Cannabinoids are pharmacologically active compounds obtained from the hemp plant Cannabis sativa, the most abundant being Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). This plant has been known to have medicinal importance for thousands of years, but mainly as an anti-inflammatory, or to relieve pain, anxiety, or mania.
These were used primarily for their recreational aspects due to their psychoactive effects in the past, but also for their ability to modulate brain activity in other areas. CBD is thought to have anti-inflammatory, anti-oxidant, anti-tumor, neuroprotective, and potential anti-obesity properties.
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Cannabinoids and the ECS
Cannabinoids interact with the endocannabinoid system (ECS) in the brain. The ECS regulates many functions such as sleep, mood, memory, appetite, reproduction, and pain sensation. It includes endocannabinoids (ECs), the enzymes that mediate their production and metabolism, and the receptors on which the ECs act.
The best understood ECs are ECs, i.e., anandamide (AEA) and 2-arachidonoylglycerol (2-AG), both of which are formed from long-chain polyunsaturated fatty acids. The ECS receptors include cannabinoid (CB) receptors, which are G-protein coupled receptors (GPCRs). Two CB receptors have been identified, the CB receptor 1 (CB1) and CB receptor 2 (CB2).
The ECS is upregulated during obesity and its linked health conditions, with an increase in the levels of endogenous cannabinoids. The reason may be that these ECs are produced in greater amounts or that their breakdown is limited. Moreover, EC receptors may be overexpressed.
The cannabinoid-1 (CB-1) receptor is responsible for the psychotropic effects of cannabis, resulting from its activation by the cannabinoid Δ9-THC. In addition, CB1 is activated by other ligands to regulate energy balance and lipogenesis, as well as stress responses.
CB-1 is important in regulating appetitive behavior, and in fact, when compounds that stimulate the cannabinoid receptors are administered, in humans and animals, they are found to eat more. These receptors are found in the brain, in the hypothalamic nuclei that control energy metabolism, as well as in the mesolimbic system where food is presented as a motivating factor rather than a nutritionally valuable item.
The levels of CB-1 receptors correlate, in rodents at least, with increased food demand. After a short fast, these receptors must be active to prompt eating.
Selective high-affinity CB-1 receptor antagonists have been found to result in lowering of food intake immediately and over the long term. When given over weeks, bodyweight is lost and stays off, in both rodents and humans. Several pharmaceuticals have observed the therapeutic potential for such compounds in the weight loss industry.
CB2 receptors are expressed on immune cells as well as the brain. Both CB1 and CB2 receptors are also found in the liver, skeletal muscle, heart, gut, bones, and adipose tissue.
Cannabinoids and obesity
Obesity is an alarming epidemic in many developed and developing countries, related as it is to increased risk for many cardiovascular conditions and insulin resistance or frank diabetes. Ischemic heart disease, stroke, fatty liver disease, hypertension, and renal disease are some of the cardiovascular outcomes following the onset of obesity.
Inflammation is a fundamental presence in obesity. Moreover, obesity begins with altered hypothalamic signaling pathways, involving hormones such as leptin, insulin, adiponectin, cholecystokinin, and ghrelin.
Not only do cannabinoids have the potential to reduce the hunger/satiety signaling and neuroinflammation in the brain, but they regulate metabolic reactions in the liver, fat, muscles and mediate anti-inflammatory responses in the blood cells. Cannabinoids are thus promising agents in the fight against obesity.
The EC levels are upregulated within the hippocampus, a key center of hedonic eating, indicating that very palatable foods might be more satisfying under these conditions, resulting in an inescapable road leading to obesity.”
ECs are important to both central and peripheral energy metabolism. ECs in the hypothalamus are upregulated, which can, along with the impaired leptin signaling, cause insulin resistance in the hypothalamus, leading in turn to peripheral metabolic syndrome.
Δ9-THC is a strongly psychoactive compound. It acts as a partial agonist of both CB1 and CB2 receptors. Δ9-THC increases appetite by activating limbic and hypothalamic CB1 receptors.
Δ9-THC also has a potential anti-obesity effect, because of its beneficial impact on the regulation of insulin sensitivity in insulin-resistant adipocytes, decreasing triglyceride content and improving the glucose uptake. In obese mice, treatment with this compound for 3-4 weeks led to stabilization of weight by reducing their intake of food.
This effect may be explained by the partial agonism of Δ9-THC, which subdues the results produced by full agonists such as anandamide on the CB1 receptor, especially when endocannabinoid stimulation is at a high basal level as in obesity.
Cannabidiol (CBD) is a negative allosteric modulator of the CB1 receptor. This is responsible for its impact on obesity. It leads to increased food intake and food acting as an incentive. However, it may reduce triglyceride accumulation in fat cells, inducing lipolysis.
It may activate fat cell mitochondria, increasing oxygen uptake, and thus reducing fat content. It also has a high affinity for the CB2 receptor, besides upregulating the PPARγ gene transcription. This gene is implicated in many key ways in glucose regulation, fat metabolism, and inflammation.
However, rodent studies did not show any improvement in lipid or glucose control, perhaps indicating the need for higher dosages. With a high-fat diet, rats did not gain weight, an effect probably due to CB2 receptor activation.
Moreover, CBD is probably able to prevent pancreatic damage in obesity. It reduced the blood levels of the pro-inflammatory cytokines, i.e., TNF-α and interferon-gamma (IFN-γ) together with inflammation mediators, such as nitric oxide (NO), cyclooxygenase (COX), and prostaglandin E2 (PGE2).
CBD also reduces cardiac dysfunction and inflammation, which often occur in diabetic complications.
CBD could therefore be potentially effective in alleviating the symptoms of insulin resistance, type 2 diabetes, and metabolic syndrome.
Δ9-Tetrahydrocannabivarin (Δ9-THCV) is a CB1/CB2 agonist at high doses, with antipsychotic effects. It increases insulin sensitivity and glucose tolerance, without decreasing the food intake or preventing weight gain. Body fat content was reduced, however.
Cannabinol (CBN) is an oxidation product of Δ9-THC, induced by light or aging. It activates both receptors, with weak psychoactive activity, and seems to increase food intake.
Some evidence indicates that obesity is less common among young adult users of cannabis. However, the psychotropic effects of some cannabinoids mean that careful research is required before they can be recommended as therapeutic agents for obesity.
Cannabinoid agonists and antagonists are being explored in the treatment of obesity. The first drug, rimonabant, a CB-1 antagonist, was quickly recalled, despite its ability to reduce body weight and improve metabolic control, due to its serious psychotropic side effects. This has been the case with other CB1 antagonists as well.
Current research is focusing on selective CB1 receptor antagonists acting at the peripheral level, compounds that do not cross the blood-brain barrier.
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