cannabinoids effect on food intake_why pot gives you munchies

Cannabinoids Effect on Food Intake: Why Pot Gives You Munchies

Neel Patel

Molecular and Cellular Biology, University of Illinois at Urbana-Champaign

Dr. Thomas Anastasio

Molecular and Cellular Biology

December 9, 2015

Cannabinoids Effect on Food Intake: Why Pot Gives You Munchies 1

Abstract

This thesis aims to provide a clearer picture of the regulatory mechanisms and pathways

associated with cannabinoids that are involved in the control of the food intake system. This

work was carried out by review of previously published results followed up with a synthesis of

these findings. Expanding upon my foundation of knowledge about the food intake system,

here I provide a framework that can be further expanded upon and utilized to propose

potential drug targets to combat obesity.

Introduction

Food intake is a daily process which we undergo without much thought, however there

are many factors that affect this decision. We often find ourselves eating out of hunger, to

supplement our bodies with proper nutrients, or in other cases, simply due to social setting.

However, in some cases, reward associated food-intake overrides the nutrient and energy

balance, a leading cause in the epidemic known as obesity. Over the last two years I have been

working towards a better understanding of how the decision to eat is made and how the neural

network is coordinated to carry out this action, as well as to terminate a meal. We can use

available data to construct data driven computational models. Applying computational biology

methods, we will be able to determine the factors that play important roles in the obesity

problem. Though through the process of this thesis there will be no computational biology

implemented, the information necessary to begin computing will be provided.

In my research thus far, I have been able to study many pathways considered to be

essential in the control of food intake. In making the decision to pursue a senior thesis I wanted

to explore a control mechanism that has been studied less. This desire, along with additional


guidance, led me to the endocannabinoid system (ECS). The ECS has been widely found to play

a role in stimulating food intake, producing an orexigenic (i.e. an increase in food intake) effect.

A cannabinoid, Δ-tetrahydrocannabinol (Δ-THC) is the active component in marijuana, which is

also known to stimulate appetite. Though I have never ingested drugs, the ongoing debate on

legalization of marijuana and the relevance to the food intake system led me to choose to

pursue this enticing topic. I will be able to shed some light on one of the effects of marijuana

while expanding the observed neural network for food intake control.

Previous research reveals an extensive and synergistic network in the modulation of

energy intake and metabolism. Among key mediators are proopiomelanocortin (POMC)

neurons in arcuate nucleus of the hypothalamus are known to produce an anorexigenic (i.e. a

decrease in food intake) effect3. This pathway has been extensively studied as one of the key

regulators of food intake. POMC neuronal activity is known to be mainly regulated by leptin, a

key hormone in the energy homeostasis system. It has been noted that leptin receptors

become unresponsive to sustained high levels of leptin in circulation, also known as leptin

resistance. Leptin resistance has been highly implicated as a factor contributing to obesity7.

There is a wealth of available research results on leptin's role in inhibiting food intake, however

due to the complex nature of the system there is yet to be an effective, long-term solution to

the obesity problem. Ghrelin is yet another hormone implicated in the control of food intake. It

plays an orexigenic role, opposing the action of leptin within the system. There are many other

hormones and neuropeptides that contribute to the regulation of food intake such as

neuropeptide Y (NPY), α-melanocyte stimulating hormone (α-MSH), cocaine-and-amphetamine

regulated transcript (CART), and corticotropin releasing hormone (CRH) to name a few. These


hormones and others come together to regulate the complex neural network that modulates

both short and long term food intake. The endogenous cannabinoids play an important role in

this complex process.

Previous research indicates that endocannabinoids (endogenous cannabinoids) relay

their signals through cannabinoid-1 receptors (CB1R)25. However, it is yet to be determined the

exact mechanism through which the ECS regulates the food-intake control system. In order to

further understanding in this field we must make determinations of how endocannabinoids are

able to relay messages from both peripheral and central hormone regulation through various

mechanisms. It will also be pivotal to determine the duration of control via the ECS. Through

my literature review research I found that the ECS integrates both anorexigenic and orexigenic

signals and ultimately induces food intake. Through this research I investigated both a short

and long term effect, though each also has a dose and time-dependent effect. I believe that my

research creates a clearer image of the ECS within the complex regulatory mechanisms of

appetite regulation.

