Category Archives: Obesity

Cannabis Improves Metabolic Dysfunction and Macrophage Signatures in Obese Mice

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“Obesity rates continue to rise, highlighting the need for new treatments that are effective, safe, and widely accessible. Aligned with the easing of restrictions on cannabis use, interest in its therapeutic potential is evolving. As such, we examined the effects of the cannabis plant with high cannabidiol (CBD) content or high Δ9-tetrahydrocannabinol (THC) content on metabolic and immune dysregulation in obese mice.

Briefly, female C57BL/6 mice were randomized into four groups (n=15/group): 1) Lean, 2) Obese Placebo, 3) Obese CBD, and 4) Obese THC. Lean mice consumed a low-fat diet for the study duration. Obese mice consumed a high-fat diet for 16 weeks prior to a 4-week cannabis (3x/week; high CBD = ~4.2 mg/kg and high THC = ~7.3 mg/kg) intervention.

Consistent with our hypothesis, obesity increased Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and metabolic dysfunction-associated steatohepatitis (MASH) both of which were significantly mitigated by either high (10.5%) CBD or high (18.16%) THC cannabis (p<0.05). Interestingly, these changes appeared to occur independent of significant weight loss or measurable changes in food intake.

Diet-induced obesity also increased infiltrating macrophages, pan macrophages, and M1-like pro-inflammatory macrophages in adipose tissue and liver. These effects were rescued by high CBD and high THC (p<0.05), providing evidence consistent with causation for the improvements in HOMA-IR and MASH.

Despite the legal complexities surrounding cannabis use, these data suggest both CBD and THC can be a viable therapy to target macrophages and improve metabolic health and immune dysregulation with obesity.”

https://pubmed.ncbi.nlm.nih.gov/40960937/

https://journals.physiology.org/doi/abs/10.1152/ajpcell.00503.2025

Cannabidiol regulates apoptosis and glial cells homeostasis in the prefrontal cortex of offspring from obese rat mothers

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“Maternal obesity during pregnancy poses significant health risks for both mother and progeny, including long-term impacts on brain function. In previous studies, we demonstrated that cafeteria diet (CAF) consumption during gestation induces neuroinflammation and behavioral deficits in the offspring, which are reversed by cannabidiol (CBD) treatment. However, the effects of CBD on apoptosis-related pathways in this context remain unclear.

Here, we investigated whether CBD treatment can modulate pro-apoptotic signaling and glial cells morphology in adult offspring of obese mothers.

Wistar rats were fed a CAF for 12 weeks before mating, during pregnancy, and lactation. Offspring received oral CBD (50 mg/kg) for 3 weeks starting at postnatal day 70. In the prefrontal cortex, we assessed apoptosis-related proteins, TNFα gene expression, and astrocytes and microglia morphology.

Male and female offspring of CAF-fed dams showed increased levels of BAD, which were mitigated by CBD treatment. JNK was also elevated in female offspring of obese mothers, and CBD reduced this increase. In females, CBD treatment led to a decrease in AKT concentrations. TNFα expression was elevated in the prefrontal cortex of male offspring of obese mothers. Additionally, a reduction in GFAP- and IBA-1-positive cells in the prefrontal cortex was observed in male offspring of obese dams, which was reversed by CBD.

These findings suggest that maternal obesity promotes a pro-apoptotic and inflammatory brain environment, and CBD may counteract these effects via modulation of glial activity and apoptotic pathways.”

https://pubmed.ncbi.nlm.nih.gov/40892197/

https://link.springer.com/article/10.1007/s11011-025-01687-7

Dietary cannabidiol oil mitigates metabolic dysfunction in mice with high-fat diet-induced obesity

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“Metabolic syndrome (MetS) is a widespread health concern driven largely by lifestyle behaviors such as dietary choices and physical inactivity. Excessive caloric intake promotes adiposity and dysregulation of metabolic signaling in adipose tissue.

