How does obesity affect this endocannabinoid?

Have you heard of anorexia, a well-known eating disorder, where ‘an’ means ‘lacking’ and ‘orexis’ means desire and appetite? Orexin is a hormone central in a system containing thousands of neurons and two receptors that trigger appetite and wakefulness. A recent study found further connections between fasting, obesity, and the endocannabinoid system through orexin.

Several changes produced after eating indirectly shift endocannabinoid system (ECS) function, causing satiation or a loss of appetite. However, it turns out that obesity causes changes in the body that floods orexin, which in turn promotes 2-AG. But orexin encourages unusual endocannabinoid metabolism, according to a study published in Molecular Metabolism (1) that critically follows up on experiments conducted in 2012. (2) And one endocannabinoid metabolite produced in excess during obesity alters normal brain chemistry.

The orexin system

50,000 to 80,000 neurons located in the hypothalamus, a central region of the brain, produce orexin. But that process stops after falling asleep. During the day, though, the signaling protein locks itself in a competitive dance with other biological messengers. Humans habitually sip caffeine-laden coffee or tea, which inhibits one particular messenger produced at night to encourage sleep (adenosine). Whereas THC and limonene promote this sleepy messenger. But caffeine also boosts orexin, essentially stimulating the wake-sleep rhythm that is normally driven by chemical messengers in the brain and body. And normally, this daily cycle ties in with appetite. Orexin liberates wakefulness and further stimulates appetite in competition with adenosine, but it relies on a component of the endocannabinoid system.

Obesity essentially encourages 2-AG synthesis in the brain, which is an endocannabinoid that selectively activates cannabinoid receptors. In fact, 2-AG levels are four times higher in mice with a leptin deficiency, although ECS alterations found in obese mice do not depend on cannabinoid receptor activity. Obesity instead hyperactivates orexin, driving 2-AG metabolism down a special pathway that encourages the production of a unique metabolite.

Endocannabinoid metabolism

Several mechanisms exist in the body that are responsible for recycling and breaking 2-AG down into various metabolites. But overactive orexin converts the endocannabinoid into one particular metabolite known as 2-AGp. 

And while 2-AG itself binds to and activates the cannabinoid 1 (CB1) receptor. Its metabolite — 2-AGp — fits the characteristics of a type of fatty acid (LPA). And LPA receptor activation increases appetite and food intake. This means that obesity chronically induces appetite through two systems that are both tied to one endocannabinoid. The study found that halting one enzyme prevented acute levels of 2-AGp. If this is true, then future research should focus CBGa and CBG as a treatment for chronic obesity due to the cannabinoid’s role in preventing 2-AG metabolism.

Pseudo-lean cannabis consumers

Obesity leads to excessive 2-AG production, dysregulating its metabolism, and encourages ECS derivation to an atypical metabolite. On the other side of the picture, though, Type I cannabis consumers are uniquely skinny, according to anecdotal evidence. Ethan Russo, MD, coined the effect The Skinny Hippy Theory. He postulated that cannabinoid intake regulates gut microbiota. Yet, a recent study led by Daniel Piomelli, Ph.D. identified pseudo-leanness in mice following a series of mild THC doses without effects on their microbiota.

Russo’s work focused on acidic cannabinoids and the terpenes limonene and pinene consumed orally, rather than active THC. And research led by Piomelli found no microbiota differences in young male mice fed five milligrams of THC per kilogram of body mass. They also found no change in food intake, circadian rhythm, or growth rate. Instead, metabolic changes occurred where fat became an energy source in place of muscle cells.

Following THC consumption, mice expressed genes in white and brown adipose (fat) tissue normally reserved for contraction in muscle cells. At the same time, low THC doses reduced genes for muscle development in mice compared to controls. Piomelli and his colleagues concluded,

Collectively, the results indicate that adolescent exposure to low-dose THC produces in male mice a lasting metabolic state characterized by lower fat mass, higher lean mass, partial resistance to diet-induced obesity and dyslipidemia, altered thermogenesis, and blunted lipolytic response to physiological and pharmacological stimuli.

Following these results, THC should essentially protect the body from true obesity, albeit with potentially negative consequences. In the end, however, metabolic disorders steer endocannabinoid function away from CB1 receptor activity and its temporary pseudo-lean side. After ceasing THC doses, though, mice returned to their expected weight based on their given diet.

Sources

1. Fernández-Rilo AC, Forte N, Palomba L, et al. Orexin induces the production of an endocannabinoid-derived lysophosphatidic acid eliciting hypothalamic synaptic loss in obesity. Mol Metab. 2023;72:101713. doi:10.1016/j.molmet.2023.101713

2. Cristino L, Busetto G, Imperatore R, et al. Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons. Proc Natl Acad Sci U S A. 2013;110(24):E2229-E2238. doi:10.1073/pnas.1219485110

3. Russo EB. Cannabis Therapeutics and the Future of Neurology. Front Integr Neurosci. 2018;12:51. Published 2018 Oct 18. doi:10.3389/fnint.2018.00051

4. Lin L, Jung KM, Lee HL, et al. Adolescent exposure to low-dose THC disrupts energy balance and adipose organ homeostasis in adulthood [published online ahead of print, 2023 May 24]. Cell Metab. 2023;S1550-4131(23)00179-1. doi:10.1016/j.cmet.2023.05.002