Category Archives: Obesity

Dual Inhibition of Cannabinoid-1 Receptor and iNOS Attenuates Obesity-induced Chronic Kidney Disease.

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British Journal of Pharmacology banner“Obesity, an important risk factor for developing chronic kidney disease (CKD), affects the kidneys by two main molecular signaling pathways: the endocannabinoid/CB1 R system, whose activation in obesity promotes renal inflammation, fibrosis, and injury; and the inducible nitric oxide synthase (iNOS), which generates reactive oxygen species resulting in oxidative stress. Hence, a combined peripheral inhibitory molecule that targets both CB1 R and iNOS may serve as an efficacious therapeutic agent against obesity-induced CKD.

KEY RESULTS:

Enhanced expression of CB1 R and iNOS in renal tubules was found in human kidney patients with obesity and other CKDs. The hybrid inhibitor ameliorated obesity-induced kidney morphological and functional changes via decreasing kidney inflammation, fibrosis, oxidative stress, and renal injury. Some of these features were independent of the improved metabolic profile mediated via inhibition of CB1 R. An additional interesting finding is that these beneficial effects on the kidney were partially associated with modulating renal adiponectin signaling.

CONCLUSIONS AND IMPLICATIONS:

Collectively, our results highlight the therapeutic relevance of blocking CB1 R and iNOS in ameliorating obesity-induced CKD.”

https://www.ncbi.nlm.nih.gov/pubmed/31454063

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14849

Prediction and Experimental Confirmation of Novel Peripheral Cannabinoid-1 Receptor Antagonists.

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Go to Volume 0, Issue ja “Small molecules targeting peripheral CB1 receptors have therapeutic potential in a variety of disorders including obesity-related, hormonal and metabolic abnormalities, while avoiding the psychoactive effects in the CNS.

We applied our in house algorithm, Iterative Stochastic Elimination, to produce a ligand-based model that distinguishes between CB1R antagonists and random molecules, by physico-chemical properties only. We screened ~2 million commercially available molecules, and found that about 500 of them are potential candidates to antagonize CB1R. We applied a few criteria for peripheral activity and narrowed that set down to 30 molecules, out of which 15 could be purchased. Ten out of those 15 showed good affinity to CB1R and two of them with nanomolar affinities (Ki of ~400 nM). The eight molecules with top affinities were tested for activity: two compounds are pure antagonists, and five others are inverse agonists.

These molecules are now being examined in vivo for their peripheral vs. central distribution, and subsequently will be tested for their effects on obesity in small animals.”

https://www.ncbi.nlm.nih.gov/pubmed/31433190

https://pubs.acs.org/doi/10.1021/acs.jcim.9b00577

Lifetime marijuana use in relation to insulin resistance in lean, overweight, and obese US adults.

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Journal of Diabetes banner“Obese individuals are more likely to show insulin resistance (IR). However, limited population studies on marijuanause with markers of IR have yielded mixed results.

The aim of this study was to examine the association of marijuana use with IR in US adults with different body mass index (BMI) status.

RESULTS:

Of all 129 509 adults aged 18 to 59 years, 50.3% were women. In current obese marijuana consumers, mean FINS in those with less than four uses per month was 52% (95% confidence interval [CI] 19%-71%) lower than in never users. In former obese consumers with eight or more uses per month and who stopped marijuana use <12 months ago, mean FINS was 47% (95% CI 18%-66%) lower than in never users. Mean FINS in those who quit marijuana 12 to 119 and 120 months and more prior the survey was 36% (95% CI 7%-57%) and 36% (95% CI 10%-54%) lower, respectively.

CONCLUSIONS:

Marijuana use is associated with lower FINS and HOMA-IR in obese but not non-obese adults, even at low frequency of less than four uses per month. Former marijuana consumers with high lifetime use had significantly lower FINS levels that persisted, independent of the duration of time since last use.”

https://www.ncbi.nlm.nih.gov/pubmed/31152633

https://onlinelibrary.wiley.com/doi/abs/10.1111/1753-0407.12958

“Cannabis linked to lower insulin levels in adults at risk of type 2 diabetes”   https://www.diabetes.co.uk/News/2019/Jul/cannabis-linked-to-lower-insulin-levels-in-adults-at-risk-of-type-2-diabetes-99514193.html

Impact of lifetime marijuana use on fasting plasma insulin levels and HOMA-IR score in obese adults with and without insulin resistance.

