The regulation of appetite by the nervous system is a hot area of research due to the raging obesity/diabetes epidemic. An international team of researchers interested in the subject—none of whom hail from either Colorado or Amsterdam—astutely noticed that "the phenomenon of cannabis-triggered feeding in a state of satiety is a hallmark of marijuana use in humans." So they injected cannabinoids into sated mice to see how the drugs affected neurons in the hypothalamus known to regulate satiety, the feeling of fullness. They figured that the cannabinoids would decrease the activity of these neurons. They figured totally wrong.

The researchers used two different molecules that stimulate cannabinoid receptor 1 (CB 1 R). When injected into mice, both molecules induced feeding in well-fed animals. POMC neurons in the hypothalamus are known to promote satiety, so the researchers assumed that activation of cannabinoid signaling would decrease the activity of these neurons, allowing the mice to start feeding again.

Paradoxically, they found that CB 1 R signaling hyperactivated the POMC neurons. And not only that; these neurons were essential in driving the feeding response to cannabinoids. When the researchers suppressed POMC activity, the stoned mice didn't eat.

POMC neurons affect the body through two main products. One is a hormone that suppresses appetite, and the other is an opioid that stimulates appetite. It turns out that CB 1 R activation had no effect on the first, but it increased the release of the second into the hypothalamus. Cannabinoids can induce this release because the CB 1 R receptor is found not only on the cell membrane but also in mitochondria, small compartments in the cell that help it convert sugars into a more useful energy carrier.

Cannabinoid binding to this receptor enhances mitochondrial activity (and thus basic metabolism) in POMC neurons. This induces the neurons to release their opioid product, which increase appetite, even in sated mice. It is well established that a single neuron can make and release different types of neuropeptides, but it's been harder to tell exactly how it manages these different molecules. Here, the researchers found that the two hormones with opposing effects are stored in different containers (called vesicles) within POMC neurons. These separate pools of containers can be regulated individually.

Since the satiety promoting action of POMC neurons was discovered in the late 1990s, they have been hailed as a key player in attenuating our appetite. Yet this work demonstrates that they are actually indispensable for pot's notorious promotion of feeding ("the munchies"), even during satiety. These neurons might be important in pot's other effects as well, and they clearly play other roles in the regulation of appetite.

Nature, 2014. DOI: 10.1038/nature14260 (About DOIs).