This study employed a mouse model of diet-induced obesity to evaluate the ability of cannabidiol (CBD), a cannabis-derived phytochemical, to mitigate metabolic dysfunction. Five-week-old mice received a standard diet or a high-fat diet (HF) with or without CBD (25 mg/kg bw) for 9 weeks.

CBD supplementation reduced weight gain and lowered serum glucose concentration in HF mice. These improvements were accompanied by reduced white adipose tissue mass and smaller adipocyte size. Additionally, CBD treatment recovered protein levels of key metabolic regulators, including peroxisome proliferator-activated receptor-γ coactivator 1 alpha and Sirtuin 1, in both inguinal and epididymal adipose tissues.

Consistently, CBD supplementation upregulated the mRNA expression of Prdm16 and promoted uncoupling protein 1 at both mRNA and protein levels, showing the browning of adipose tissues. Upstream, CBD supplementation increased transient receptor potential vanilloid 1 (TRPV1) in HF mice at both the mRNA and protein levels, which possibly helped orchestrate the observed improvements.

In summary, dietary CBD mitigates weight gain and improves the metabolic health of HF-challenged mice, potentially through the promotion of white adipose tissue browning.”

https://pubmed.ncbi.nlm.nih.gov/40712842/

“Dietary cannabidiol mitigates body and adipose weight gain in obesity mice.”

https://www.sciencedirect.com/science/article/pii/S0955286325002037?via%3Dihub

Short-Term Incubation of H9c2 Cardiomyocytes with Cannabigerol Attenuates Diacylglycerol Accumulation in Lipid Overload Conditions

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“Fatty acids (FAs) play a crucial role in human physiology, including energy production and serving as signaling molecules. However, a dysregulation in their balance can lead to multiple disorders, such as obesity and metabolic syndrome. These pathological conditions alter the balance between the heart’s energetic substrates, promoting an increased reliance on FAs and decreased cardiac efficiency.

A therapeutic application of a non-psychotropic phytocannabinoid, cannabigerol (CBG), seems to be a promising target since it interacts with different receptors and ion channels, including cannabinoid receptors-CB1 and CB2, α2 adrenoceptor, or 5-hydroxytryptamine receptor.

Therefore, in the current study, we evaluated a concentration-dependent effect of CBG (2.5 µM, 5 µM, and 10 µM) on H9c2 cardiomyocytes in lipid overload conditions. Gas-liquid chromatography and Western blotting techniques were used to determine the cellular lipid content and the level of selected proteins involved in FA metabolism, glucose transport, and the insulin signaling pathway. The glucose uptake assay was performed using a colorimetric method.

Eighteen-hour CBG treatment in the highest concentration (10 µM) significantly diminished the accumulation of diacylglycerols (DAGs) and the saturation status of this lipid fraction. Moreover, the same concentration of CBG markedly decreased the level of FA transporters, namely fatty acid translocase (CD36) and plasma membrane fatty acid-binding protein (FABPpm), in the presence of palmitate (PA) in the culture medium.

The results of our experiment suggest that CBG can significantly modulate lipid storage and composition in cardiomyocytes, thereby protecting against lipid-induced cellular dysfunction.”

https://pubmed.ncbi.nlm.nih.gov/40643519/

“In our research, we presented evidence suggesting that CBG treatment, especially in higher concentrations (10 µM), may offer substantial benefits in the states associated with excessive lipid availability, which was demonstrated in the H9c2 cell model. The results obtained in our experiment suggest that CBG possesses the ability to alter the metabolism of H9c2 cells by influencing FA storage and utilization while also attenuating the inflammatory pathways activated in a high-lipid environment. These findings indicate that CBG may represent a promising therapeutic candidate for further investigation concerning lipotoxicity and insulin resistance development. Moreover, CBG is predisposed to be a metabolic modulator by altering the levels and cellular location of CD36, a major regulator of myocardial lipid metabolism and a therapeutic target for metabolic disturbances.”

