It has been commonly observed that smoking marijuana (Cannabis sativa) induces the “munchies”. Indeed, the neural circuits in the hypothalamus that regulate satiety can be disrupted by cannabinoids derived from marijuana. New research published in Nature (Koch et al. 2015) reveals a key role for pro-opiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (ARC) in regulating food intake. Stimulating cannabinoid receptor 1 (CB1R) in the ARC activates POMC neurons and increases food consumption in fed mice. These findings describe an important new mechanism in controlling feeding behavior.
Activation of CB1R by cannabinoids can stimulate feeding in mice even in a state of satiety. Under normal conditions, POMC-expressing neurons are associated with promoting satiety. In their 2015 Nature study, Koch et al. demonstrate by immunohistochemistry that presynaptic terminals of POMC neurons are co-labeled with CB1R (figure). Interestingly, when POMC-EGFP mice (C57BL/6J-Tg(Pomc-EGFP)1Low/J, 009593) were treated with a low dose of the CB1R agonist arachidonyl-29-chloroethylamide (ACEA), the mice became hyperphagic (that is, they increased their food intake) and POMC neurons were activated as measured by increased expression of the proto-oncogene cFOS. Further, treatment with the CB1R inverse agonist rimonabant (RIMO) diminished POMC neuron activity and decreased food consumption, even in fasted mice. This data is counterintuitive to the notion that POMC neuron stimulation promotes satiety.
To further explore the role of POMC neurons in stimulating feeding, the Koch team used DREADD (Designer-Receptors-Exclusively-Activated-by-Designer-Drugs) technology to selectively stimulate or inhibit POMC neurons. These genetically engineered G-protein-coupled receptors (GPCRs) are constructed to allow precise temporal and spatial control of GPCR signaling in vivo using small, inert molecules as inducers. DNA constructs directing cre-dependent DREADD molecule expression were delivered as adenoviruses to the ARC of POMC-cre mice (STOCK Tg(Pomc1-cre)16Lowl/J, 005965). Cre-mediated recombination in virally transduced POMC neurons inverts the GPCR gene to allow clozapine-N-oxide (CNO) induced expression of either an inhibitory (Gi) or stimulatory (Gq) G-protein. CNO induction of inhibitory DREADD (Gi) reduced cFOS immunolabeling in the ARC, indicating decreased activation of POMC neurons. DREADD inhibition also blocked hyperphagia induced by the CB1R agonists, ACEA and WIN-55,212-2 mesylate (WIN) in the transduced POMC neurons. In contrast, CNO-induced stimulatory DREADD (Gq) activated POMC neurons (measured by increased cFOS expression) and significantly increased food intake in mice treated with the CB1R agonist ACEA. Together, these results demonstrate that cannabinoid activation of POMC neurons plays an important role in stimulating food intake, even during satiety.
Prior publications reported intracellular localization of CB1R with the mitochondria in neurons. Using electron microscopy, Koch et al. found CB1R localized to mitochondria in POMC neurons. ACEA activation led to a dose-dependent increase in coupled mitochondrial respiration, which is known to increase reactive oxygen species (ROS). ROS have been reported to upregulate mitochondrial uncoupling protein 2 (Ucp2) expression. Koch et al. report increased Ucp2 mRNA transcription in the hypothalamus of ACEA-stimulated mice. When Ucp2 knockout mice were treated with ACEA, mitochondrial respiration was not altered, POMC activation was decreased, and CB1R-induced feeding was not observed. These results demonstrate that cannabinoids alter mitochondrial respiration in hypothalamic neurons through a Ucp2-coupled mechanism.
In conclusion, Koch et al. demonstrate a previously unappreciated role for POMC neurons in the regulation and control of satiety in the hypothalamus. Cannabinoid receptors override normal satiety mechanisms via a mitochondrial Ucp2-mediated pathway. Ucp2 has also been implicated in the abnormal POMC neuron function in diet-induced obesity. Perhaps further studies into these mechanisms will lead to new therapeutics to better regulate satiety and to help treat diseases associated with obesity.