Experimental Approach

The approach I took in this thesis differs a lot from the typical wet-lab type of research.

Working with Dr. Anastasio I was able to create the necessary timeline and plan to move

forward with my thesis. Most research is driven by data gathered through one's own lab work,

however I have taken an alternative and less common approach. Rather than running my own

laboratory tests I worked to incorporate the findings from many articles that have already been

published. The process involved the utilization of review articles, sent to me by MIP graduate

student Shayan Tabe Bordbar, to build a foundation upon which I can expand my knowledge.


The review articles also served to help in the discovery of primary source articles which were

also approved by Shayan. The University of Illinois research database was instrumental in

locating published articles that were relevant to the problem at hand. These primary source

articles provided information on specific interactions. Each article focused on a different aspect

of the neural network that regulates food intake but, very few attempted to synthesize their

findings with other findings in the field. Through the course of the thesis I put together each

piece of information much like putting together pieces of a puzzle.

Upon accumulating a list of primary sources I was able to move onto the central part of

the thesis. Through this process I was able to utilize many articles in order to extrapolate key

regulatory mechanisms and the pathways in which they were implicated. Gathering this

information however was only the first step in this process. Though each article served its own

purpose, the true challenge was in bringing each piece of information together. This was done

by organizing the information from each paper into its own category. The initial breakdown I

chose in order to better approach the question at hand was general, peripheral, and central

effects. This was followed by extrapolation as to how these systems may connect to each

other. Prior to bringing each of these works together I had to summarize the findings of each

individually. By summarizing each article individually I am able to gain a more firm

understanding before moving further to synthesize all of this information together. This firm

understanding is necessary in order to draw rational conclusions. A well-grounded

interpretation of these articles will guide this field of research forward by making connections

between previously isolated results and creating a clearer picture as to how this neural network

regulates food intake.


Results

General Effects of Cannabinoids on Food Intake

Before diving into specific mechanisms through which cannabinoids regulate food intake

we must examine general effects. This includes regulation of both cannabinoid levels and food

intake that occur on a large scale basis. The principal areas of breakdown within this category

will be general effects through CB1Rs, the effects of marijuana and its active components, the

opioid-cannabinoid interaction, and leptin-cannabinoid interactions. These general effects may

be further incorporated as I move forward with the findings of this thesis.

Cannabinoids have been noted to play a role in the regulation of food intake and are

considered a potential target for anti-obesity drugs. A specific CB1R antagonist, SR141716, has

been studied extensively as a potential treatment. Through experimentation, SR141716 has

been found to decrease both the body weight and energy intake of high fat diet (HFD)-fed

mice25. The reduction in energy intake indicates a decrease in food intake in animals. Such a

decrease can be attained in many ways including decrease in meal size, meal frequency, or

even meal duration. This decrease in food intake is dose-dependent27. At lower doses

SR141716 significantly decreases food intake, but these effects are diminished at higher doses.

It was also determined that treatment with CB1R antagonist was able to reverse the decrease

in sensitivity to, and increase the levels of, insulin. Both of these effects are typically associated

with obesity. Upon further investigation it was concluded that SR141716 produced only a

transient effect on food intake, but a sustained effect on body weight25. This finding suggests

that reduction of food intake contributes to the initial decrease of body weight, but does not

produce the sustained decrease. The sustained decrease of body weight was a result of


increased energy expenditure. To ensure these effects were a direct result of SR141716 action

at CB1Rs, there was a comparison in food intake of both CB1-knockout (CB1-KO) and wild-type

(WT) mice. It was determined that SR141716 was not able to induce any difference in food

intake in CB1-KO mice27. CB1R antagonist SR141716 caused a transient decrease in food intake

only in the presence of CB1Rs, suggesting that activation of CB1Rs by cannabinoids causes an

increase in food intake.

One cannabinoid of particular interest is the active component of marijuana; Δ-THC.

