A follow up to this earlier tweet: An interesting new take on the science of obesity: Why you crave Twinkies after smoking marijuana wapo.st/1vTRXZ5
The article does not fully explore or expound on what they learned that made this study so interesting, so I thought I would add some additional notes. For starters, here is a link to the Nature paper that was referenced in the article: Hypothalamic POMC neurons promote cannabinoid-induced feeding
The CB1 receptor, one of the 2 the primary neuronal receptors for THC has been well established as being associated with increased eating caused by THC. This figure gives a summary of what is known about the endocannabinoid system (from Pacher, P. and Kunos, G. (2013), Modulating the endocannabinoid system in human health and disease – successes and failures. FEBS Journal, 280: 1918–1943) :
This led to the development of drugs for inhibiting CB1 as a means of treating obesity. The most prominent of these was rimonabant, a CB1 antagonist (reviewed in Pharmacol Rep. 2009 Mar-Apr;61(2):217-24.). The drug was never approved in the United States because of the serious psychiatric side effects including depression and suicide associated with the treatment. However, the idea of CB1 receptor blockade is still an attractive one because of the peripheral effects of endocannabinoids on metabolism (from Br J Pharmacol. 2011 Aug;163(7):1423-31.).
What made the Nature paper interesting was the fact that it revealed a surprising effect of endocannabinoids in the brain. Let’s start by reviewing the 2 types of neurons most highly associated with eating behavior in the brain: the NPY and POMC neurons in the arcuate nucleus (Nature 404, 661-671(6 April 2000)).
Stimulation of NPY/AgRP neurons increases eating through the release of NPY and AgRP which stimulate effector neurons in the paraventricular nucleus. Stimulating POMC neurons increases satiety (decreases hunger) through the release of alpha-MSH and stimulation of different neurons in the paraventricular nucleus.
Based on this simplistic dichotomy, it would be expected that endocannabaoids (and THC) would inhibit POMC neurons and limit alpha-MSH release. However, when POMC neurons were stimulated in this study, it resulted in activation of POMC neurons. What is interesting about this is that the POMC neurons didn’t produce alpha-MSH, they produced the beta-endorphin. The POMC protein contains the sequences for both alpha-MSH and beta-endorphin (as well as other peptides, see figure below from (http://www.endotext.org/chapter/normal-physiology-of-acth-and-gh-release-in-the-hypothalamus-and-anterior/2/#toc-pomc-gene-structure)).
Somehow the CB1 receptor was selectively able to instruct the POMC neuron to release one of the POMC derived peptides and not the other. This stimulation was unexpected and may help explain the mechanism by which rimonabant caused depression via inhibiting endorphin release. This could yield the possibility of developing targeted drugs that inhibit the CB1 receptor on NPY/AgRP neurons but do not inhibit the endorphin release from the POMC neurons.