Recently, research has greatly expanded the knowledge of the endocannabinoid system (ECS) and its involvement in several therapeutic applications. Cannabinoid receptors (CBRs) are present in nearly every mammalian tissue, performing a vital role in different physiological processes (neuronal development, immune modulation, energy homeostasis). The ECS has an essential role in metabolic control and lipid signaling, making it a potential target for managing conditions such as obesity and diabetes. Its malfunction is closely linked to these pathological conditions. Additionally, the immunomodulatory function of the ECS presents a promising avenue for developing new treatments for various types of acute and chronic inflammatory conditions. Preclinical investigations using peripherally restricted CBR antagonists that do not cross the BBB have shown promise for the treatment of obesity and metabolic diseases, highlighting the importance of continuing efforts to discover novel molecules with superior safety profiles. The purpose of this review is to examine the roles of CB1R and CB2Rs, as well as their antagonists, in relation to the above-mentioned disorders.
According to the World Health Organization (WHO), diabetes mellitus (DM) and obesity are considered epidemics due to their increasing incidence. Obesity is involved in the etiopathogenesis of DM, as well as its complications, posing a significant threat to public health as an important determinant of insulin resistance. The link between the two is well known and has even led to the development of the term “diabesity”, which is used to suggest the combined adverse health effects of the conditions. Obesity affects both developed and developing countries, with alarming increases in prevalence rates. Current estimates suggest that over 2 billion people have elevated body weight, and 641 million are obese. The economic burden of obesity is also significant, with the annual expenditure on treatment in the United States (US) alone exceeding USD 211 billion.
In regard to DM, the WHO considers it a priority among non-communicable diseases (NCDs), and, alongside others, such as cardiovascular disease, cancer, and respiratory disease, DM accounts for the majority of premature deaths due to NCDs.
Although NCDs mainly fall into five disease groups (cancer, cardiovascular diseases, mental health, chronic obstructive pulmonary disease, and diabetes), diabetes is the only one that demonstrated a substantial increase in burden from 1990 to 2019 when evaluated by disability-adjusted life-years (DALYs), being an important cause of DALYs: it was estimated that in 2017, it accounted for 2.6% of global DALYs. According to the International Diabetes Federation (IDF), in 2017, there were approximately 451 million adults living with the disease, a number that is expected to grow to 693 million by 2045 if the current trend continues, while the 10th edition of the IDF Diabetes Atlas reports that, in 2021, more than 1 out of 10 adults were diabetic, and this number is expected to rapidly expand. In regard to costs, it is estimated that health expenditures related to diabetes were USD 966 billion in 2021. Costs are expected to increase to USD 1054 billion by 2045.
An important feature of both obesity and DM is the inflammation of tissues. This can be seen in pancreatic islets, muscles, the liver, and adipose tissue, all of which are insulin target tissues. Several studies have linked chronic tissue inflammation to these disorders, with tumor necrosis factor-α (TNF-α) levels being increased in adipose tissue in obesity. Proinflammatory cytokines can impair the action of insulin via the activation of signaling molecules (e.g., inhibitor of nuclear factor kappa-B kinase subunit β (IKK-β) and c-Jun N-terminal kinase (JNK)). Another determinant of insulin resistance is the increased number of adipose tissue macrophages (ATMs), which are the most abundant immune cells in adipose tissue. Acute inflammation is frequently addressed with non-steroidal anti-inflammatory drugs (NSAIDs), as well as corticosteroids, but the long-term use of these medications can result in complications, such as gastrointestinal side effects and glucocorticoid-induced osteoporosis, making their use in chronic inflammatory diseases difficult. Disease-modifying drugs such as methotrexate and leflunomide are useful in treating autoimmune diseases, but their effectiveness may decrease with continued use.