https://www.mdpi.com/2073-4409/14/13/998

Cannabidiol improves metabolic profiles and alleviates liver inflammation and fibrosis in conditions of androgenic obesity and polycystic ovary syndrome

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“Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, with an estimated prevalence of 10%–15%.1 In addition to its reproductive features, that is, hyperandrogenism, anovulation, and polycystic ovarian morphology, PCOS is strongly associated with metabolic disturbances, including obesity, insulin resistance and an elevated risk of metabolic associated steatotic liver disease (MASLD).1 These complications not only worsen the quality of life but also increase long-term morbidity and mortality of women living with PCOS. The coexistence of these metabolic traits complicates clinical management and increases the risk of developing type-2 diabetes and cardiovascular diseases.

Lifestyle modifications are considered first-line interventions in PCOS, but they frequently fail to achieve sustained weight loss or ideal metabolic control, particularly in patients with pronounced hormonal perturbations (e.g., persistent hyperandrogenism) or psychological distress. Pharmacological approaches, such as metformin and GLP-1 receptor agonists, are currently used to handle metabolic complications, but they have limitations regarding efficacy, tolerability and/or accessibility, and are not universally approved for management of PCOS. Moreover, these treatments might overlook the inflammatory and fibrotic dimensions of PCOS, which are increasingly recognized as central contributors to its pathogenesis.

Cannabidiol (CBD), a non-psychotropic phytocannabinoid from Cannabis sativa,5 has garnered attention due to its anti-inflammatory, antioxidant and metabolic regulatory properties. Preclinical studies suggest that CBD acts as a negative allosteric modulator of the cannabinoid CB1 receptor (CB1R),6 and engages additional targets, such as PPARγ7 and the Nrf2 signalling pathway.8 Given these pleiotropic actions, CBD represents an attractive candidate for addressing the complex metabolic profile of PCOS. In this study, we evaluated the metabolic and hepatic effects, including proteomic profiles, of CBD in a validated murine model of PCOS associated with androgenic obesity (AO),9 aiming to provide insights into its therapeutic potential and underlying mechanisms of action.”

https://pubmed.ncbi.nlm.nih.gov/40635171/

“This study provides compelling preclinical evidence that CBD exerts broad metabolic benefits in a murine model of PCOS with androgenic obesity. Treatment with CBD led to significant reductions in weight gain, adiposity, insulin resistance, indices of hepatic fibrosis and systemic inflammation, with prominent favourable actions on MASLD traits. Liver proteomic and circulating biomarker analyses strongly supported the reprogramming of disease-associated molecular pathways caused by CBD, underscoring its potential to mitigate the multifactorial pathophysiology of PCOS.”

https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.16602

The Impact of Major and Minor Phytocannabinoids on the Maintenance and Function of INS-1 β-Cells Under High-Glucose and High-Lipid Conditions

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“Type 2 diabetes mellites (T2DM) is the most common form of diabetes and affects a significant portion of the population. Obesity-related increases in free fatty acids and glucose in the diet contribute to β-cell dysfunction and loss, ultimately leading to the onset of T2DM.

The endocannabinoid system, which is present throughout the body, plays a vital role in regulating various physiological processes, including those in the pancreas. This system has been implicated in metabolic disorders like obesity and diabetes, as it helps to regulate appetite, food intake, and fat production.

Phytocannabinoids from Cannabis sativa have the potential to influence the endocannabinoid system, offering a promising therapeutic approach for diabetes and its complications.

Using high-glucose-high-lipid (HGHL)-induced INS-1 β-cells, we investigated the protective effects of two major (THC and CBD) and three minor (THCV, CBC, and CBG) phytocannabinoids on high glucose-high lipid (HGHL)-induced apoptosis, cell cycle disruption, and impaired function of beta-cells.