Both intraperitoneal injection of Δ-THC in mice and marijuana smoking in humans have been

shown to stimulate appetite. More specifically, Δ-THC has been shown to preferentially

increase food intake for high-fat and sweet (HFS) food items5,16. Measured on a more detailed

time scale, Δ-THC injection in mice was shown to increase feeding of standard chow, HFD, and

HFS, however HFD feeding was still greatest one hour after injection. As the experiment

reached the two hour mark there was a clear preference shown for both HFD and HFS over

standard chow16. There was also an increase in overall daily food intake with administration of

Δ-THC through smoking marijuana. In comparison to placebo-administered control humans, Δ-

THC produced an increase of anywhere from 100 to 700 kcal daily5. As was also noted in mouse

experiments, here they showed that humans also preferred solid, sweet foods. Upon more

detailed examination it was determined that this increase in daily food intake was not a result

of calories ingested through meals but rather through snacks and furthermore was a direct

result of an increase in the number of snacking occasions5. Through the results of these

experiments we can extrapolate that Δ-THC, a cannabinoid and the active component of


marijuana, stimulates appetite and increases food intake by increasing the frequency of solid,

sweet snack occurrences.

Both cannabinoids and opioids are known to induce food intake, but very little work has

been done to determine if they work together. That they do interact was confirmed by

administration of both opioid and cannabinoid antagonists, which produced an anorexigenic

effect. Interestingly, it was determined that the reduction in food intake detected through

administration of opioid and cannabinoid antagonists was greater than the sum of antagonizing

each receptor individually15. This information suggests that opioids and cannabinoids work

together and increase food intake in a synergistic manner.

Leptin has been heavily implicated in the regulation of food intake. As noted previously,

leptin regulates many factors in order to reduce food intake. This includes an upregulation of

anorexigenic neuropeptides such as α-MSH and downregulation of orexigenic factors such as

NPY. Leptin also regulates endocannabinoid levels. Acute treatment with leptin reduces

hypothalamic levels of the two main endocannabinoids, which are anandamide (AEA) and 2-

arachidonoylglycerol (2-AG), in order to decrease food intake7. Endocannabinoid and leptin

signals are both integrated in the appetitive neural circuit. Cannabinoids increase feeding

through CB1Rs in the lateral hypothalamus, which inhibit gamma-aminobutyric acid (GABA)

transmission to perifornical melanin-concentrating hormone (MCH) positive neurons. Leptin is

able to disrupt this orexigenic signal of endocannabinoids through downregulation of voltage-

gated calcium currents. This downregulation of cellular calcium levels also disrupts

endocannabinoid synthesis12. In contrast to wild type animals which have increased leptin

levels following standard (STD) diet, CB1R-KO mice show decreased leptin levels after eating


the same food. It is also worth noting that in CB1R-KO mice there is a reduction in body weight

after 14 weeks on STD diet26. On this diet, CB1R-KO mice show a reduction in body weight

compared to WT animals that is further reduced when injected with leptin. This result likely

suggests a mechanism through which cannabinoids are acting against leptin's anorexigenic

effects. Though CB1R-KO mice ate less than WT mice (not of statistical significance), both

consumed high levels of STD food but CB1R-KO mice are leaner than WT controls. This suggests

that the reduction in weight gain and fat storage is likely to be related to metabolic changes26.

Central Effects

Cannabinoids exert many of their effects through central pathways within the brain.

One of the key regions of regulation is the forebrain, but the ventral tegmental area (VTA) of

the midbrain also plays a role. The forebrain region most closely associated with food intake is

the hypothalamus.

Endocannabinoid levels are known to fluctuate relative to the level of satiation. Both Δ-

THC and AEA are able to induce overeating in rats, which is defined as feeding beyond satiation.

It has been noted that in control animals, AEA levels are increased in limbic forebrain and 2-AG

levels are increased in the hypothalamus during periods of food deprivation. Both

endocannabinoids are found to be increased in food-deprived rats, while 2-AG levels decrease

during feeding14. The decrease in 2-AG levels during feeding indicates 2-AG contributes to food

intake initiation rather than maintenance.

While feeding states cause fluctuation in cannabinoid levels, cannabinoid levels are also

able to regulate the levels of some of the neuropeptides involved in food-intake. Of particular

interest, cannabinoids regulate levels of NPY and ß-endorphins in the hypothalamic arcuate


nucleus (ARC) of rats. This regulation is key because both NPY and ß-endorphins stimulate food

intake. Presence of CB1R-antagonists decreased NPY and ß-endorphin levels while CB1R

agonists have the opposite effect1. However, CB1R antagonists decreased food intake to the

same level in both WT and NPY-KO mice. This indicates that CB1R effects are not mediated

through NPY despite NPY levels being modulated by cannabinoids.

