2005).
It has been shown that the effects of ghrelin on food intake and AMPK activity are absent in CB1 knock-out (KO) or CB1 receptor antagonist rimonabant-treated rodents (Kola et al., 2008). Ghrelin also increased the hypothalamic endocannabinoid content in wild-type (WT) mice, but not in CB1 KO or rimonabant-treated mice (Kola et al., 2008). These results suggested that an intact cannabinoids signalling system is necessary for the effects of ghrelin on AMPK activity.
Materials and methods
Discussion AMPK is a highly conserved serine/threonine kinase which is identified as one of the key players in the regulation of appetite and metabolism (Minokoshi et al., 2004). Several upstream regulators of AMPK have been identified (Lim et al., 2010), and AMPK is also known to mediate the effects of some metabolic hormones and elements (Lim et al., 2010). In general, activated AMPK will lead to the stimulation of appetite and activation of catabolic processes such as fatty acid oxidation, glycolysis, increased glucose uptake and mitochondrial biogenesis (Lim et al., 2010). Inhibition of AMPK activity conversely leads to hepatic gluconeogenesis, lipogenesis, and glycogen synthesis (Lim et al., 2010). Acute injections of ghrelin and cannabinoids have been shown to increase appetite in rats (Kirkham, 2003, Wren et al., 2001b) and mice (Avraham et al., 2004, Kola et al., 2008, Sun et al., 2004, Wiley et al., 2005). HU210 is a highly potent synthetic cannabinoid receptor agonist ( values of 0.061 and 0.52nM at cloned human CB1 and CB2 receptors respectively – data from Tocris Bioscience). In this study, we attempted to investigate the effects of HU210 injection on food intake (Fig. 2A and B). It is known that food intake in mice is more difficult to measure than rat models (Graham Tobin and Russell, 2007). Food intake in control mice showed a trend to increase with higher doses of HU210 injection (Fig. 2A) and no significant difference in food intake was found in the GHS-R KO mice (Fig. 2B). We speculated that the presence of GHS-R1a may be required for the orexigenic effects of cannabinoids. A future study investigating the effects of a CB1 agonist on food intake in the presence of a ghrelin receptor antagonist will be useful.