The peripheral inflammatory and immune responses in autoimmune diseases, such as rheumatoid arthritis, psoriasis, and Crohn’s disease, have been successfully modulated by biological drugs such as infliximab and adalimumab in recent years. These drugs are largely ineffective in treating CNS inflammation and immune system irregularities. The blood–brain barrier (BBB) permeability prevents 98% of small-molecule medicines and all high-molecular-weight drugs from crossing. In addition, neuroinflammation accelerates the progression of CNS disorders such as Alzheimer’s, Parkinson’s, and traumatic brain injury. Hence, there is a major need for innovative treatment techniques to modulate inflammation, as well as neuroinflammation.
The ECS is a complex system that is involved in several physiological and pathological processes in mammals. It is pivotal in the regulation of appetite, metabolism, and reward, with calorie intake and energy expenditure being some of the metabolic processes that it influences. The major components of the ECS are its receptors and their endogenous ligands. These receptors are named cannabinoid receptors, with type 1 (CB1R) and type 2 (CB2R) being the most known, while anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are their most studied endogenous ligands. CBR can be found in several tissues, including the liver, brain, adipose tissue, and pancreas, and their activation leads to an increase in lipogenesis and decreased insulin sensitivity. It has also been suggested that marijuana, or Cannabis sativa (family Cannabaceae), may also regulate hunger, commonly referred to as “the munchies”. ∆9-Tetrahydrocannabinol (∆9-THC), its main orexigenic component, increases energy expenditure.
Despite the success of existing treatments, obesity and diabetes remain major health concerns, and there is a continuous search for novel treatments that can better aid patients is of high importance, due to the multifactorial and complex nature of these disorders, as well as their complications.
Modulating this system with CBR antagonists has been shown to lower appetite and food intake while also enhancing insulin sensitivity and glucose metabolism. This has attracted interest in their potential involvement in the management of diabetes, obesity, the underlying inflammation, and their associated health conditions.
In spite of promising preclinical data, the development of such antagonists for clinical use has been hampered by their central side effects, which include psychiatric adverse events and an increased risk of depression and suicidal ideation. However, it is important to note that not all individuals experience these side effects, and the degree of their severity can vary widely due to interindividual reactivity. There are still numerous compelling reasons to continue and deepen the scientific study of their prospective usage. Ongoing efforts to develop new compounds with improved safety profiles hold great potential for the future, with peripherally restricted CBR antagonists that do not cross the BBB having shown promise in preclinical studies for the treatment of obesity and metabolic disorders.
The present review aims to explore the roles of CB1R and CB2R and their antagonists, with reference to several diseases, including DM, obesity, inflammation, and immunomodulation. Due to the fact there is still a stigma associated with cannabis use, and many people believe that all cannabinoids are harmful and addictive, this paper can also help to dispel myths and misconceptions about these compounds by providing accurate and evidence-based information and thus a more nuanced understanding of these compounds and their potential therapeutic benefits.
The ECS plays a significant part in the regulation of energy balance, neurodevelopment, and other aspects of the body that show its involvement in the pathogenesis of diseases, as well as the prevention and treatment of illness. The regulation of energy metabolism is greatly influenced by cannabinoid-receptor type 1 (CB1R) and type 2 (CB2R), their best-studied endogenous ligands, and enzymes for ECB synthesis and metabolism. The best-studied primary endogenous ligands are AEA and 2-AG, which are synthesized from omega-6 polyunsaturated fatty acid (PUFA) and arachidonic acid (AA), respectively. While AEA is a partial agonist with a high affinity for CB1Rs, 2-AG is a full agonist of CB1Rs and CB2Rs. In addition to interacting with CBRs, both AEA and 2-AG can bind and activate the transient receptor potential vanilloid 1 (TRPV1). AEA is an agonist for several forms of the peroxisome proliferator-activated receptor (PPAR) family.
Aside from AEA and 2-AG, the body contains N-acyl ethanolamine and 2-acylglycerol, two other endogenous cannabinoids derived from n-6 and n-3 PUFAs such a