Cannabinoid-1 receptor messenger ribonucleic acid (mRNA) is greater in the

ventromedial hypothalamus (VMH) than in other hypothalamic regions11. Injection of

anandamide directly into the VMH dose-dependently causes an increase in food intake11. It

was once again noted that the endocannabinoid effect did not persist once the meal was

initiated, consistent with the idea that they are necessary only for initiation and not

maintenance of the meal.

It is necessary to keep in mind that there may be a difference in the effects of

endogenous cannabinoids, AEA, and exogenous cannabinoids, Δ-THC. Administration of either

Δ-THC or AEA in rats leads to hypothermic temperatures relative to control19. The hypothermic

temperature indicates that both Δ-THC and anandamide play a role in thermogenic control,

likely through energy expenditure regulation. This was further confirmed by the locomotor test

indicating that each of these cannabinoids significantly decrease locomotor activity. While Δ-

THC and AEA both equally activate the lateral septum and paraventricular nucleus (PVN), Δ-THC

caused significantly greater activation in the nucleus accumbens (NAc), caudate, putamen, and

central nucleus of the amygdala (CeA)19. The critical difference is that Δ-THC is able to

stimulate dopamine (DA) release into the NAc while AEA is not able to do so. This difference in

activation may be a result of two different CB1-receptor subtypes: CB1 and CB1A. While


anandamide shows an equal affinity for both receptor subtypes, Δ-THC shown significantly

greater affinity for the CB1 receptor19. The disparity in receptor affinity can lead to variance in

activation through many different brain regions as is noted above.

Forebrain signaling of cannabinoids plays a role in the regulation of energy metabolism.

Uncoupling protein-1 (UCP1) is a proton carrier within mitochondria that help mediate energy

metabolism. UCP1 mRNA levels are increased in the brown adipose tissue (BAT) of mice that

lack CB1Rs, which is indicative of increased thermogenic capacity13,22. Furthermore, a decrease

in 2-AG levels in the forebrain is associated with an increase in energy dissipation13. This

suggests that more energy is used for the same tasks in CB1R-KO mice relative to WT.

Cannabinoid levels may also be responsible for lipogenesis, allowing alteration in fat mass. In

CB1R-KO mice there is a marked reduction in percentage of fat mass with a slight increase in

the percentage of lean mass both in comparison to WT mice2. These results suggest that CB1Rs

influence energy metabolism through UCP1 and play a role in regulation of fat content.

POMC neurons within the hypothalamus are able to regulate endocannabinoid levels.

These POMC neurons are the source of the calcium-dependent endocannabinoid production

discussed previously in regards to decreased GABAergic transmission8. This is evident due to

the constitutive release of endocannabinoids in the ARC, more specifically localized in POMC

neurons. The endocannabinoids act retrogradely to inhibit presynaptic GABA release in order

to upregulate endocannabinoid levels in the ARC8. This suggests that GABA release may serve

as a tonic inhibitory mechanism for ARC cannabinoid levels. Cannabinoids are able to stimulate

release of certain neuropeptides from POMC neurons that would otherwise not be secreted.

POMC neurons are traditionally anorexigenic and rely, in part, on the release of α-MSH for this.


However, CB1Rs in association with mitochondrial uncoupling protein-2 (UCP2) are able to

promote ß-endorphin release in place of α-MSH17. ß-endorphin is known to promote feeding.

CB1R activation is able to inhibit glutamatergic input to the ARC. This will selectively decrease

the excitability of ARC POMC neurons and thus promote food intake9.

Cannabinoids also regulate other hormones and systems. Cannabinoid activation of

CB1Rs decreases GABA release and by decreasing inhibition of MCH neurons causes an indirect

excitation of MCH neurons10. Interestingly, the decrease in both GABAergic and glutamatergic

transmission should, but do not cancel out each other’s effects. This is something that was not

addressed in results I read and needs to be further studied. Anandamide is also implicated in

regulation of hypocretin. A reduction in glutamate release decreases the excitation, and thus

inhibits, hypocretin neurons10. This system was further studied and it was determined that the

central melanocortin system is not necessary for the cannabinoid-induced increase in food

intake. This was confirmed due to the lack of MCH stimulation in response to intra-VTA

cannabinoid injection23. In association with meal termination, however, there was a noted

increase in DA within NAc. This implies that cannabinoids rely on DA release to terminate a

meal and promote satiety23. Endocannabinoids also regulate glutamatergic transmission in the

VTA. It has been suggested that endocannabinoids are produced and released during the

depolarization of DA cells and will act retrogradely onto presynaptic CB1Rs to reduce glutamate

release20. This reduction in glutamate can be associated with the decrease in excitability of

many neurons.