Our results showed that all five phytocannabinoids reduced HGHL-induced apoptosis, likely by decreasing TXNIP protein levels. Additionally, THC and all three minor phytocannabinoids provided protective effects against functional impairments caused by HGHL exposure.”

https://pubmed.ncbi.nlm.nih.gov/40363798/

“Our findings demonstrate that all five phytocannabinoids tested effectively mitigate high-glucose–high-lipid (HGHL)-induced apoptosis in INS-1 β-cells, primarily through their mitigatory effects on thioredoxin-interacting protein (TXNIP). Among the tested compounds, THC exhibited the most pronounced impact on reducing TXNIP levels and apoptotic biomarkers, suggesting that THC may be the most promising candidate for counteracting oxidative stress and apoptosis in HGHL-induced β-cells.”

https://www.mdpi.com/1420-3049/30/9/1991

The endocannabinoid and paracannabinoid systems in natural reward processes: possible pharmacological targets?

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“Natural rewards such as food, mating, and social interaction are essential for survival and species preservation, and their regulation involves a complex interplay of motivational, cognitive, and emotional processes.

Over the past two decades, increasing attention has been directed toward the endocannabinoid system and its paracannabinoid counterpart as key modulators of these behaviors.

This review aims to provide an integrated overview of the roles played by the endocannabinoid and paracannabinoid systems in regulating natural reward-driven behaviors, focusing on feeding, reproductive behavior, and social interaction.

We highlight how the endocannabinoid system – mainly through CB1 receptor signaling – modulates central and peripheral circuits involved in energy homeostasis, reward processing, and emotional regulation. In parallel, we explore the role of paracannabinoids, such as oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA), which act primarily via non-cannabinoid receptors and contribute to the regulation of appetite, sexual motivation, and social behavior.

Special attention is given to the relevance of these systems in the pathophysiology of obesity, eating disorders, sexual dysfunctions, and social impairments, as well as their potential as pharmacological targets.

Overall, the evidence discussed supports a broader conceptualization of endocannabinoid and paracannabinoid signaling as pivotal regulators of natural rewards and opens new avenues for the development of targeted interventions for motivational and reward-related disorders.”

https://pubmed.ncbi.nlm.nih.gov/40274041/

“Endocannabinoid/paracannabinoid therapies offer promising innovative drug development.”

https://www.sciencedirect.com/science/article/pii/S0031938425001301?via%3Dihub

The role of tetrahydrocannabivarin (THCV) in metabolic disorders: A promising cannabinoid for diabetes and weight management

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“Disorders of the metabolism, including obesity and type 2 diabetes, represent significant global health challenges due to their rising prevalence and associated complications. Despite existing therapeutic strategies, including lifestyle interventions, pharmacological treatments, and surgical options, limitations such as poor adherence, side effects, and accessibility issues call attention to the need for novel solutions.

Tetrahydrocannabivarin (THCV), a non-psychoactive cannabinoid derived from Cannabis sativa, has emerged as a promising agent to manage metabolic disorders.

Unlike tetrahydrocannabinol (THC), THCV exhibits an antagonistic function on the CB1 receptor and a partial agonist function on the CB2 receptor, thus enabling appetite suppression, enhanced glucose regulation, and increased energy expenditure.

Preclinical studies demonstrated that THCV improves insulin sensitivity, promotes glucose uptake, and restores insulin signaling in metabolic tissues. Additionally, THCV reduces lipid accumulation and improves the mitochondrial activity in adipocytes and hepatocytes, shown through both cell-based and animal research. Animal models further revealed THCV’s potential to suppress appetite, prevent hepatosteatosis, and improve metabolic homeostasis.

Preliminary human trials support these findings, thereby showing that THCV may modulate appetite and glycemic control, though larger-scale studies are necessary to confirm its clinical efficacy and safety. THCV’s unique pharmacological profile positions it as a possible therapeutic candidate to address the multifaceted challenges of obesity and diabetes. Continued research should concentrate on optimizing formulations, undertaking well-designed clinical studies, and addressing regulatory hurdles to unlock its full potential”

https://pubmed.ncbi.nlm.nih.gov/40270953/

https://www.aimspress.com/article/doi/10.3934/Neuroscience.2025003

Cannabidiol oil delays pancreatic islet dysfunction in Wistar rats under hypercaloric diet

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“Hypercaloric diet (HCD) intake can lead to metabolic alterations, such as metabolic syndrome and type-2 diabetes mellitus.

