Category Archives: Obesity

New insights on the role of the endocannabinoid system in the regulation of energy balance.

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“Within the last 15 years, the endocannabinoid system (ECS) has emerged as a lipid signaling system critically involved in the regulation of energy balance, since it exerts a regulatory control on every aspect related to the search, the intake, the metabolism and the storage of calories.

An overactive endocannabinoid-cannabinoid type 1 (CB1) receptor signaling promotes the development of obesity, insulin resistance and dyslipidemia, representing a valuable pharmacotherapeutic target for obesity and metabolic disorders.

However, due to psychiatric side effects, the first generation of brain-penetrant CB1 receptor blockers developed as anti-obesity treatment was removed from the European market in late 2008.

Since then, recent studies have identified new mechanisms of action of the ECS in energy balance and metabolism, as well as novel ways of targeting the system that may be efficacious for the treatment of obesity and metabolic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26374449

Tetrahydrocannabivarin (THCv) reduces Default Mode Network and increases Executive Control Network Resting State Functional Connectivity in Healthy Volunteers.

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“The cannabinoid CB1 Neutral Antagonist Tetrahydrocannabivarin (THCv) has been suggested as a possible treatment for obesity but without the depressogenic side-effects of inverse antagonists such as Rimonabant.

Our findings are the first to show that treatment with the CB1 neutral antagonist THCv decreases resting state functional connectivity in the Default Mode network and increases connectivity in the Cognitive Control network and Dorsal Visual Stream network.

This effect profile suggests possible therapeutic activity of THCv for obesity where functional connectivity has been found to be altered in these regions.”

http://www.ncbi.nlm.nih.gov/pubmed/26362774

Combination cannabinoid and opioid receptor antagonists improves metabolic outcomes in obese mice.

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“This study demonstrates that the combination of rimonabant, naloxone and norBNI is effective at producing weight loss over a sustained period of time without altering performance in standardised mouse behaviour tests. Fos expression patterns offer insight into the neuroanatomical substrates subserving these physiological and behavioural changes.

These results indicate that CB1-targeted drugs for weight loss may still be feasible.”

http://www.ncbi.nlm.nih.gov/pubmed/26360587

G protein-coupled receptor 18: A potential role for endocannabinoid signalling in metabolic dysfunction.

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“Endocannabinoids are products of dietary fatty acids that are modulated by an alteration in food intake levels.

Overweight and obese individuals have substantially higher circulating levels of the arachidonic acid-derived endocannabinoids, anandamide and 2-arachidonoyl glycerol, and show an altered pattern of cannabinoid receptor expression.

These cannabinoid receptors are part of a large family of G protein-coupled receptors (GPCRs).

GPCRs are major therapeutic targets for various diseases within the cardiovascular, neurological, gastrointestinal and endocrine systems, as well as metabolic disorders such as obesity and type 2 diabetes mellitus.

Obesity is considered a state of chronic low grade inflammation elicited by an immunological response.

Interestingly, the newly deorphanised G protein-coupled receptor GPR18, which is considered to be a putative cannabinoid receptor, is proposed to have an immunological function.

In this review, the current scientific knowledge on GPR18 is explored including its localisation, signalling pathways and pharmacology.

Importantly, the involvement of nutritional factors and potential dietary regulation of GPR18 and its (patho)physiological roles are described.

Further research on this receptor and its regulation will enable a better understanding of the complex mechanisms of GPR18 and its potential as a novel therapeutic target for treating metabolic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26337420

Pro-inflammatory obesity in aged cannabinoid-2 receptor deficient mice.

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“Cannabinoid-1 receptor signaling increases the rewarding effects of food intake and promotes the growth of adipocytes, whereas CB2 possibly opposes these pro-obesity effects by silencing the activated immune cells that are key drivers of the metabolic syndrome.

Pro- and anti-orexigenic cannabimimetic signaling may become unbalanced with age because of alterations of the immune and endocannabinoid system…

CB2 agonists may fortify CB2-mediated anti-obesity signaling without the risk of anti-CB1 mediated depression that caused the failure of rimonabant.”

http://www.ncbi.nlm.nih.gov/pubmed/26303348

[The endocannabinoid system role in the pathogenesis of obesity and depression].

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“Excessive consumption and obesity do not always have to be strictly pathological. The adjustment of food intake as well as the pleasure of eating are the results of the circulation of neurotransmitters, hormones and glucocorticoids which have an ability to regulate the activity of many receptors connected with G protein, including endocannabinoid receptors.

The key role of endocannabinoids in pathogenesis of obesity is their overproduction by adipose cells.

Endocannabinoids (eCBs) affect CB1 receptors and increase hunger, willingness to intake food, decrease peristalsis and delay stomach emptying.

In obese people increased levels of both central and peripheral endocannabinoids are observed. It may be connected with higher availability of endocannabinoid precursors to synthesis from adipose tissue and lipids.

Raised concentration of eCBs in the body may be the consequence of their catabolism dysfunction. There is a positive correlation between amount the number of receptors in the peripheral tissues and obesity increase.

