Cannabinoid Receptor Signaling in Central Regulation of Feeding Behavior: A Mini-Review

Abstract

Cannabinoids are lipid messengers that modulate a variety of physiological processes and modify the generation of specific behaviors. In this regard, the cannabinoid receptor type 1 (CB₁) represents the most relevant target molecule of cannabinoids so far. One main function of central CB₁ signaling is to maintain whole body energy homeostasis. Thus, cannabinoids functionally interact with classical neurotransmitters in neural networks that control energy metabolism and feeding behavior. The promotion of CB₁ signaling can increase appetite and stimulate feeding, while blockade of CB₁ suppresses hunger and induces hypophagia. However, in order to treat overeating, pharmacological blockade of CB₁ by the inverse agonist rimonabant not only suppressed feeding but also resulted in psychiatric side effects. Therefore, research within the last decade focused on deciphering the underlying cellular and molecular mechanisms of central cannabinoid signaling that control feeding and other behaviors, with the overall aim still being the identification of specific targets to develop safe pharmacological interventions for the treatment of obesity. Today, many studies unraveled the subcellular localization of CB₁ and the function of cannabinoids in neurons and glial cells within circumscribed brain regions that represent integral parts of neural circuitries controlling feeding behavior. Here, these novel experimental findings will be summarized and recent advances in understanding the mechanisms of CB₁-dependent cannabinoid signaling being relevant for central regulation of feeding behavior will be highlighted. Finally, presumed alternative pathways of cannabinoids that are not driven by CB₁ activation but also contributing to control of feeding behavior will be introduced.

Keywords: anorexia; cachexia; cannabinoid receptor type 1; endocannabinoids; feeding behavior; hypothalamus; obesity; overeating.

Figure 1

Principles of central CB₁ signaling in control of feeding behavior. (A) Retrograde signaling of eCBs at presynaptic CB₁ impacts feeding (Bellocchio et al., 2010). (B) Postsynaptic CB₁ at POMC neurons affects feeding in DIO (Morello et al., 2016). (C) Cannabinoids interfere with mitochondrial CB₁ in hypothalamic feeding regulation (Koch et al., 2015). (D) Whether activity-dependent subcellular distribution of CB₁(Thibault et al., 2013) accounts for control of food intake is still open. (E) Astroglial CB₁ regulates the metabolic effects of leptin in cultured astrocytes (Bosier et al., 2013), and thus might contribute to astrocyte-dependent control of feeding behavior in the hypothalamus (Kim et al., 2014). (F) Enzymes of eCB synthesis or degradation control eCB levels in a spatial and temporal manner (Pertwee, 2014). Moreover, eCBs not only function as CB₁ ligands, but also as substrates of specific enzymes, such as lipoxygenases (LOX), cyclooxygenases (COX), or cytochrome P450, supporting the idea that the ECS might also transmit metabolic effects independently from CB₁ signaling (non-CB₁).