Ghrelin is another important orexigenic hormone. Ghrelin's effect is mediated through

the central activation of the ECS18. Ghrelin is known to carry out its orexigenic effect by


inhibiting excitatory input onto parvocellular neurons in the PVN. However, this effect is

eliminated in the presence of CB1R antagonist. This heavily implicates CB1Rs in the mediation

of ghrelin action. Not only is ghrelin unable to induce food intake in CB1R-KO mice, but in WT

mice an increase in ghrelin is associated with increased hypothalamic 2-AG levels18. Thus it is

thought that ghrelin acts through CB1Rs by promoting the production of cannabinoids such as

2-AG.

Peripheral Effects

Though many effects of cannabinoids are mediated through central pathways, there are

still some less-explored peripheral pathways as well. Ghrelin, released in the stomach, is one of

the peripheral hormones that is associated with feeding. In hedonic, or pleasure based,

feeding, palatable foods activate the reward circuitry via the release of DA, endocannabinoids

and opiates. Palatable food is also associated with an increase in peripheral ghrelin levels more

so than is observed with non-palatable food21. In addition to increased levels of ghrelin, 2-AG is

also present in higher levels following exposure to palatable foods. 2-AG levels are transiently

increased prior to feeding but decrease following ingestion of food21. Thus it can be inferred

that the peripheral levels of 2-AG in the small intestine and ghrelin within the stomach are

associated with hedonic feeding.

Though the association seems clear, the mechanism connecting olfactory processes and

feeding have not been extensively studied. It has been determined that CB1Rs are present in

the granule cell layer (GCL) of the olfactory bulb and that CB1R activation is required within the

main olfactory bulb (MOB) for hyperphagic response following fasting24. An increase in AEA


levels is associated with both increase in food intake and odor detection in a dose-dependent

manner24. It was determined that CB1R activation is necessary for the stimulation of appetite.

Peripheral cannabinoid levels are able to alter feeding. Specifically in the small intestine

there is a seven-fold increase in AEA levels following a 24 hour fast6. It was determined that

this increase in cannabinoid levels was not due to a decrease in AEA degradation, thus

indicating an increase in synthesis as the cause. After peripheral sensory terminals in the gut

were destroyed the CB1R agonist and antagonist actions no longer impacted food intake6.

Thus, peripheral cannabinoid receptor activation is necessary to stimulate food intake.

Discussion

There are many mechanisms that come together in order to promote feeding. It has

become evident that Δ-THC produces a clear orexigenic effect through CB1Rs. Cannabinoids

however do not carry out this effect alone. They work with opioids, leptin, ghrelin, MCH, and

the olfactory system. As expected, in most cases cannabinoids activate orexigenic components

and inhibit anorexigenic components. Of note is the fact that both leptin and cannabinoids are

able to regulate POMC neurons. This provides a new narrative for POMC neuron's role in the

regulation of food intake. Based on the results of the studies discussed it is likely that leptin

and cannabinoids are able to induce the release of different neuropeptides from POMC

neurons. Leptin will induce the release of α-MSH while cannabinoids induce the release of ß-

endorphins. Leptin is able to decrease cannabinoid levels, and thus acts through multiple

pathways in order to inhibit food intake. Leptin itself promotes α-MSH release to inhibit food

intake while keeping cannabinoid levels low and preventing ß-endorphin release and in turn


decreasing stimulation of appetite. This correlation is likely of great importance and should be

explored further moving forward in an attempt to treat obesity.