It is thought that expression of CB1 receptors in mesolimbic system is connected with motivation to consume food in response to rewarding factor.

The appetite increase after cannabinoids use is probably caused by rewarding action of the consumed food and it results from excessive dopaminergic transmission in award system.

The pharmacological inhibition of endocannabinoids activity leads to weight loss, but may also have negative consequences such as decreased mood, reduced tolerance of pain, intensified anxiety, anhedonia, depressive symptoms, even suicidal thoughts.

In post mortem examinations a decrease in CB1 receptor density in grey matter of glial cells in patients with major depression was identified. The pleiotropic and extensive activity of endocannabinoid system can influence a range of neurotransmitters thereby modulating the psychiatric life phenomena, simultaneously being involved in metabolism control and energetic system of human body.

Hence it is a link between metabolic disorders and depression and anxiety disorders. Therefore, in obese people depressive comorbidity is higher and it significantly worsens prognosis and decreases life quality.”

http://www.ncbi.nlm.nih.gov/pubmed/26277182

Therapeutic potential of cannabis-related drugs.

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“In this review, I will consider the dual nature of Cannabis and cannabinoids.

The duality arises from the potential and actuality of cannabinoids in the laboratory and clinic and the ‘abuse’ of Cannabis outside the clinic.

The therapeutic areas currently best associated with exploitation of Cannabis-related medicines include pain, epilepsy, feeding disorders, multiple sclerosis and glaucoma.

As with every other medicinal drug of course, the ‘trick’ will be to maximise the benefit and minimise the cost.

After millennia of proximity and exploitation of the Cannabis plant, we are still playing catch up with an understanding of its potential influence for medicinal benefit.”

http://www.ncbi.nlm.nih.gov/pubmed/26216862

Hydroxytyrosol Inhibits Cannabinoid CB1 Receptor Gene Expression in 3T3-L1 Preadipocyte Cell Line.

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“The 3T3-L1 preadipocyte cell line is a well characterized cell model for studying the adipocyte status and the molecular mechanisms involved in differentiation of these cells. 3T3-L1 preadipocytes have the ability to synthesize and degrade endocannabinoid anandamide (AEA) and their differentiation into adipocytes increases the expression of cannabinoid (CB1) and PPAR-γ receptors.

Clinically, the blocking stimulation of the endocannabinoid pathway has been one of the first approaches proposed to counteract the obesity and obesity-associated diseases (such as diabetes, metabolic syndrome and cancer).

In this connection, here we studied in cultured 3T3-L1 pre-adipocytes the effects of n-3-PUFA, α-Linolenic acid (OM-3), n-6-PUFA, Linoleic acid (OM-6) and hydroxytyrosol (HT) on the expression of CB1 receptor gene and the adipogenesis-related genes PPAR-γ, Fatty Acid Synthase (FAS) and Lipoprotein Lipase (LPL).

HT was able to inhibit 3T3-L1 cell differentiation by down-regulating cell proliferation and CB1 receptor gene expression. HT exhibited anti-adipogenic effects, whereas OM-3 and OM-6 exerted an inhibitory action on cell proliferation associated with an induction of the preadipocytes differentiation and CB1 receptor gene expression.

Moreover, the expression of FAS and LPL genes resulted increased after treatment with both HT and OM-3 and OM-6.

The present study points out that the intake of molecules such as HT, contained in extra virgin olive oil, may be considered also in view of antiobesity and antineoplastic properties by acting directly on the adipose tissue and modulating CB1 receptor gene transcription.”

http://www.ncbi.nlm.nih.gov/pubmed/26189725

Exploring structural requirements for peripherally acting 1,5-diaryl pyrazole-containing cannabinoid 1 receptor antagonists for the treatment of obesity.

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“Peripherally acting cannabinoid 1 (CB1) receptor antagonists are considered as potential therapeutics for the treatment of obesity with desired efficacy and reduced central nervous system side effects.

The prediction accuracy and reliability of the best developed CoMSIA model have been validated using well-established methods. Using the inputs from the best CoMSIA contour maps, several novel highly selective peripherally acting CB1 receptor antagonists have been designed and reported herein.”

A comprehensive patents review on cannabinoid 1 receptor antagonists as antiobesity agents.

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“Obesity is a rapidly expanding worldwide health problem.

Various targets are investigated presently for the treatment of obesity, but there remains an unmet need for an effective drug therapy with acceptable efficacy levels and reduced side effects.

Targeting peripherally located cannabinoid 1 (CB1) receptors is an attractive strategy as these receptors play a vital role in energy homeostasis.

Areas covered: CB1 receptor antagonists constitute one of the most important categories of compounds of interest for the control of obesity.

In this review, the authors focus on recent advances (since 2007) in diverse chemical classes of patented compounds belonging to the category of CB1 receptor antagonists.

Expert opinion: Safer CB1 receptor antagonists for the treatment of obesity can be discovered by developing such compounds that act peripherally. Increasing the polar service area, decreasing the lipophilicity and designing of neutral antagonists and allosteric inhibitors are some interesting strategies that could offer promising results.”

http://www.ncbi.nlm.nih.gov/pubmed/26161824