2-AG belongs to the endocannabinoid system, a lipid signaling network composed of endogenous cannabinoids, their G protein-coupled receptors, chiefly cannabinoid receptor type 1 (CB1) and type 2 (CB2), and the enzymes that synthesize and degrade these messengers. Unlike classical neurotransmitters, endocannabinoids are synthesized on demand from membrane lipids and travel backward across synapses to modulate neuronal firing. 2-AG is produced primarily by diacylglycerol lipase (DAGL) from membrane diacylglycerol precursors and is rapidly hydrolyzed by monoacylglycerol lipase (MAGL). This tight enzymatic control means that 2-AG signaling is exquisitely sensitive to metabolic state, dietary composition and tissue-specific enzyme expression, a property that becomes pathological when the system is chronically overdriven.

The review’s most striking thread concerns the brain. In the hypothalamus, CB1 receptors are densely expressed on appetite-regulating circuits, including the NPY/AgRP neurons of the arcuate nucleus that drive hunger. Endocannabinoid signaling at these synapses is orexigenic, meaning it promotes food intake, and it interacts with hormonal signals such as ghrelin and orexin. Studies cited in the review show that the orexigenic effect of ghrelin is mediated through central activation of the endocannabinoid system, and that orexin-A can repress satiety-inducing POMC neurons via stimulation of endocannabinoid signaling, contributing to weight gain. In obesity, peripheral endocannabinoid signaling in the gut also inhibits satiation signaling, blunting the normal gut-brain feedback that terminates a meal. The result is a feed-forward loop: more 2-AG, more reward-driven and hyperphagic eating, more adiposity, and again more 2-AG.

Diet itself may fuel this loop. One landmark study highlighted in the review found that dietary linoleic acid, abundant in modern processed foods, elevates endogenous 2-AG and anandamide levels and induces obesity in animal models. Because 2-AG is synthesized from arachidonic acid-containing membrane lipids, the fatty acid composition of the diet can directly shape the tone of endocannabinoid signaling. This provides a mechanistic bridge between the industrial food environment and the neurobiology of overeating, and it suggests that the obesity pandemic is not simply a failure of willpower but a biochemical consequence of altered lipid substrates reaching the enzymes that manufacture endocannabinoids.

Beyond the brain, the review details how 2-AG acts on adipose tissue, liver, skeletal muscle and pancreas through CB1 and, in immune cells, CB2 receptors. In adipocytes, endocannabinoid signaling promotes adipogenesis, the formation and enlargement of fat cells, and stimulates glucose uptake via phosphatidylinositol 3-kinase and calcium-dependent mechanisms. In the liver, activation of hepatic CB1 receptors stimulates fatty acid synthesis and is required for the development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. Conversely, CB1 receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity, while peripheral CB1 inverse agonism reduces obesity by reversing leptin resistance. These findings establish the endocannabinoid system as a genuine peripheral regulator of energy storage, not just a central appetite switch.

At the molecular level, the review maps how 2-AG signaling intersects with canonical metabolic pathways. CB1 activation couples to the insulin/PI3K/AKT axis, with evidence that CB1 mediates high-fat diet-induced insulin resistance by increasing forkhead box O1 (FOXO1) activity in obese mice. It also modulates AMP-activated protein kinase (AMPK), the cellular energy sensor: CB1 blockade has been shown to ameliorate hepatic fat infiltration and inflammation while increasing the Nrf2-AMPK pathway in diabetic rat models, and the CB1 receptor mediates the peripheral effects of ghrelin on AMPK activity. Interactions with peroxisome proliferator-activated receptors (PPARs) and the inflammatory transcription factor NF-κB further entangle endocannabinoid tone with lipid metabolism and inflammation. The review argues that these convergences allow elevated 2-AG to amplify metabolic dysfunction across multiple pathways simultaneously, which helps explain why obesity is so often accompanied by insulin resistance, fatty liver disease and chronic low-grade inflammation as a coherent syndrome rather than as separate conditions.