Incorporating the information from this thesis it is evident that CB1R activation

throughout the body leads to stimulation of appetitive behavior. It is also important to note

that by inhibiting CB1R activation it is possible to combat the typical effects associated with

obesity. Through this thesis I was able to identify instances in which antagonizing CB1Rs

reversed the insensitivity to insulin and increase in body fat percentage. More extensive

studies of cannabinoid-associated food intake will shed light on the complexity of food intake

regulation and may introduce novel drug targets to combat obesity. Of note is the previously

discussed paradox of both decreased inhibitory and excitatory transmission. This needs to be

further studied in order to better understand how the food intake system is modulated by

cannabinoids. Perhaps the most effective approach will involve a cocktail of drugs that will

modulate the food-intake control system at different points. As we have noted the bimodal

regulation of POMC neurons may be a critical regulatory point in food intake. Perhaps by

titrating the levels of an agonist and an antagonist of leptin and cannabinoid receptors,

respectively, we may be able to succeed using a multi-drug approach to the disorder of obesity

in which many single-drug approaches have failed.

Acknowledgements

First and foremost I would like to thank Dr. Thomas Anastasio for providing me with the

opportunity to conduct this research. Through this opportunity I have been able to expand my

knowledge and was able to develop the skills necessary to complete a thesis of this nature and


be successful as I move forward in the research world. I would also like to acknowledge the

effort put forth to assist me through this process by MIP graduate student Shayan Tabe

Bordbar. The continuous support and input throughout the process allowed me to successfully

complete this thesis as well.

References

1 Bakkali-Kassemi, L., Ouezzani, S., Magoul, R., Merroun, I., Lopez-Jurado, M., & Errami, M. (2010). Effects of cannabinoids on neuropeptide Y and β-endorphin expression in the rat hypothalamic arcuate nucleus. British Journal of Nutrition Br J Nutr, 105, 654-660.

2 Cota, D., Marsicano, G., Tschop, M., Grubler, Y., Flachskamm, C., Schubert, M., . . . Pagotto, U.

(2003). The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. The Journal of Clinical Investigation, 112(3), 423-431.

3 Cowley, M., Smart, J., Rubinstein, M., Cerdan, M., Diano, S., Horvath, T., . . . Low, M. (2001).

Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature, 411, 480-484.

4 Di Marzo, V., Goparaju, S., Wang, L., Liu, J., Batkal, S., Jaral, Z., . . . Kunos, G. (2001). Leptin-

regulated endocannabinoids are involved in maintaining food intake. Nature, 410, 822-825.

5 Foltin, R., Fischman, M., & Byrne, M. (1988). Effects Of Smoked Marijuana On Food Intake And

Body Weight Of Humans Living In A Residential Laboratory. Appetite, 11, 1-14. 6 Gomez, R., Navarro, M., Ferrer, B., Trigo, J., Bilbao, A., Del Arco, I., . . . De Fonseca, F. (2002). A

Peripheral Mechanism for CB1 Cannabinoid Receptor-Dependent Modulation of Feeding. The Journal of Neuroscience, 22(21), 9612-9617.

7 Heek, M., Compton, D., France, C., Tedesco, R., Fawzi, A., Graziano, M., . . . Davis, H. (1997).

Diet-induced obese mice develop peripheral, but not central, resistance to leptin. Journal of Clinical Investigation J. Clin. Invest., 99(3), 385-390.

8 Hentges, S., Low, M., & Williams, J. (2005). Differential Regulation of Synaptic Inputs by

Constitutively Released Endocannabinoids and Exogenous Cannabinoids. Journal of Neuroscience, 25(42), 9746-9751.


9 Ho, J., Cox, J., & Wagner, E. (2007). Cannabinoid-induced hyperphagia: Correlation with inhibition of proopiomelanocortin neurons? Physiology & Behavior, 92(3), 507-519.

10 Huang, H., Acuna-Goycolea, C., Li, Y., Cheng, H., Obrietan, K., & Pol, A. (2007). Cannabinoids

Excite Hypothalamic Melanin-Concentrating Hormone But Inhibit Hypocretin/Orexin Neurons: Implications for Cannabinoid Actions on Food Intake and Cognitive Arousal. Journal of Neuroscience, 4870-4881.

11 Jamshidi, N., & Taylor, D. (2001). Anandamide administration into the ventromedial

hypothalamus stimulates appetite in rats. British Journal of Pharmacology, 134, 1151-1154.