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“To explore the association of marijuana use with mean plasma fasting insulin levels and homeostasis model assessment of insulin resistance (HOMA-IR) score in obese adults with different HOMA-IR.

RESULTS:

A total of 65,209 obese individuals aged 18 to 59 years were included. In obese individuals who never used marijuana(reference), the mean value (± standard deviation) was 19.0 (± 12.8) μU/mL for plasma fasting insulin and 4.78 (± 3.49) for HOMA-IR. In individuals with HOMA-IR < 2.13 or ≥ 5.72, we found no association of marijuana use with HOMA-IR. In those with HOMA-IR < 5.72, the highest tertile of MLU (i.e., ≥ 1799 times) was associated with 12% decrease (95% confidence intervals, 4-19%) in the fasting insulin and 10% decrease in HOMA-IR (95% CI 1-19%), as compared with their counterparts who never used marijuana. In those with HOMA-IR ≥ 2.13, we found a marked impact of marijuana use only in adults who used marijuana ≥ 1799 times, with 13% decrease (95% CI 5-19%) in fasting insulin and 10% decrease (95% CI 3-18%) in HOMA-IR score.

CONCLUSIONS:

Marijuana use is associated with reduced fasting insulin levels and HOMA-IR score in US obese adults with HOMA-IR ≥ 2.13, but not in those with HOMA-IR < 2.13 or ≥ 5.72. The impact of marijuana use is the greatest after long-term exposure and is independent of BMI.”

https://www.ncbi.nlm.nih.gov/pubmed/31367991

https://link.springer.com/article/10.1007%2Fs00592-019-01390-x

Overcoming the psychiatric side effects of the cannabinoid CB1 receptor antagonists: Current approaches for therapeutics development.

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“The cannabinoid receptor 1 (CBR1) is involved in a variety of physiological pathways and has long been considered a golden target for therapeutic manipulation. A large body of evidence in both animal and human studies suggests that CB1R antagonism is highly effective for the treatment of obesity, metabolic disorders and drug addiction. However, the first-in-class CB1R antagonist/inverse agonist, rimonabant, though demonstrating effectiveness for obesity treatment and smoking cessation, displays serious psychiatric side effects, including anxiety, depression and even suicidal ideation, resulting in its eventual withdrawal from the European market. Several strategies are currently being pursued to circumvent the mechanisms leading to these side effects by developing neutral antagonists, peripherally restricted ligands, and allosteric modulators. In this review, we describe the progress in the development of therapeutics targeting the cannabinoid receptor 1 in the last two decades.”

https://www.ncbi.nlm.nih.gov/pubmed/31284863

http://www.eurekaselect.com/173316/article

Diet, endocannabinoids, and health.

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Nutrition Research“Healthy aging includes freedom from disease, ability to engage in physical activity, and maintenance of cognitive skills for which diet is a major lifestyle factor. Aging, diet, and health are at the forefront of well-being for the growing population of older adults with the caveat of reducing and controlling pain. Obesity and diabetes risk increase in frequency in adults, and exercise is encouraged to control weight, reduce risk of type II diabetes, and maintain muscle mass and mobility.

One area of research that appears to integrate many aspects of healthy aging is focused on understanding the endocannabinoid system (ECS) because of its role in systemic energy metabolism, inflammation, pain, and brain biology. Physical activity is important for maintaining health throughout the life cycle. The benefits of exercise facilitate macronutrient use, promote organ health, and augment the maintenance of metabolic activity and physiological functions. One outcome of routine exercise is a generalized well-being, and perhaps, this is linked to the ECS.

