Hypothalamic endocannabinoids in obesity: an old story with new challenges

Abstract

The crucial role of the hypothalamus in the pathogenesis of obesity is widely recognized, while the precise molecular and cellular mechanisms involved are the focus of intense research. A disrupted endocannabinoid system, which critically modulates feeding and metabolic functions, through central and peripheral mechanisms, is a landmark indicator of obesity, as corroborated by investigations centered on the cannabinoid receptor CB1, considered to offer promise in terms of pharmacologically targeted treatment for obesity. In recent years, novel insights have been obtained, not only into relation to the mode of action of CB receptors, but also CB ligands, non-CB receptors, and metabolizing enzymes considered to be part of the endocannabinoid system (particularly the hypothalamus). The outcome has been a substantial expansion in knowledge of this complex signaling system and in drug development. Here we review recent literature, providing further evidence on the role of hypothalamic endocannabinoids in regulating energy balance and the implication for the pathophysiology of obesity. We discuss how these lipids are dynamically regulated in obesity onset, by diet and metabolic hormones in specific hypothalamic neurons, the impact of gender, and the role of endocannabinoid metabolizing enzymes as promising targets for tackling obesity and related diseases.

Cannabidiol treatment improves metabolic profile and decreases hypothalamic inflammation caused by maternal obesity

“…Elevated hypothalamic endocannabinoid content has been associated with higher orexigenic signaling of ghrelin ( 123 – 125 ) and defective leptin signaling, observed in genetic models of obesity such as obese Zucker rats and db/db and ob/ob mice ( 126 , 127 ). These findings suggest that endocannabinoid mediators contribute to hyperphagia and obesity, which also supports the restorative effects of CBD treatment, once it reduces endocannabinoid signaling, especially through CB1 receptors ( 128 ). When it comes to inflammation, effects of CBD via CB2 receptor are more distinguished, since this receptor is more predominantly expressed on immune cells, including glial cells.…”

Role of astroglial ACBP in energy metabolism flexibility and feeding responses to metabolic challenges in male mice

“…Indeed, endocannabinoids, that are well known to stimulate feeding, activate POMC neurons leading to increased food intake via the release of the hunger promoting POMC-derived beta-endorphin and stimulation of downstream mu-opioid receptor (26). Interestingly, fasting (27) and cold exposure (28) are known to increase circulating and/or hypothalamic endocannabinoid levels to stimulate feeding and regulate energy metabolism flexibility (29). It is thus tempting to speculate that in conditions associated with increased endocannabinoid tone such as cold and fasting, endogenous ACBP may potentiate the release of beta-endorphin by POMC neurons, rather than alpha-MSH, to promote feeding.…”

Central Regulation of Brown Fat Thermogenesis in Response to Saturated or Unsaturated Long-Chain Fatty Acids

“…CPT1C has been proposed to be a sensor of malonyl-CoA levels [ 8 , 28 , 48 ], and its role in the energy homeostasis and metabolic adaptation depends on this FA intermediary [ 27 , 49 ]. Recent investigations have found that malonyl-CoA binding provides CPT1C the potential to interact and regulate the activity of other downstream proteins such as ABHD6 [ 50 , 51 ] and SAC1 [ 52 ], both involved in brain metabolic flexibility, and AMPA-type glutamate receptors trafficking to the cell surface in neurons [ 52 ], whereas this regulation is lost in conditions of malonyl-CoA depletion [ 50 , 52 ]. CPT1C was also essential for neuronal activation evoked by ICV oleic acid, since the number of c-Fos-positive cells was not increased but reduced in PaV and VMH in CPT1C-KO exposed to oleic acid.…”