Mitochondria emerge as a particularly intriguing nexus. Endocannabinoid signaling influences mitochondrial biogenesis and oxidative metabolism in adipocytes: CB1 blockade promotes mitochondrial biogenesis through endothelial nitric oxide synthase expression in white fat cells and can induce transdifferentiation of white adipocytes toward a brown fat phenotype, which burns energy rather than storing it. CB1 receptors also mediate depot-specific effects on differentiation, inflammation and oxidative metabolism in different white adipose tissue depots. Because impaired mitochondrial function in muscle and fat is a hallmark of insulin resistance and lipotoxicity, the review suggests that 2-AG-driven suppression of mitochondrial oxidative capacity may be a key mechanism linking endocannabinoid overactivity to the metabolic inflexibility observed in obesity and type 2 diabetes.

Inflammation is the third pillar of the review’s argument. Obese adipose tissue is infiltrated by macrophages, and the polarization of these immune cells toward pro-inflammatory M1 states drives systemic insulin resistance. Here the two cannabinoid receptors diverge sharply. CB1 signaling in macrophages appears to worsen metabolic inflammation: decreasing CB1 signaling in Kupffer cells, the liver’s resident macrophages, improves insulin sensitivity in obese mice, and CB1 blockade attenuates adipose tissue inflammation through microRNA-mediated regulation of macrophage signaling. CB2, by contrast, is largely anti-inflammatory. CB2 agonists such as JWH-133 attenuate chronic inflammation by restraining M1 macrophage polarization via the Nrf2/HO-1 pathway in diet-induced obese mice, and CB2 activation has been implicated in reducing fat storage and promoting adipose browning. The review, which builds on the group’s earlier work on CB2 in hepatic steatosis and fibrosis, frames selective CB2 activation and peripheral CB1 blockade as complementary pharmacological strategies.

The therapeutic history of this field is cautionary but instructive. The CB1 antagonist SR141716 (rimonabant) produced robust weight loss and improved metabolic parameters in diet-induced obese mice and was briefly approved in Europe, but it was withdrawn after psychiatric adverse events, a consequence of blocking CB1 receptors in the brain. The lesson, the authors argue, is that future therapies must target the periphery or the enzymes that control 2-AG levels rather than central receptors wholesale. Inhibitors of DAGL, the synthetic enzyme for 2-AG, and MAGL, its degradative enzyme, offer such an approach, and DAGL inhibition has already shown efficacy in preclinical models of excessive reward-driven intake. Peripherally restricted CB1 antagonists and CB2 agonists, including plant-derived compounds such as beta-caryophyllene, a dietary CB2 ligand, represent additional avenues. Even exercise appears to retune the endocannabinoid system in high-fat diet-induced obesity, suggesting lifestyle interventions may partly work through this axis.

The review is careful to distinguish direct evidence for 2-AG from extrapolation, noting that much of the mechanistic data comes from rodent models and that human studies, such as the finding that plasma 2-AG is a biomarker of age- and menopause-related insulin resistance and dyslipidemia in lean individuals, remain limited. Yet the convergence of evidence across the gut-brain-adipose axis is compelling. If 2-AG truly sits at the crossroads of appetite, adipogenesis, insulin signaling, mitochondrial function and inflammation, then modulating the 2-AG/endocannabinoid axis with tissue-selective tools could yield the next generation of obesity treatments, ones that address the disease’s biology rather than only its energy arithmetic. As obesity reaches pandemic proportions in every household, decoding this fat-derived signal may prove one of the most consequential tasks in metabolic medicine.

Subject of Research: The role of the endocannabinoid 2-arachidonoylglycerol in obesity, inflammation and metabolic dysfunction

Article Title: Beyond energy balance: 2-arachidonoylglycerol at the crossroads of obesity, inflammation, and metabolic dysfunction

Article References: Kumari, S., Nayak, B., & Deshmukh, R. (2026). Beyond energy balance: 2-arachidonoylglycerol at the crossroads of obesity, inflammation, and metabolic dysfunction. Molecular Biology Reports, 53(1), Article 1706. https://doi.org/10.1007/s11033-026-12909-1