The purpose of this review is to briefly present the current knowledge of key components of the ECS that contribute to appetite and influence systemic energy metabolism, and dietary factors that alter the responses of ligand binding and activation of cannabinoidreceptors and its role in the brain. Herein, the objectives are to (1) explain the role of the ECS in the body, (2) describe the relationship between dietary polyunsaturated fatty acids and macronutrient intake and systemic metabolism, and (3) present areas of promising research where exercise induces endocannabinoid production in the brain to benefit well-being. There are many gaps in the knowledge of how the ECS participates in controlling pain through exercise; however, emerging research will reveal key relationships to understand this system in the brain and body.”

https://www.ncbi.nlm.nih.gov/pubmed/31280882

https://www.sciencedirect.com/science/article/pii/S027153171930572X?via%3Dihub

Lifetime marijuana use in relation to insulin resistance in lean, overweight and obese U.S. adults.

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Journal of Diabetes banner“Obese individuals are more likely to show insulin resistance (IR). However, limited population studies on marijuana use with markers of IR yield mixed results.

METHODS:

We abstracted data from the 2009-2016 National Health and Nutrition Examination Survey (NHANES). We estimated the minimal lifetime marijuana use using the duration of regular exposure and the frequency of use. We used generalized linear models to determine the association of marijuana use with both fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) in lean, overweight and obese individuals, separately. We used interview weight years of data to account for the unequal probability of sampling and non-response.

RESULTS:

Of the total of 129,509 adults aged 18 to 59 years, 50.3% were women. In current obese consumers, the mean insulin in those with < 4 uses/months was 52% (95% CI: 19% to 71%) lower than in never users. Former obese consumers with ≥ 8 uses/month and who stopped marijuana use < 12 months showed 47% (95% CI: 18% to 66%) lower insulin. Those with last use of 12-119 months and ≥ 120 months had 36% (95% CI: 7% to 57%) and 36% (95% CI: 10% to 54%) lower insulin, respectively.

CONCLUSIONS:

Marijuana use is associated with lower fasting insulin and HOMA-IR in obese but not in non-obese adults, even at low frequency of < 4 uses per month. Former consumers with high lifetime use had a significant lower insulin levels which persists, independent of the duration of time since last use.”

https://www.ncbi.nlm.nih.gov/pubmed/31152633

https://onlinelibrary.wiley.com/doi/abs/10.1111/1753-0407.12958

“Study: Cannabis Protective Against Diabetes Among Those Overweight”  https://norml.org/news/2019/06/20/study-cannabis-protective-against-diabetes-among-those-overweight

“Cannabis use could help prevent diabetes”  https://mogreenway.com/2019/06/24/cannabis-use-could-help-prevent-diabetes/

“Cannabis linked to lower insulin levels in adults at risk of type 2 diabetes”  https://www.diabetes.co.uk/news/2019/jul/cannabis-linked-to-lower-insulin-levels-in-adults-at-risk-of-type-2-diabetes-99514193.html

Cannabidiol inhibits sucrose self-administration by CB1 and CB2 receptor mechanisms in rodents.

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Addiction Biology banner

“A growing number of studies suggest therapeutic applications of cannabidiol (CBD), a recently U.S. Food and Drug Administration (FDA)-approved medication for epilepsy, in treatment of many other neuropsychological disorders. However, pharmacological action and the mechanisms by which CBD exerts its effects are not fully understood.

Here, we examined the effects of CBD on oral sucrose self-administration in rodents and explored the receptor mechanisms underlying CBD-induced behavioral effects using pharmacological and transgenic approaches.

Systemic administration of CBD produced a dose-dependent reduction in sucrose self-administration in rats and in wild-type (WT) and CB1-/- mice but not in CB2-/- mice. CBD appeared to be more efficacious in CB1-/- mice than in WT mice.

Similarly, pretreatment with AM251, a CB1R antagonist, potentiated, while AM630, a selective CB2R antagonist, blocked CBD-induced reduction in sucrose self-administration, suggesting the involvement of CB1 and CB2 receptors.