Phytocannabinoid cannabidiol (CBD) is a GPR55 receptor antagonist involved in insulin secretion and other functions in pancreatic islet. The therapeutic use of CBD has been suggested for diabetes, but little is known regarding its effects on pancreatic islet physiology.

Our aim was to evaluate the effects of CBD oil on pancreatic islets, from Wistar rats under HCD.

Male rats were divided in 4 groups: Normal diet vehicle-treated (control) and CBD-treated group. Rats under HCD were subdivided in treated with vehicle (HCD) and with CBD oil administered 21 mg/Kg orally, 0.5 ml in 3 days per week; controls received coconut oil as vehicle. Body weight, food intake, and water consumption were recorded. After 20 weeks, glucose tolerance curve was performed; serum insulin was determined by ELISA, and pancreas was removed for histological and gene expression analysis for insulin, glucagon, PDX-1, MafA and GPR55 receptor.

CBD treatment reduced body weight and food intake but increased fluid consumption, independently of diets. In control group, CBD did not alter blood glucose and serum insulin, but modified expression for GPR55 receptor, glucagon, insulin and MafA. Rats under HCD and treated with CBD decreased glycaemia, insulinaemia, islets relative area, GPR55-positive cells, PDX-1 and MafA gene expression, meanwhile insulin and glucagon expression was increased.

In conclusion, CBD ameliorated HCD effects through changes in insulin, glucagon and GPR55 receptor expressions. We assume CBD interacts with other receptors beside GPR55.”

https://pubmed.ncbi.nlm.nih.gov/40106970/

“The effects of hypercaloric diet in pancreatic islets are ameliorated by CBD.”

https://www.sciencedirect.com/science/article/pii/S0753332225001878?via%3Dihub

Weight Loss and Therapeutic Metabolic Effects of Tetrahydrocannabivarin (THCV)-Infused Mucoadhesive Strips

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“Objective: Metabolic syndrome is due to dysregulation that starts with fat accumulation, causing inflammatory response, insulin resistance, dyslipidemia, hypertension, and fatty liver disease. The endocannabinoid system, via cannabinoid receptor type 1 (CB1), has been shown to be involved with energy homeostasis and regulation of appetitive behavior via activity in the hypothalamus, limbic forebrain and amygdala and in the peripheral tissues including adipose, liver and muscle. Therefore, two phytocannabinoids, tetrahydrocannabivarin (THCV), a CB1 neutral antagonist, and cannabidiol (CBD), a negative allosteric modulator of CB1, are expected to have therapeutic metabolic benefits, including weight loss.

Method: A placebo-controlled study was conducted on 44 subjects (31 females and 13 males) with an average age of 51.75. The study evaluated the efficacy of two different doses of THCV and CBD (8 mg THCV/10 mg CBD in the lower dose and 16 mg THCV/20 mg CBD in the higher dose), taken once daily for 90 days via mucoadhesive oral strips, for weight loss and improvement of certain metabolic markers.

Results: Use of the THCV/CBD strip was associated with statistically significant weight loss, decreases in abdominal girth, systolic blood pressure, and total and LDL cholesterol. The study was limited by small sample sizes in both the high dose and placebo groups.

Conclusions: The 16 mg/20 mg daily dose was superior for weight loss compared to the 8 mg/10 mg daily dose; both sets of results differed from placebo in a way that was statistically significant. The results of this study were congruent with the prior unpublished studies of a hemp extract containing significant percentages of THCV, CBDV and CBD.”

https://pubmed.ncbi.nlm.nih.gov/39968488/

https://publications.sciences.ucf.edu/cannabis/index.php/Cannabis/article/view/206