12 Jo, Y., Chen, Y., Chua, S., Talmage, D., & Role, L. (2005). Integration of Endocannabinoid and

Leptin Signaling in an Appetite-Related Neural Circuit. Neuron, 48(6), 1055-1066. 13 Jung, K., Clapper, J., Fu, J., D'agostino, G., Guijarro, A., Thongkham, D., . . . Piomelli, D. (2012).

2-Arachidonoylglycerol Signaling in Forebrain Regulates Systemic Energy Metabolism. Cell Metabolism, 299-310.

14 Kirkham, T., Williams, C., Fezza, F., & Marzo, V. (2002). Endocannabinoid levels in rat limbic

forebrain and hypothalamus in relation to fasting, feeding and satiation: Stimulation of eating by 2-arachidonoyl glycerol. British Journal of Pharmacology, 136, 550-557.

15 Kirkham, T., & Williams, C. (2001). Synergistic effects of opioid and cannabinoid antagonists

on food intake. Psychopharmacology, 153, 267-270. 16 Koch, J. (2001). Δ9-THC stimulates food intake in Lewis rats: Effects on chow, high-fat and

sweet high-fat diets. Pharmacology Biochemistry and Behavior, 68, 539-543. 17 Koch, M., Varela, L., Kim, J., Kim, J., Hernandez-Nuno, F., Simonds, S., . . . Horvath, T. (2015).

Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature, 519, 45-50.

18 Kola, B., Farkas, I., Christ-Crain, M., Wittmann, G., Lolli, F., Amin, F., . . . Korbonits, M. (2008).

The Orexigenic Effect of Ghrelin Is Mediated through Central Activation of the Endogenous Cannabinoid System. PLoS ONE, 3(3), 1-8.

19 Mcgregor, I., Arnold, J., Weber, M., Topple, A., & Hunt, G. (1998). A comparison of Δ9-THC

and anandamide induced c-fos expression in the rat forebrain. Brain Research, 19-26. 20 Melis, M., Perra, S., Muntoni, A., Pillolla, G., & Gessa, G. (2004). Endocannabinoids Mediate

Presynaptic Inhibition of Glutamatergic Transmission in Rat Ventral Tegmental Area Dopamine Neurons through Activation of CB1 Receptors. Journal of Neuroscience, 24(1), 53-62.


21 Monteleone, P., Piscitelli, F., Scognamiglio, P., Monteleone, A., Canestrelli, B., Marzo, V., &

Maj, M. (2012). Hedonic Eating Is Associated with Increased Peripheral Levels of Ghrelin and the Endocannabinoid 2-Arachidonoyl-Glycerol in Healthy Humans: A Pilot Study. The Journal of Clinical Endocrinology & Metabolism, 97(6), 917-924.

22 Quarta, C., Bellocchio, L., Mancini, G., Mazza, R., Cervino, C., Braulke, L., . . . Pagotto, U.

(2010). CB1 signaling in forebrain and sympathetic neurons is a key determinant of endocannabinoid actions on energy balance. Cell Metabolism, 11, 273-285.

23 Sinnayah, P., Jobst, E., Rathner, J., Caldera-Siu, A., Tonelli-Lemos, L., Eusterbrock, A., . . .

Cowley, M. (2008). Feeding Induced by Cannabinoids Is Mediated Independently of the Melanocortin System. PLoS ONE, 3(5), 1-12.

24 Soria-Gomez, E., Bellocchio, L., Reguero, L., Lepousez, G., Martin, C., Bendahmane, M., . . .

Masricano, G. (2014). The endocannabinoid system controls food intake via olfactory processes. Nature Neuroscience, 17(3), 407-415.

25 Trillou, C., Arnone, M., Delgorge, C., Gonalons, N., Keane, P., Maffrand, J., & Soubrié, P.

(2002). Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology Am J Physiol Regul Integr Comp Physiol, 284, 345-353.

26 Trillou, C., Delgorge, C., Menet, C., Arnone, M., & Soubrié, P. (2004). CB1 cannabinoid

receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Int J Obes Relat Metab Disord International Journal of Obesity, 28, 640-648.

27 Wiley, J., Burston, J., Leggett, D., Alekseeva, O., Razdan, R., Mahadevan, A., & Martin, B.

(2005). CB 1 cannabinoid receptor-mediated modulation of food intake in mice. British Journal of Pharmacology, 145, 293-300.

cannabinoids effect on food intake_why pot gives you munchies

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