Taken together, the present findings suggest that CBD may have therapeutic potential in reducing binge eating and the development of obesity.”

https://www.ncbi.nlm.nih.gov/pubmed/31215752

https://onlinelibrary.wiley.com/doi/abs/10.1111/adb.12783

Countering the Modern Metabolic Disease Rampage With Ancestral Endocannabinoid System Alignment.

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 Image result for frontiers in endocrinology

“When primitive vertebrates evolved from ancestral members of the animal kingdom and acquired complex locomotive and neurological toolsets, a constant supply of energy became necessary for their continued survival. To help fulfill this need, the endocannabinoid (eCB) system transformed drastically with the addition of the cannabinoid-1 receptor (CB1R) to its gene repertoire. This established an eCB/CB1R signaling mechanism responsible for governing the whole organism’s energy balance, with its activation triggering a shift toward energy intake and storage in the brain and the peripheral organs (i.e., liver and adipose).

Although this function was of primal importance for humans during their pre-historic existence as hunter-gatherers, it became expendable following the successive lifestyle shifts of the Agricultural and Industrial Revolutions. Modernization of the world has further increased food availability and decreased energy expenditure, thus shifting the eCB/CB1R system into a state of hyperactive deregulated signaling that contributes to the 21st century metabolic disease pandemic.

Studies from the literature supporting this perspective come from a variety of disciplines, including biochemistry, human medicine, evolutionary/comparative biology, anthropology, and developmental biology. Consideration of both biological and cultural evolution justifies the design of improved pharmacological treatments for obesity and Type 2 diabetes (T2D) that focus on peripheral CB1R antagonism. Blockade of peripheral CB1Rs, which universally promote energy conservation across the vertebrate lineage, represents an evolutionary medicine strategy for clinical management of present-day metabolic disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/31156558

https://www.frontiersin.org/articles/10.3389/fendo.2019.00311/full

Cannabinoid Receptor 1 Blockade Attenuates Obesity and Adipose Tissue Type 1 Inflammation Through miR-30e-5p Regulation of Delta-Like-4 in Macrophages and Consequently Downregulation of Th1 Cells.

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 Image result for frontier in immunology“Obesity is characterized by chronic low-grade inflammation that contributes to development of cardiometabolic disorders. Cannabinoid receptor 1 (CB1) antagonists attenuate diet-induced obesity (DIO) and related inflammation, although the precise anti-inflammatory mechanisms involved have not been fully explored. In the current study we used a mouse model of DIO intervention to determine the microRNA (miRNA, miR)-mediated anti-obesity and anti-inflammatory effects of the CB1 antagonist, AM251. DIO mice that were fed high-fat diet (HFD) for 12 weeks were treated with AM251 (10 mg/kg) for an additional 4 weeks. HFD + AM251 mice experienced rapid and prolonged weight loss and reduced inflammatory M1 adipose tissue macrophage (ATM) infiltration. To investigate miRNA-mediated regulation of ATMs, F4/80+ cells from stromal vascular fractions (SVF) of epididymal fat were subjected to miR microarray analysis. Several miRs were differentially expressed in AM251-treated mice that were independent of calorie restriction. Prominently, miR-30e-5p was upregulated in ATMs from HFD + AM251 mice while the miR-30e-5p target, DLL4, was downregulated. Consistent with a decrease in DLL4-Notch signaling, fat storage and pro-inflammatory cytokine/chemokine expression was reduced following AM251 treatment. Furthermore, we found that AM251-treated macrophages can suppress DLL4-mediated Th1 polarization in CD4+ T cells. Together these data demonstrate that blocking CB1 receptors leads to upregulation of miR-30e-5p and down regulation of DLL4 in ATMs, which in turn suppress DLL4-Notch signaling-induced polarization of inflammatory Th1 cells and adipocyte energy storage. This combined effect of ATMs and T cells leads to an anti-inflammatory state and attenuation of DIO. These data support therapeutic potential of miR-30 in the treatment of cardiometabolic disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/31134094

https://www.frontiersin.org/articles/10.3389/fimmu.2019.01049/full