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12909-1

Keywords: 2-arachidonoylglycerol, endocannabinoid system, obesity, CB1 receptor, CB2 receptor, inflammation, insulin resistance, hypothalamus, adipose tissue, mitochondria, MAGL, metabolic dysfunction

The endocannabinoid system consists of lipid signaling molecules called endocannabinoids, principally anandamide and 2-arachidonoylglycerol, along with their G-protein-coupled receptors, CB1 and CB2, and the enzymes that synthesize and degrade these messengers. CB1 receptors are abundant on nociceptive sensory neurons in the dorsal root ganglia, where their activation dampens the release of pain-transmitting neurotransmitters. CB2 receptors are found predominantly on immune cells, including mast cells and macrophages, and their engagement suppresses the release of proinflammatory cytokines. Beyond these classic receptors, cannabinoids also interact with non-cannabinoid targets such as the ion channel TRPV1, the nuclear receptor PPAR-gamma, serotonin receptors, and orphan G-protein-coupled receptors like GPR18 and GPR55, giving the system an unusually broad pharmacological reach.

What makes this system particularly relevant to endometriosis is that it is not merely a bystander. Human studies have documented elevated systemic levels of endocannabinoids and related mediators across the menstrual cycle in women with endometriosis, and cannabinoid receptor expression has been detected directly in endometriotic lesions. Animal work has shown that the CB1 receptor contributes to the development of ectopic lesions in a mouse model of the disease, while other studies report decreased expression of cannabinoid receptors in the eutopic and ectopic endometrium of patients with adenomyosis, a closely related condition. In other words, the endocannabinoid machinery appears to be rewired in diseased tissue, positioning it as both a marker and a potential driver of pathology.

The review organizes the therapeutic logic of cannabinoids around three mechanistic pillars: inflammation, nociceptive signaling, and lesion proliferation. On the inflammatory front, endometriosis is characterized by a peritoneal environment awash with proinflammatory cytokines, activated macrophages, and degranulating mast cells, all of which sensitize nearby nerve fibers. Cannabinoids attenuate this cascade by inhibiting proinflammatory cytokine signaling and reducing the release of inflammatory mediators from mast cells and peritoneal macrophages. Cannabidiol, the non-psychoactive phytocannabinoid, has been shown in molecular studies to blunt the inflammatory and oxidative processes associated with endometriosis, and CB2-selective agonists reduce cytokine release in blood mononuclear cells. Because neurogenic inflammation, driven by mast cells and nerve fiber interactions, is increasingly recognized as central to endometriosis pain, this immunomodulatory action is a plausible route to symptom control.

The second pillar concerns direct suppression of pain signaling and sensitization. Endometriosis-associated pain involves peripheral, central, and cross-sensitization, in which repeated nociceptive input from pelvic lesions amplifies responses throughout the nervous system, sometimes producing comorbid pain syndromes such as fibromyalgia. Cannabinoids counter this at multiple levels. Activation of peripheral CB1 and CB2 receptors suppresses the maintenance of inflammatory nociception, and genetic studies indicate that cannabinoid analgesia is mediated largely through peripheral type 1 cannabinoid receptors on nociceptors. Cannabidiol acts on TRPV1 signaling pathways in cultured dorsal root ganglion neurons, and CB1 receptor agonists can prevent nerve growth factor-induced sensitization of TRPV1 in sensory neurons, a mechanism directly relevant to the elevated TRPV1 expression observed in the dorsal root ganglia of rats with endometriosis and in peritoneal endometriotic foci of women with chronic pelvic pain.

The third pillar is antiproliferative. Endometriotic lesions behave somewhat like benign tumors, proliferating, invading, and recruiting new blood vessels. Synthetic cannabinoid agonists such as WIN 55212-2 have been shown to target proliferation, angiogenesis, and apoptosis via MAPK/AKT signaling in human endometriotic cell lines and in a murine model of the disease. Cannabinoid agonists exert antiproliferative effects on deep infiltrating endometriosis tissue, and cannabidiol demonstrated anti-inflammatory, antioxidative, and antiangiogenic effects in an experimental rat model. Natural delta-9-tetrahydrocannabinol has even shown disease-modifying effects on endometriosis-associated pain in animal studies, suggesting that cannabinoids might not only mask symptoms but also slow lesion growth, a property that no current medical therapy can claim.

The mechanistic enthusiasm is mirrored by striking epidemiological reality. Surveys from Australia, New Zealand, Canada, Germany, and the United States consistently show that large numbers of women with endometriosis are already using cannabis, often illicitly or without medical supervision, to self-manage their pain, and many report perceived effectiveness. A national survey of Australian women identified cannabis as a common self-management strategy, and international cross-sectional research conducted during the COVID-19 pandemic documented continued and in some cases increased use. National survey data further indicate substantial willingness among women to try cannabis for gynecological conditions. This grassroots adoption has outpaced the clinical evidence, creating a situation in which patients are experimenting on themselves with products of variable composition and dosing, while physicians lack the trial data needed to guide them.

The review’s authors argue that this gap makes properly controlled clinical trials an urgent priority. Several challenges stand in the way. Cannabinoid pharmacology is complicated by the entourage effect, in which combinations of phytocannabinoids and terpenes may produce effects different from isolated compounds, and by the psychoactivity of THC, which limits tolerable doses. However, recent structural and pharmacological advances are opening new doors. The discovery of a cryptic pocket in the CB1 receptor that drives peripheral and functional selectivity suggests it may be possible to design analgesics that activate pain-relieving pathways without central psychoactive effects. Separately, the sodium channel Nav1.8 has been identified as an analgesic target for non-psychotomimetic phytocannabinoids, offering another route to pain relief without intoxication. Such advances could yield peripherally restricted cannabinoid medicines tailored to endometriosis, an approach that would sidestep many of the regulatory and tolerability obstacles that have hampered the field.

There is also an opioid angle that gives the research public-health urgency. Women with endometriosis are frequently prescribed opioids for their pain, and cohort studies in US administrative claims data have documented chronic opioid use and its complication risks in this population. Cannabinoids interact with the opioid system, and a growing body of preclinical and clinical evidence supports an opioid-sparing effect of cannabinoids for analgesia. Because cannabinoid receptor expression has been detected in endometriotic lesions of women with the disease, some researchers have proposed cannabinoid-based approaches as an alternative to opioid-based pain medication. If clinical trials confirm meaningful analgesia, cannabinoids could help reduce opioid exposure in a patient population disproportionately affected by long-term opioid therapy and its attendant risks of dependence and hyperalgesia.

Cautious optimism is the appropriate stance. The evidence base remains dominated by in vitro studies and animal models, and human interventional data are still sparse, while the endocannabinoid system also plays fundamental roles in endometrial and placental biology, raising questions about reproductive safety that trials must address. Yet the convergence of epidemiological demand, mechanistic plausibility across inflammation, nociception, and proliferation, and emerging medicinal chemistry that promises non-psychoactive, peripherally targeted drugs makes the endocannabinoid system one of the most compelling therapeutic frontiers in endometriosis research. As the Wayne State team concludes, the system’s regulation of nociception, inflammation, and lesion growth warrants rigorous clinical evaluation, and for the millions of women whose pain has outlasted every existing therapy, that evaluation cannot come soon enough.

Subject of Research: The role of the endocannabinoid system in the mechanisms and treatment of endometriosis-associated pain

Article Title: The Endocannabinoid System in Endometriosis-Associated Pain: Mechanisms, Molecular Targets, and Therapeutic Implications

Article References: Stone, A. M., Veltre, V. L., Camp, O. G., Biernat, M. M., & Abu-Soud, H. M. (2026). The Endocannabinoid System in Endometriosis-Associated Pain: Mechanisms, Molecular Targets, and Therapeutic Implications. Reproductive Sciences. https://doi.org/10.1007/s43032-026-02201-9

Image Credits: AI Generated

DOI: 10.1007/s43032-026-02201-9

Keywords: endometriosis, endocannabinoid system, cannabinoids, cannabidiol, chronic pelvic pain, CB1 receptor, CB2 receptor, inflammation, nociception, TRPV1, lesion proliferation, clinical trials